Vaginal pharmaceutical composition containing miconazole and luliconazole or their salts

Abstract

The present invention relates to a vaginal pharmaceutical composition for treating vaginal infections comprising miconazole or a salt thereof and luliconazole or a salt thereof, a method for preparing the same, and use thereof for treating / preventing vaginal infections.

Description

[Technical field]

[0001] The present invention relates to a vaginal pharmaceutical composition for treating vaginal infections, comprising miconazole or a salt thereof and luliconazole or a salt thereof.

[0002] In particular, the present invention relates to a vaginal pharmaceutical composition for treating vaginal infections and a method for preparing the same.

[0003] More particularly, the present invention relates to a vaginal pharmaceutical composition comprising miconazole or a salt thereof, luliconazole or a salt thereof, and at least one pharma- ceutically acceptable excipient, a method for preparing the same, and a method for using the same to treat vaginal infections.

[0004] Vaginal yeast infections are common genital fungal infections. Approximately 20% of women are infected annually. Approximately 75% of women will have at least one infection in their lifetime. Vulvovaginal candidiasis is a relatively common yeast infection. Yeast infections, also known as candidiasis, monilia, and monilia vaginitis, are one of the most frequent vaginal infections. These vaginal infections are caused by fungus-like yeasts of the genus Candida (formerly Monilia), specifically species including C. albicans, C. tropicalis, C. psuedotropicalis, C. glabrata, C. parapsilosis, C. krusei, C. stellatoidea, as well as Bacteroides fragilis and Gardnerellavaginalis. Generally, 90% of yeast infections are caused by C. albicans.

[0005] These Candida fungi normally grow in low concentrations in the oral cavity, digestive tract, and vagina, coexisting with the normal flora of these areas without adversely affecting health or physiology. Lactobacillus lactic acid bacteria keep their growth in check. However, when the system is out of balance, these bacteria are no longer effective. This causes yeast overgrowth, which results in symptoms of vaginal yeast infection such as vaginal itching, swelling around the vagina, burning sensation during urination or intercourse, pain during intercourse, stinging, redness, rash, and vaginal discharge.

[0006] Types of vaginal infections include yeast infections, bacterial vaginosis, trichomoniasis, sexually transmitted infections (STIs), chlamydia infection, gonorrhea, viral vaginitis (herpes), trichomoniasis, non-infectious vaginitis, and atrophic vaginitis.

[0007] For intravaginal treatment, many types of tablets, capsules, foams, pessaries, ointments, and creams containing a wide variety of existing drugs in conventional delivery systems are available for short-term or long-term treatment. More effective treatments for Candida infections usually involve administering an anti-yeast drug into the vagina and repeating the intravaginal administration of the drug at selected intervals over a period of days to weeks.

[0008] Miconazole nitrate is a synthetic imidazole antifungal agent that acts selectively on fungal cell membranes. Chemically, miconazole nitrate is 1-[2,4-dichloro-β-{(2,4-dichlorobenzyl)oxy}phenethyl]imidazole mononitrate and has a molecular weight of 479.15. Its empirical formula is C 18 H 14 C 14 N 2 O H N O 3 Miconazole nitrate is a compound represented by structural formula I: TIFF2025507426000001.tif51129

[0009] Miconazole nitrate is a white to almost white powder that is soluble in water and organic solvents such as ethanol, DMSO, dimethylformamide (DMF), propylene glycol, or pyridine.

[0010] Miconazole nitrate vaginal creams, 2% and 4%, approved in the United States under the trade names MONISTAT-7 and MONISTAT-3 on February 15, 1991 and March 30, 1998, respectively, are prescribed to treat vaginal yeast infections and relieve the associated external itching and inflammation.

[0011] Luliconazole is an imidazole antifungal drug. Chemically, luliconazole is (2E)-2-[(4R)-4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-2-imidazol-1-ylacetonitrile. Luliconazole is an R enantiomer and contains one chiral center. The double bond adjacent to the dithiolane group is in the E configuration. Its molecular weight is 354.28. Its empirical formula is C 14 H 9 Cl 2 N 3 S 2 Luliconazole is a compound represented by structural formula II. TIFF2025507426000002.tif52129

[0012] Luliconazole is a pale yellow to yellow solid. It is poorly soluble in water, soluble in acetonitrile and dimethylsulfoxide, and slightly soluble in chloroform and methanol.

[0013] Luliconazole topical cream (1%) was approved in the United States on November 14, 2013 under the brand name Luzu, and is indicated for the treatment of interdigital tinea pedis, genital tinea, and tinea corporis caused by Trichophyton rubrum and Epidermophyton floccosum in individuals aged 18 years and older.

[0014] US Pat. No. 1,008,6008 discloses a topical paste containing one or more antifungal agents, an inert powder of excipients, and a pharma- ceutically acceptable topical carrier. This patent application generally discloses antifungal agents such as clotrimazole, ketoconazole, miconazole, oxiconazole, econazole, luliconazole, terbinafine, nystatin, fluconazole, voriconazole, itraconazole, caspofungin, micafungin, naftifine, butenafine, amorolfine, ravuconazole, posaconazole, flucytosine, sertaconazole, efinaconazole, enilconazole, saperconazole, sulconazole, terconazole, tioconazole, nikkomycin Z, