CN118662507A - External composition for improving chloasma - Google Patents

Abstract

The present invention is a topical composition for improving chloasma, including pimecrolimus, tretinoin, azelaic acid and a dermatologically acceptable carrier. The concentrations of pimecrolimus, tretinoin and azelaic acid are 0.05%-5.0%, 0.001%-1% and 5.0%-25.0% respectively by mass concentration. The dermatologically acceptable carrier is a cream, an ointment, a gel, an emulsion, a foam, a local mixture, a solution, an emulsion or any suitable topical dosage form. The dermatologically acceptable carrier includes an oil phase or an aqueous phase or a combination of an oil phase and an aqueous phase. The pH value of the topical composition is 5.0±2.0. Advantages of the present invention: The formula and preparation method of the topical composition are reasonably designed, and the topical composition containing tretinoin, azelaic acid and pimecrolimus as the main effective active pharmaceutical ingredients is used to improve chloasma, can be used topically for a long time, has good safety and tolerability, and can effectively improve pigmentation.

Description

A topical composition for improving chloasma

Technical Field

The invention relates to an external composition, in particular to an external medicinal composition which can effectively treat and improve facial chloasma.

Background Art

Melasma is a common, chronic, acquired skin disease that presents as irregularly shaped, pigmented yellow spots on the cheeks, forehead, and jawline, primarily affecting women of childbearing age. It is a very common disease, but its true incidence is unknown. The onset of melasma is associated with many factors, but the most important factors remain ultraviolet radiation, genetic predisposition, and endocrine dysfunction. The incidence of melasma in Asian women of childbearing age is as high as 30%, and it is prone to recurrence and difficult to cure.

Hydroquinone and its derivatives are the gold standard for first-line topical medications for the treatment of melasma. The higher the concentration, the stronger the efficacy. However, they can cause severe irritation to the skin. The main disadvantages of these drugs are irritant contact dermatitis and permanent pigmentation.

Azelaic acid is currently used to treat M-type melasma, with the concentration of topical ingredients being 15% to 20%, but due to the high concentration used, 1% to 5% of patients experience itching, burning, stinging, and numbness, and 1% of patients experience erythema, dryness, desquamation, and contact dermatitis. Retinoic acid drugs are also widely used to treat M-type melasma. Pimecrolimus is a calcineurin inhibitor immunosuppressant indicated for the treatment of mild to moderate atopic dermatitis in non-immunocompromised adults and children aged 2 years and older.

US20090457731A discloses the use of a fluocinolone acetonide, retinoic acid and hydroquinone composition cream for the sustained treatment of melasma. However, the primary problem with the long-term use of topical corticosteroids is that melasma is a recurrent disease, so it is indeed necessary to solve the problem of how to maintain the therapeutic effect achieved after acute treatment for a long time.

The global melasma treatment market size was valued at USD 267.32 million in 2021 and is expected to reach USD 516.21 million by 2031, at a CAGR of 6.8% during the forecast period. The global melasma treatment market has witnessed significant growth in recent years, driven by the rising incidence of melasma and the growing interest in skin care and beauty treatments. However, despite the market growth, challenges remain in the field of melasma treatment. The limited effectiveness of certain treatments, potential side effects, and the recurrence of melasma remain concerns for patients and healthcare professionals. Nonetheless, continued research and development efforts, as well as the growing awareness of skin care and skin diseases, are expected to drive further innovation in the melasma treatment market, making it possible to address these challenges and provide better solutions for melasma patients around the world.

Summary of the invention

The present invention provides an external composition for improving chloasma, the purpose of which is to overcome the above-mentioned deficiencies in the prior art and provide an external composition that can be used topically for a long time and is safe, tolerable and has good efficacy.

The technical solution of the present invention is a topical composition for improving chloasma, comprising the following components:

Component a: an immunosuppressant molecule or a pharmaceutically acceptable salt or ester thereof;

Component b: vitamin A derivative or a pharmaceutically acceptable salt or ester thereof;

Component c: dicarboxylic acid or its derivative or its pharmaceutically acceptable salt or ester;

Component d: a dermatologically acceptable carrier.

Preferably, the component a is pimecrolimus, the component b is tretinoin, and the component c is azelaic acid.

Preferably, in terms of mass concentration, the pimecrolimus concentration is 0.05%-5.0%, the retinoic acid concentration is 0.001%-1%, and the azelaic acid concentration is 5.0%-25.0%.

More preferably, the concentration of pimecrolimus is 0.5%-2.5%, the concentration of retinoic acid is 0.005%-0.5%, and the concentration of azelaic acid is 10.0%-20.0%.

More preferably, the concentration of pimecrolimus is 1.0%-2.0%, the concentration of retinoic acid is 0.01%-0.25%, and the concentration of azelaic acid is 14.0%-16.0%.

As the most preferred embodiment, the concentration of pimecrolimus is 1.0%, the concentration of retinoic acid is 0.05%, and the concentration of azelaic acid is 15.0%.

Preferably, the dermatologically acceptable carrier is a cream, ointment, gel, lotion, foam, topical mixture, solution, emulsion or any suitable topical dosage form.

Further preferably, the dermatologically acceptable carrier comprises an oil phase or an aqueous phase or a combination of an oil phase and an aqueous phase.

Preferably, the pH value of the topical composition is 5.0±2.0.

Preferably, the topical composition is effectively penetrated in a therapeutically effective amount for treating patients suffering from melasma and related skin diseases.

Advantages of the present invention: The formula and preparation method of the topical composition are reasonably designed. The topical composition containing retinoic acid, azelaic acid and pimecrolimus as main effective active pharmaceutical ingredients is used to improve chloasma, can be used topically for a long time, has good safety and tolerability, and can effectively improve pigmentation.

DETAILED DESCRIPTION

The present invention is further described in detail below with reference to examples and specific implementation methods.

The present invention provides an external composition for treating skin diseases such as chloasma and its recurrence and a preparation method thereof. In the following content, unless otherwise specified, the concentration unit of the composition components is the weight percentage of the total composition.

Melasma is a common, chronic skin disease that presents as hyperpigmented, irregularly shaped yellow spots on the cheeks, forehead and jawline, primarily affecting women of childbearing age. Terms such as skin disease, hyperpigmentation, darkening of the skin or dark spots may also be used to describe melasma. Relapse is when melasma reappears after a period of complete resolution.

An external composition for improving chloasma, comprising:

(a) an immunosuppressant molecule or a pharmaceutically acceptable salt or ester thereof;

(b) a vitamin A derivative or a pharmaceutically acceptable salt or ester thereof;

(c) a dicarboxylic acid or a derivative thereof, or a pharmaceutically acceptable salt or ester thereof.

As a preferred embodiment, component (a) immunosuppressant is a drug for suppressing individual immune response, used for treating autoimmune diseases or organ transplantation, to suppress immunity and improve the acceptance of the drug. The immunosuppressant can be selected from subclasses such as calmodulin enzyme inhibitors, Janus kinase inhibitors, corticosteroids, IMDH inhibitors, mTOR inhibitors, biological preparations for immunosuppression and monoclonal antibodies.

As a further preferred embodiment, the immunosuppressant is selected from calmodulin inhibitors.

As a further preferred embodiment, the immunosuppressant is selected from pimecrolimus or tacrolimus.

As the most preferred embodiment, the immunosuppressant is selected from pimecrolimus.

As a preferred embodiment, component (b) vitamin A derivatives, i.e., tretinoin drugs, are selected from any generation of tretinoin drugs, such as 1st, 2nd, 3rd or 4th generation tretinoin drugs.

As a further preferred embodiment, the tretinoin drug is selected from the first generation tretinoin.

As a further preferred embodiment, the retinoic acid drug is selected from retinoic acid, retinal and isotretinoin.

As the most preferred embodiment, the retinoic acid drug is selected from retinoic acid.

As a preferred embodiment, the dicarboxylic acid derivative of component (c) is selected from acids having antimicrobial and anti-inflammatory effects, which can gently exfoliate, lighten pigmentation and calm redness of the skin.

As the most preferred embodiment, the dicarboxylic acid derivative is selected from azelaic acid, which has antimicrobial and anti-inflammatory effects, can gently exfoliate, lighten pigmentation and calm skin redness.

As a preferred embodiment, a topical composition for improving chloasma is a topical composition composed of a component (a) with a mass concentration of 0.05%-5.0%, a component (b) with a mass concentration of 0.001%-1%, and a component (c) with a mass concentration of 5.0%-25.0%, such as a cream, ointment, gel, lotion, solution, emulsion, foam, tincture or paste, etc., and the composition is used to treat skin diseases or conditions, such as chloasma and recurrence of chloasma.

As a further preferred embodiment, the mass concentration of component (a) is 0.5%-2.5%, the mass concentration of component (b) is 0.005%-0.5%, and the mass concentration of component (c) is 10.0%-20.0%.

As a further preferred embodiment, the mass concentration of component (a) is 1.0%-2.0%, the mass concentration of component (b) is 0.01%-0.25%, and the mass concentration of component (c) is 14.0%-16.0%.

As the most preferred embodiment, the mass concentration of component (a) is 1.0%, the mass concentration of component (b) is 0.05%, and the mass concentration of component (c) is 15.0%.

As a preferred embodiment, it further comprises a pH-dependent or pH-independent thickener and is formulated into a gel.

Thickener is used to increase the volume of composition.Topical composition of the present invention can suitably contain thickener, provides viscosity for preparation.Thickener is miscible with aqueous or non-aqueous fluid or soluble in aqueous or non-aqueous fluid is preferred, but not necessary.Non-limiting embodiments of suitable thickener include acacia, alginic acid and its salts, hyaluronic acid and its salts, carbomer (also referred to as carboxyvinyl polymer, is cross-linked polyacrylic acid), carboxymethyl cellulose, ethyl cellulose, gel, carboxyvinyl polymer (also referred to as carboxyvinyl polymer, is cross-linked polyacrylic acid), ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyhydroxyamine, polyvinyl pyrrolidone, polyvinyl alcohol, xanthan gum, magnesium aluminum silicate and bentonite.Thickener can also be present in the oil or lipophilic part in the formula.Suitable lipophilic thickener includes cetyl alcohol, stearyl alcohol, glyceryl stearate, white beeswax, microcrystalline wax, hydrogenated polyisobutane polymer and emulsifying wax.

As a preferred embodiment, the thickener is a carbon polymer, such as and polycarbophil (The Lubrizol Corporation). Homopolymers are polymers of acrylic acid crosslinked with allyl sucrose or pentaerythritol allyl ether. Carbopol copolymers are polymers of acrylic acid and C10-C30 alkyl acrylate crosslinked with pentaerythritol allyl ether. The block polymer is a carbomer homopolymer or copolymer, containing a block copolymer of polyethylene glycol and a long chain alkyl acid ester. Polycarbophil is an acrylic acid polymer cross-linked with divinyl glycol.

Alternatively, as a preferred embodiment, the thickener is a pH-independent polyacrylamide thickener, such as a mixture of acrylamide/sodium acryloyldimethyl tert-butyl copolymer and isohexadecane and polysorbate 80 sold by SEPPIC as SIMULGEL 600, a mixture of polyacrylamide with isoparaffin C13-12 and laureth-7, for example, the product sold by SEPPIC under the name SEPIGEL 305, a combination of acrylic polymers with hydrophobic chains, such as PEG-150/decyl/SMDI copolymer (polycondensate, whose ingredients include at least polyethylene glycol containing 150 or 180 moles of ethylene oxide, decyl alcohol and methylene bis(4-cyclohexyl isocyanate) (SMDI) sold under the name ACULYN 44, a modified starch series with a content of 35% (by weight) in a mixture of propylene glycol (39%) and water (26%), such as the modified potato starch sold under the name StructureSolanace, or a mixture thereof.

As a further preferred embodiment, the pH-dependent thickener can be selected from single or combination of carbomer homopolymer types A, B and C, and the pH-independent thickener can be selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and novel polymers.

As a further preferred embodiment, the thickener includes a novel polymer combination as a viscosity modifier, a texture modifier or a novel polymer combination for improving the appearance of the formulation. The novel polymer can be selected from Sepineo DERM (hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer), Duo (propylene glycol monolaurate (and) ethylcellulose (and) propylene glycol isostearate), SEPINEO ^™ P 600 (acrylamide/sodium acryloyldimethyl taurate copolymer/isohexadecane and polysorbate 80), but are not limited thereto.

As a preferred embodiment, a penetration enhancer (penetration enhancer) is also included.

A penetration enhancer is a compound that increases the permeability of an active drug molecule through the skin or mucous membranes, such as by temporarily reducing the impermeability of the skin or mucous membranes. In general, a penetration enhancer is an ingredient used to increase the permeability of a steroid through the skin or mucous membranes, such as by temporarily reducing the impermeability of the skin or mucous membranes. Penetration enhancers are also known as "accelerators" and "absorption enhancers."

As a further preferred embodiment, the penetration enhancer includes but is not limited to polyols, glycols (except propylene glycol), ethers, glycol ethers, esters, thioethers, fatty acids, fatty acid esters, fatty alcohols, essential oils, terpenes, terpenoids, polyethylene glycol fatty acids, polyethylene glycol fatty acid esters, polyethylene glycol fatty alcohols and mixtures thereof, including polyethylene glycol, polyethylene glycol monolaurate and butanediol; thioethers, including diethylene glycol monoethyl ether and diethylene glycol monomethyl ether; fatty acids, including lauric acid, oleic acid and valeric acid; fatty acid esters, including isopropyl myristate, isopropyl palmitate, methyl propionate and ethyl oleate; nitrogen-containing compounds, including urea, dimethylacetamide, dimethylformamide-2-pyrrolidone, ethanolamine, methyl-2-pyrrolidone, diethanolamine and triethanolamine; terpenes; terpenoids; alkanones; organic acids, including salicylic acid, citric acid and succinic acid; and compositions comprising one or more of the above materials. In certain embodiments, the penetration enhancer used in the pharmaceutical composition of the present invention is diethylene glycol monoethyl ether. In certain embodiments, the penetration enhancer is not polypropylene glycol. The penetration enhancer can be used as a solvent alternately.

As a preferred embodiment, a surfactant or an emulsifier is also included.

As a further preferred embodiment, the surfactant or emulsifier includes but is not limited to disodium cocamide diacetate, oxyethylated glyceryl cocoate (7 EO), PEG-20 hexadecene succinate, PEG-15 stearyl ether, castor oil monoethanolamide monosulfosuccinate, oxyethylene hydrogenated castor oil triglyceride containing 60 ethylene oxide units, such as BASF's RH 60 or Products sold under the trademark RH 40 (polyoxyl 40 hydrogenated castor oil), polymers such as polyetheramides (block copolymers of ethylene oxide and propylene oxide), and fatty substances that are not solid at room temperature, such as sesame oil, sweet almond oil, apricot kernel oil, sunflower seed oil, octoxyglyceryl palmitate (or 2-ethylhexylglyceryl palmitate), octoxyglyceryl behenate (or 2-ethylhexylglyceryl behenate), dioctyl adipate and tartrates of branched glycols. Sorbitan fatty acid esters are a series of mixtures of sorbitol and its mono- and dianhydrides with partial esters of fatty acids. Sorbitan esters include 20, ARLACEL 40, ARLACEL 60, ARLACEL 80, ARLACEL 83, ARLACEL 85, ARLACEL 987 and ARLACELC products, PEG-6 stearate, glyceryl stearate and PEG-32 stearate ( 63), PEG-6 stearate and PEG-32 stearate ( 1500), glyceryl stearate and PEG 100 stearate ( 165) and their mixtures. Stearic acid polyethylene glycol ether is another type of emulsifier that can be used for emulsions. Examples of stearic acid polyethylene glycol ether include but are not limited to stearane-2, stearane-4, stearane-6, stearane-7, stearane-10, stearane-11, stearane-13, stearane-15, stearane-20, stearyl alcohol polyethylene glycol ether (stearane 21) and any mixture thereof. Other emulsifiers include sodium lauryl sulfate, hexadecyl trialkyl ammonium bromide, polyoxyethylene sorbitol fatty acid esters and mixtures thereof.

As a further preferred embodiment, the emulsifier is a nonionic emulsifier, including an emulsifier that can be broadly defined as a condensation product of a long-chain alcohol (such as a C8-30 alcohol) and a sugar or starch polymer (i.e., a glycoside). Various sugars include, but are not limited to, glucose, fructose, mannose, and galactose, and various long-chain alcohols include, but are not limited to, decyl alcohol, hexadecyl alcohol, stearyl alcohol, lauryl alcohol, myristyl alcohol, oleyl alcohol, and mixtures thereof. Other useful nonionic emulsifiers include condensation products of oxyalkylene with fatty acids, such as oxyalkylene esters of fatty acids. Other nonionic surfactants include condensation products of oxyalkylene with 2 moles of fatty acids, such as oxyalkylene diesters of fatty acids.

As a further preferred embodiment, the emulsifier may also include any of the various cationic, anionic, oligomeric cationic and amphoteric surfactants known in the art. Examples of anionic emulsifiers include, but are not limited to, alkyl isosulfates, alkyl and alkyl ether sulfates and their salts, alkyl and alkenyl ether phosphates and their salts, alkyl methyl taurates and fatty acid soaps (such as alkali metal salts and sodium or potassium salts). Examples of amphoteric and oligomeric emulsifiers include those broadly described as derivatives of aliphatic secondary and tertiary amines, wherein the aliphatic radical may be straight or branched, wherein one aliphatic substituent contains from about 8 to about 22 carbon atoms and one contains an anionic water-soluble group, such as carboxyl, sulfonic acid, sulfate, phosphoric acid or phosphonic acid. Specific examples include, but are not limited to, alkyl iminoacetic acid esters, iminodialkanoic acid esters and aminoalkanoic acid esters, imidazoline ammonium and ammonium derivatives. Other suitable amphoteric and oligomeric emulsifiers include betaines, soda acid, hydroxy soda acid, alkyl sarcosinates and alkanoyl sarcosinates.

As a further preferred embodiment, the emulsifier is a silicone emulsifier, typically an organically modified organopolysiloxane, sometimes also referred to as a silicone surfactant. Useful silicone emulsifiers include dimethicone copolyols. These materials are polydimethylsiloxanes that have been modified to include polyether side chains, such as polyethylene oxide chains, polypropylene oxide chains, mixtures of these chains, and polyether chains containing molecules derived from ethylene oxide and propylene oxide.

As a further preferred embodiment, the emulsifier is a polymeric emulsifier such as those sold under the trade name Pemulen ^™ (The Lubrizol Corporation, Wickliffe, Ohio) which are acrylic polymers modified with long chain (C10-C30) alkyl acrylates and crosslinked with pentaerythritol allyl ether.

As a further preferred embodiment, the emulsifier is a secondary emulsifier or a secondary emulsifier, including but not limited to polyoxyethylene glycerides, such as oleoyl macroglycerol ( M 1944CS), linoleyl macroglyceride ( M 2125CS), Capryloyl Macroglycerol Cetyl Alcohol (and) Ceteth-20 (and) Steareth-20 (EMULCIRE ^TM 61 WL 2659), Glyceryl Stearate (and) PEG-75 Stearate ( 64), d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and mixtures thereof.

As a further preferred embodiment, the emulsifier can be selected from nonionic or ionic surfactants according to the HLB value required for the oil phase. Specifically, the combination of hydrophilic surfactants and lipophilic surfactants is to better meet the requirements of low HLB value and high HLB value. More specifically, the combination of emulsifiers is selected from sorbitan fatty acid esters and polyoxyethylene sorbitan fatty acid esters. Polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monostearate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene 20 sorbitan monooleate, polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 sorbitan monoisostearate.

As a preferred embodiment, an oil phase is also included.

As a further preferred embodiment, the oil phase can be selected from fatty oils or alcohols with a higher carbon content, but is not limited to medium chain triglycerides, isopropyl myristate, mineral oil, cetyl alcohol, stearyl alcohol, cetearyl alcohol, and oleyl alcohol.

As a further preferred embodiment, the medium chain triglyceride is selected from the medium chain triglyceride of olive oil, coconut oil or palm kernel oil. The medium chain alcohol is preferably the medium chain triglyceride of coconut oil. In another embodiment of the present invention, the fatty acid ester is selected from higher fatty acids, such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid and undecylenic acid. The fatty acid ester is preferably isopropyl myristate or isopropyl palmitate. Alternatively, the oil phase component can be selected from hard paraffin, white soft paraffin and low viscosity or high viscosity liquid paraffin.

As a preferred embodiment, a moisturizer is also included.

A humectant refers to a hygroscopic substance, usually a molecule with multiple hydrophilic groups (most commonly hydroxyl groups), but amine and carboxyl groups (sometimes esterified) are also encountered; the affinity for forming hydrogen bonds with water molecules is crucial here. As a further preferred embodiment, the humectant is selected from glycerol, propylene glycol, sorbitol, mannitol, xylitol, maltitol, polymerized polyols (such as polydextrose) or natural extracts (such as perilla, lactic acid or urea), or diluted solutions thereof in any proportion. In one embodiment, the humectant for moisturizing effect is selected from allantoin, cholesterol, squalene, fatty acids, fatty alcohols, sodium hyaluronate or a combination of multiple humectants. In other embodiments, the polyol is selected from polyethylene glycol, propylene glycol, hexylene glycol, butylene glycol, glycerol, erythritol or sorbitol. The polyol is preferably propylene glycol or hexylene glycol.

As a preferred embodiment, a preservative is also included.

As a further preferred embodiment, the preservative is selected from the group consisting of phenoxyethanol, parabens such as methylparaben and propylparaben, sodium benzoate, benzalkonium chloride, propylene glycol, sorbate, benzyl alcohol, butylhydroxytoluene, urea derivatives such as diazolidinyl urea, etc., or any combination thereof.

As a preferred embodiment, an antioxidant is also included.

Antioxidants refer to substances that inhibit oxidation or inhibit reactions promoted by oxygen or peroxides. As a further preferred embodiment, antioxidants include, but are not limited to, alpha-tocopherol, TPGS, glutathione, ascorbic acid, lipoic acid, uric acid, sorbic acid, carotene, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), monothioglycerol, potassium pyrosulfite, sodium ascorbate, sodium bisulfite, sodium thiosulfate, sodium pyrosulfite, sodium sulfite, panthenol, sodium benzoate, propyl gallate, and tert-butylhydroquinone. In certain embodiments, the pharmaceutical composition comprises BHT, alpha-tocopherol, and sodium thiosulfate as antioxidants. In certain embodiments, the content of one or more antioxidants is about 0.05% to about 1% of the weight of the composition.

As a preferred embodiment, a wetting agent is also included.

Wetting agent is used to help active agent disperse or suspend in aqueous carrier.As further preferred embodiment, wetting agent is a surfactant, such as nonionic surfactant.Including but not limited to sodium paraformaldehyde, octanol-9, nonyl octanol-9, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyethylene amide, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate and sorbitan trioleate.In certain embodiments, pharmaceutical composition comprises sodium paraformaldehyde as wetting agent.

As a preferred embodiment, a pH adjuster is also included.

As a further preferred embodiment, the pH adjusting agent maintains the pH value of the pharmaceutical composition at about 4-8. Suitable pH adjusting agents include, but are not limited to, triethanolamine, sodium hydroxide, potassium hydroxide, hydrochloric acid, phosphoric acid, and citric acid. In certain embodiments, an acid-base combination for adjusting and maintaining the pH value is included.

Some of the above excipients may have more than one function in the composition. For example, an excipient may be both a solvent and a penetration enhancer, or both a solvent and a carrier. The above classification of excipients should not be construed as any form of limitation or restriction.

Example 1: Gel

Preparation steps:

(a) Polymer phase: Dissolve benzoic acid and disodium edetate in a mixture of purified water, polysorbate 80 and glycerol. Dissolve methylparaben in propylene glycol at a higher temperature and add to the aqueous phase. Disperse carbomer 980 and sodium hyaluronate under stirring and heating if necessary.

(b) Drug (Oil) Phase: Mix oleyl alcohol, sorbitan oleate, benzyl alcohol, and medium chain triglycerides with stirring. Add butylated hydroxytoluene and stir to dissolve. Add pimecrolimus and mix for 20 minutes with stirring, homogenization, or a combination of both. Add tretinoin and mix for 10 minutes with stirring, homogenization, or a combination of both. Heat if necessary.

(c) Emulsification: Add the oil phase to the polymer phase and mix for 20-30 minutes while stirring or homogenizing or a combination of both. Cool to a target temperature of 50±5°C while stirring or homogenizing or a combination of both.

(d) Adding azelaic acid: Add azelaic acid to the emulsion for 30 minutes while stirring, homogenizing, or a combination of both.

(e) pH adjustment: 10% sodium hydroxide solution was added under stirring to adjust the pH to 4-6.

Example 2: Gel

Preparation steps:

(a) Aqueous phase: Dissolve benzoic acid and disodium EDTA in a mixture of purified water, propylene glycol and glycerin.

(b) Drug (Oil) Phase: Mix oleyl alcohol, isopropyl myristate, and medium chain triglycerides with stirring. Add butylated hydroxytoluene and stir to dissolve. Add pimecrolimus and mix for 20 minutes with stirring, homogenization, or a combination of both. Add tretinoin and mix for 10 minutes with stirring, homogenization, or a combination of both. Heat if necessary.

(c) Emulsification: Add the oil phase to the water phase and mix for 20-30 minutes while stirring or homogenizing or a combination of both. Cool to a target temperature of 50±5°C while stirring or homogenizing or a combination of both.

(d) Addition of Azelaic Acid: Azelaic acid was added to the emulsion for 30 minutes with stirring or homogenization or a combination of both.

(e) Add polymer: Add Sepineo P600 and homogenize, then stir for 30 minutes.

Example 3: Gel

Preparation steps:

(a) Aqueous phase: Dissolve benzoic acid and disodium EDTA in a mixture of purified water, propylene glycol and glycerin.

(b) Drug (Oil) Phase: Mix oleyl alcohol, isopropyl myristate, and medium chain triglycerides with stirring. Add butylated hydroxytoluene and stir to dissolve. Add pimecrolimus and mix for 20 minutes with stirring, homogenization, or a combination of both. Add tretinoin and mix for 10 minutes with stirring, homogenization, or a combination of both. Heat if necessary.

(c) Emulsification: Add the oil phase to the water phase and mix for 20-30 minutes while stirring or homogenizing or a combination of both. Cool to a target temperature of 50±5°C while stirring or homogenizing or a combination of both.

(d) Addition of Azelaic Acid: Azelaic acid was added to the emulsion for 30 minutes with stirring or homogenization or a combination of both.

(e) Add polymer: Add Sepineo DERM and homogenize, then stir for 30 minutes.

Example 4: Gel

Preparation steps:

(a) Polymer phase: Disodium EDTA was dissolved in a mixture of purified water, propylene glycol and glycerol. Carbomer was added and hydrated for 40 minutes under stirring.

(b) Drug (oil) phase: Mix medium chain triglycerides, oleyl alcohol, Oleique CC 497, and Duo. Add butylated hydroxytoluene and dissolve with stirring. Add pimecrolimus and mix for 20 minutes with stirring, homogenizing, or a combination of both. Add tretinoin and mix for 10 minutes with stirring, homogenizing, or a combination of both. Heat if necessary.

(c) Emulsification: Add the oil phase to the polymer phase and mix for 20-30 minutes under stirring or homogenization or a combination of both. Cool to a target temperature of 50±5°C under stirring or homogenization or a combination of both.

(d) Adding azelaic acid: Add azelaic acid to the emulsion for 30 minutes while stirring, homogenizing, or a combination of both. Cool to a target temperature of 38 ± 2 °C while stirring, homogenizing, or a combination of both.

(e) Adding sodium benzoate: Dissolve sodium benzoate in purified water and add, stirring and mixing for 30 minutes.

Example 5: Gel

The difference from Example 4 is that the components do not contain retinoic acid.

Example 6: Gel

The difference from Example 4 is that the components do not contain pimecrolimus.

Example 7: Gel

The difference from Example 4 is that the composition does not contain azelaic acid.

Example 8: Gel

The difference from Example 4 is that the components do not contain tretinoin and pimecrolimus.

Example 9: Gel

The difference from Example 4 is that the components do not contain retinoic acid and azelaic acid.

Example 10: Gel

The difference from Example 4 is that the components do not contain pimecrolimus and azelaic acid.

Example 11: Cream

Preparation steps:

(a) Oil phase: Heat and mix Crodamol CAP, CBS and Arlacel 983. Add butylated hydroxytoluene and dissolve under stirring. Add pimecrolimus and tretinoin mixture one by one under stirring until uniform.

(b) Water phase: Dissolve benzoic acid in a mixture of propylene glycol and purified water at 70±5°C.

(c) Emulsification: Add the oil phase to the water phase for 30 minutes while stirring, homogenizing, or a combination of both. Cool the emulsion to a target temperature of 50 ± 5 °C while stirring, homogenizing, or a combination of both:

(d) Adding azelaic acid: Add azelaic acid to the emulsion for 30 minutes while stirring, homogenizing, or a combination of both. Cool the emulsion to a target temperature of 38 ± 2 °C while stirring, homogenizing, or a combination of both.

(e) Adjusting pH: The pH of the cream was adjusted to 4.0-6.0 with 10% sodium hydroxide solution or pure citric acid solution, and then mixed for 30 minutes under stirring.

Example 12: Cream

Preparation steps:

(a) Water phase: Mix purified water and propylene glycol. Add and dissolve sodium cetearyl sulfate while stirring. Heat to 70±5℃.

(b) Oil phase: Heat and melt oleyl alcohol, cetyl alcohol, stearyl alcohol, mono- and di-glycerol fatty acid esters, medium chain triglycerides and benzyl alcohol. Add butylated hydroxytoluene and stir to dissolve. Add pimecrolimus and tretinoin one by one and mix under stirring until uniform.

(c) Emulsification: Add the oil phase to the water phase for 30 minutes under stirring, homogenization or a combination of both. Cool to a target temperature of 50±5°C under stirring or homogenization or a combination of both.

(d) Adding azelaic acid: Add azelaic acid to the emulsion for 30 minutes while stirring, homogenizing, or a combination of both. Cool the emulsion to a target temperature of 38 ± 2 °C while stirring, homogenizing, or a combination of both.

(e) Adjusting pH: The pH of the cream was adjusted to 4.0-6.0 with 10% sodium hydroxide solution or pure citric acid solution, and then mixed for 30 minutes under stirring.

Example 13: Cream

Preparation steps:

(a) Water phase: Disperse xanthan gum in glycerol at room temperature for 30 minutes. Add purified water to hydrate for 30 minutes and then heat to 70±5°C. Dissolve sorbic acid and methyl paraben in purified water at 70±5°C and then add to the polymer phase.

(b) Oil phase: Heat and melt stearic acid, isopropyl myristate, polyoxyethylene 40 stearate and stearyl alcohol at 70±5°C. Add butylated hydroxytoluene and dissolve under stirring. Add pimecrolimus and tretinoin one by one under stirring and mix until uniform.

(c) Emulsification: Add the oil phase to the water phase for 30 minutes under stirring, homogenization or a combination of both. Cool to a target temperature of 50±5°C under stirring or homogenization or a combination of both.

(d) Adding azelaic acid: Add azelaic acid to the emulsion for 30 minutes while stirring, homogenizing, or a combination of both. Cool the emulsion to a target temperature of 38 ± 2 °C while stirring, homogenizing, or a combination of both.

Example 14: Cream

Preparation steps:

(a) Aqueous phase: Dissolve benzoic acid in a mixture of glycerol and purified water under stirring, and then heat the solution to 70±5°C.

(b) Oil phase: Heat, mix and melt Labrasol, cetearyl alcohol, isopropyl myristate, polyoxyethylene 40 stearate, sorbitan monostearate and oleyl alcohol at 70±5°C with stirring. Add butylated hydroxytoluene and dissolve with stirring. Add pimecrolimus and tretinoin one by one with stirring and mix until uniform.

(c) Emulsification: Add the oil phase to the water phase for 30 minutes while stirring, homogenizing or a combination of both. Cool to a target temperature of 50 ± 5 °C while stirring, homogenizing or a combination of both.

(d) Adding azelaic acid: Add azelaic acid to the emulsion for 30 minutes while stirring, homogenizing, or a combination of both. Cool the emulsion to a target temperature of 38 ± 2 °C while stirring, homogenizing, or a combination of both.

Example 15: Emulsion

Preparation steps:

(a) Water phase: Stir and heat purified water, octanol-9 and glycerin at 70±5°C. Add benzoic acid, methylparaben and propylparaben in sequence and dissolve under stirring. Add sodium hyaluronate, soluble collagen, Pemulen TR-1 and Carbopol 981 one by one under stirring and dissolve or disperse them uniformly.

(b) Oil phase: Benzyl alcohol and butyl hydroxytoluene are dissolved in a mixture of mineral oil and isopropyl myristate at a temperature of 70±5° C. Pimecrolimus and tretinoin are added one by one under stirring until the mixture is uniform.

(c) Emulsification: Add the oil phase to the water phase for 30 minutes under stirring, homogenization or a combination of both. Cool the bulk to a target temperature of 50±5°C under stirring or homogenization or a combination of both.

(d) Adding azelaic acid: Add azelaic acid to the emulsion for 30 minutes while stirring, homogenizing, or a combination of both. Cool the emulsion to a target temperature of 38 ± 2 °C while stirring, homogenizing, or a combination of both.

(e) pH adjustment: Adjust the pH to 5.0-6.0 using triethanolamine diluted with purified water.

Example 16: Emulsion

Preparation steps:

(a) Water phase: Stir and heat purified water and glycerin at 70±5°C. Add disodium ethylenediaminetetraacetate, sodium thiosulfate and methyl paraben in sequence and dissolve under stirring. Add Pemulen TR-1 and Carbopol 971 one by one under stirring to make them evenly dissolved or dispersed.

(b) Oil phase: Dissolve butylated hydroxytoluene in medium chain triglycerides at 70±5°C.

(c) Emulsification: Add the oil phase to the water phase under stirring, homogenization or a combination of both for 30 minutes.

(d) Drug phase: Pimecrolimus and tretinoin were added one by one to the mixture of benzyl alcohol, Labrasol, PEG 400, vitamin E and diethylene glycol monoethyl ether and stirred until homogeneous.

(e) Adding azelaic acid: Add azelaic acid to the emulsion for 30 minutes while stirring, homogenizing, or a combination of both. Cool the emulsion to a target temperature of 38 ± 2 °C while stirring, homogenizing, or a combination of both.

(f) pH adjustment: Adjust the pH to 5.0-6.0 using sodium hydroxide diluted with purified water.

Example 17: Emulsion

Preparation steps:

(a) Water phase: Mix purified water, propylene glycol and glycerin. Add sodium cetearyl sulfate and disodium EDTA and stir to dissolve at 70±5℃.

(b) Oil phase: oleyl alcohol, cetyl alcohol, stearyl alcohol, mono- and di-glycerol fatty acid esters, medium-chain triglycerides and benzyl alcohol. Add and dissolve butylated hydroxytoluene under stirring. Add pimecrolimus and retinoic acid mixture one by one under stirring until uniform.

(c) Emulsification: Add the oil phase to the water phase for 30 minutes under stirring, homogenization or a combination of both. Cool to a target temperature of 50±5°C under stirring or homogenization or a combination of both.

(d) Adding azelaic acid: Add azelaic acid to the emulsion for 30 minutes while stirring, homogenizing, or a combination of both. Cool the emulsion to a target temperature of 38 ± 2 °C while stirring, homogenizing, or a combination of both.

(e) pH adjustment: adjust the pH to 4.0-6.0 with anhydrous citric acid and sodium hydroxide.

Example 18: Emulsion

Preparation steps:

(a) Water phase: Heat and mix purified water and propylene glycol under stirring, add disodium ethylenediaminetetraacetate, methylparaben and propylparaben one by one and stir to dissolve. Add sodium lauryl sulfate and sodium citrate and dissolve under stirring.

(b) Heat and melt glyceryl stearate SE, sorbitan stearate, cetyl alcohol, stearyl alcohol, light mineral oil and oleyl alcohol. Add pimecrolimus and tretinoin mixture one by one under stirring until uniform.

(c) Emulsification: Add the oil phase to the water phase for 30 minutes under stirring, homogenization or a combination of both. Cool to a target temperature of 50±5°C under stirring or homogenization or a combination of both.

(d) Adding azelaic acid: Add azelaic acid to the emulsion for 30 minutes while stirring, homogenizing, or a combination of both. Cool the emulsion to a target temperature of 38 ± 2 °C while stirring, homogenizing, or a combination of both.

Example 19: Ointment

Preparation steps: Heat, melt and mix mono- and diglycerides, mineral oil and white petrolatum at a temperature of 70 ± 5 ° C. Add butylated hydroxytoluene and disperse the ointment base under stirring. Cool the ointment base to a temperature of 50 ± 5 ° C. Add retinoic acid and disperse the ointment base under stirring, homogenization or a combination of the two. Add pimecrolimus and disperse the ointment base under stirring or homogenization or a combination of the two. Add azelaic acid and disperse the ointment base under stirring, homogenization or a combination of the two.

Example 20: Ointment

Preparation steps: Heat, melt and mix oleyl alcohol, medium chain triglycerides, sorbitan sesquioleate, microcrystalline wax and mineral oil at a temperature of 70±5°C. Add butylated hydroxytoluene and disperse the ointment base under stirring. Cool the ointment base to a temperature of 50±5°C. Add retinoic acid and disperse the ointment base under stirring, homogenization or a combination of both. Add pimecrolimus and disperse the ointment base under stirring or homogenization or a combination of both. Add azelaic acid and disperse the ointment base under stirring, homogenization or a combination of both.

Example 21: Ointment

Preparation steps: Heat, melt and mix oleyl alcohol, mono- and di-glycerides, medium-chain triglycerides, emulsifying wax, white beeswax, benzyl alcohol, mineral oil and white petrolatum at a temperature of 70 ± 5 ° C. Add butylated hydroxytoluene and disperse the ointment base under stirring. Cool the ointment base to a temperature of 50 ± 5 ° C. Add retinoic acid and disperse the ointment base under stirring, homogenization or a combination of the two. Add pimecrolimus and disperse the ointment base under stirring or homogenization, or a combination of the two. Add azelaic acid and disperse the ointment base under stirring, homogenization or a combination of the two.

Example 22: Ointment

Preparation steps: Melt the polyethylene glycol ointment base at a temperature of 70±5°C. Add retinoic acid and disperse the ointment base under stirring, homogenization or a combination of the two. Add pimecrolimus and disperse the ointment base under stirring, homogenization or a combination of the two. Add azelaic acid and disperse the ointment base under stirring, homogenization or a combination of the two.

Example 23: Foam

Preparation steps:

(a) Oil phase: melt cetyl alcohol, white petrolatum, Polyoxyl 20Cetostearyl Ether, light mineral oil, dl-α-tocopherol, isopropyl myristate, oleyl alcohol and stearyl alcohol at 70±5°C. Add pimecrolimus and tretinoin mixture one by one under stirring until uniform.

(b) Water phase: Heat and mix propylene glycol and purified water while stirring. Add disodium EDTA and disodium hydrogen phosphate and stir to dissolve.

(c) Emulsification: Add the oil phase to the water phase for 30 minutes under stirring, homogenization or a combination of both. Cool the bulk to a target temperature of 50±5°C under stirring or homogenization or a combination of both.

(d) Adding azelaic acid: Add azelaic acid to the emulsion for 30 minutes while stirring, homogenizing, or a combination of both. Cool to a target temperature of 38±2°C while stirring, homogenizing, or a combination of both.

(e) Filling: Load the container and the propellants propane, dimethyl ether and butane into the container. Seal the container and check the seal integrity.

Example 24: Foam

Preparation steps:

(a) Oil phase: Heat and melt cetearyl alcohol, dimethyl isosorbide, medium chain triglycerides, mono- and di-glycerides, polyoxyl (40) stearate and polysorbate 80 at 70±5°C. Add pimecrolimus and tretinoin mixture one by one under stirring until uniform.

(b) Water phase: Heat purified water while stirring. Add benzoic acid and dissolve it while stirring. Add methylcellulose and xanthan gum in propylene glycol while stirring, and add water from the polymer dispersion while stirring to hydrate it.

(c) Emulsification: Add the oil phase to the water phase for 30 minutes under stirring, homogenization or a combination of the two. Cool the dispersion to a target temperature of 50±5°C under stirring or homogenization or a combination of the two.

(d) Adding azelaic acid: Add azelaic acid to the emulsion for 30 minutes while stirring, homogenizing, or a combination of both. Cool the emulsion to a target temperature of 38±2°C while stirring, homogenizing, or a combination of both.

(e) pH adjustment: Adjust the pH to 4.0-6.0 with sodium hydroxide.

(f) Filling: Load the container and the propellants propane, butane and isobutane into the container. Seal the container and check whether the seal is intact.

Example 25: Foam

Preparation steps:

(a) Oil phase: Stir and heat to melt white petrolatum, mineral oil, isopropyl myristate, cyclomethicone, cetyl alcohol, sorbitan laurate and ceteareth-20 at 70±5°C. Add pimecrolimus and tretinoin mixture one by one under stirring until uniform.

(b) Water phase: Heat and mix purified water and propylene glycol. Add citric acid and potassium citrate and stir to dissolve at 70±5°C.

(c) Emulsification: Add the oil phase to the water phase for 30 minutes under stirring, homogenization or a combination of both. Cool the emulsion to a target temperature of 50±5°C under stirring or homogenization or a combination of both.

(d) Add azelaic acid: Add azelaic acid to the emulsion for 30 minutes while stirring, homogenizing, or a combination of both. Add phenoxyethanol and continue stirring for 10 minutes. Cool to a target temperature of 38 ± 2 °C while stirring or homogenizing, or a combination of both.

(e) Filling: Fill the container and charge the propellant P70 into the container. Seal the container and check the seal integrity.

Example 26: Foam

Preparation steps:

(a) Oil phase: heat, melt and mix soybean oil, coconut oil, light mineral oil, cyclomethicone, cetearyl alcohol, stearic acid, myristyl alcohol, hydrogenated castor oil, beeswax, stearyl alcohol and phenylethyl alcohol at 70±5° C. Add silicon dioxide under stirring and fully disperse under stirring.

(b) Drug phase: Add retinoic acid under stirring and mix for 10 minutes under stirring or homogenization or a combination of both. Add pimecrolimus under stirring and mix for 10 minutes under stirring or homogenization or a combination of both. Add azelaic acid under stirring and mix for 30 minutes under stirring or homogenization or a combination of both.

(c) Filling: Putting into container, adding propellant and sealing the container.

Embodiment 27

Preparation steps:

(a) Heat, melt and mix cetyl alcohol, oleyl alcohol, stearyl alcohol, mono- and di-glycerides, medium chain triglycerides and mineral oil at 70±5°C.

(b) Add and dissolve pimecrolimus in the oil phase at 70±5°C with stirring.

(c) Add and dissolve Azelaic Acid in Propylene Glycol, Benzyl Alcohol and Labrasol under stirring until a clear solution is formed. Add the Main Phase and mix under stirring or homogenization or a combination of both.

(d) Cooling: Cool the body to a temperature of 40±2°C under stirring, homogenization or a combination of both.

(e) Add and dissolve the retinoic acid in isopropanol at room temperature with stirring. Add the main phase and mix with stirring or homogenization or a combination of both.

Embodiment 28

Preparation steps:

(a) Propylene glycol, oleyl alcohol, dimethyl isosorbide, cetearyl alcohol and polyethylene glycol are heated at 70±5°C, melted and mixed.

(b) adding and dissolving pimecrolimus in the oil phase at 70±5°C under stirring, homogenization or a combination of both.

(c) Azelaic acid is added and dissolved in diethylene glycol monoethyl ether, dimethyl sulfoxide, benzyl alcohol and Labrasol under stirring or homogenization or a combination of both until a clear solution is formed.

Add the main phase and stir for 10 minutes

(d) Cooling: Cool the body to a temperature of 40±2°C under stirring, homogenization or a combination of both.

(e) Add and dissolve the retinoic acid in isopropanol at room temperature with stirring. Add the main phase and mix under stirring or homogenization or a combination of both.

Embodiment 29

Preparation steps: Add retinoic acid to ethanol while stirring, homogenizing, or a combination of the two. Add pimecrolimus to the main phase and mix while stirring or homogenizing, or a combination of the two. Add azelaic acid to the main phase and mix while stirring or homogenizing, or a combination of the two.

Embodiment 30

Preparation steps: Mix ethanol and isopropanol under stirring. Add retinoic acid solution under stirring, homogenization, or a combination of both. Add pimecrolimus to the main phase and mix under stirring or homogenization, or a combination of both. Add azelaic acid to the main phase and mix under stirring or homogenization, or a combination of both.

Example 31: Efficacy Study

A randomized, multicenter, investigator-blind controlled study conducted in different centers recruited a total of 100 subjects with moderate to severe melasma. The subjects were divided into four groups, each with 25 people. The topical composition prepared in each embodiment was applied topically to the affected facial area once a day before going to bed for 8 weeks. No subject lost the opportunity for follow-up, and all subjects indicated compliance with the treatment regimen. During acute treatment, apply SPF60 sunscreen at least twice a day (morning and noon). If sun exposure cannot be avoided, reapply every two hours. Subjects were asked to self-assess the use of melasma after 4 and 8 weeks of treatment, with the scoring criteria being "very satisfied", "satisfied", "neither satisfied nor dissatisfied", "dissatisfied" and "very dissatisfied".

Number of subjects 25 25 25 25 Group Example 4 Example 5 Example 6 Example 7 Very satisfied 30% 4% 12% 4% satisfy 58% 44% 36% 16% Neither satisfied nor dissatisfied 8% 32% 40% 48% Dissatisfied 4% 12% 8% 20% Very dissatisfied 0% 8% 4% 12%

The results are expressed as a percentage of the population. All subjects in the triple combination group containing azelaic acid, pimecrolimus and tretinoin reported the best results among all groups, with only 1 subject (4%) dissatisfied and 2 subjects neither satisfied nor dissatisfied (8%). The triple combination product containing azelaic acid, pimecrolimus and tretinoin showed very satisfactory results compared to the other three groups of products. In addition to a significant reduction in pigmentation, they also reported an improvement in skin quality and texture, and a reduction in skin pores. No serious side effects were found. Only two volunteers reported irritation or burning within a few days of using the gel, but the symptoms disappeared naturally after a few minutes.

The results showed that the triple combination therapy containing azelaic acid, pimecrolimus and tretinoin was effective in treating melasma and could maintain the improvement of melasma achieved by previous treatments.

The above is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, which all fall within the protection scope of the present invention.

Claims (10)

1. A topical composition for improving chloasma is characterized by comprising the following components:

component a: an immunosuppressant molecule or a pharmaceutically acceptable salt or ester thereof;

Component b: a vitamin a derivative or a pharmaceutically acceptable salt or ester thereof;

a dicarboxylic acid or a derivative thereof or a pharmaceutically acceptable salt or ester thereof;

Component d, a dermatologically acceptable carrier.

2. A topical composition for improving chloasma according to claim 1, wherein component a is pimecrolimus, component b is tretinoin and component c is azelaic acid.

3. The composition for external use for improving chloasma according to claim 2, wherein the pimecrolimus concentration is 0.05% -5.0%, the tretinoin concentration is 0.001% -1% and the azelaic acid concentration is 5.0% -25.0% by mass concentration.

4. A topical composition for improving chloasma as claimed in claim 3, wherein the pimecrolimus concentration is 0.5% -2.5%, the tretinoin concentration is 0.005% -0.5% and the azelaic acid concentration is 10.0% -20.0%.

5. The composition for external use for improving chloasma according to claim 4, wherein the pimecrolimus concentration is 1.0% -2.0%, the tretinoin concentration is 0.01% -0.25% and the azelaic acid concentration is 14.0% -16.0%.

6. The composition for external use for improving chloasma according to claim 5, wherein the pimecrolimus concentration is 1.0%, the tretinoin concentration is 0.05%, and the azelaic acid concentration is 15.0%.

7. A topical composition for improving chloasma according to any one of claims 1 to 6, wherein the dermatologically acceptable carrier is a cream, ointment, gel, emulsion, foam, topical mixture, solution, emulsion or any suitable topical formulation.

8. A topical composition for improving chloasma according to claim 7, wherein said dermatologically acceptable carrier comprises an oil phase or a water phase or a combination of oil and water phases.

9. The topical composition for improving chloasma according to claim 8, wherein the pH of the topical composition is 5.0±2.0.

10. A topical composition for improving chloasma as claimed in claim 9, wherein said topical composition is effective for penetration in a therapeutically effective amount for the treatment of patients suffering from chloasma and related skin disorders.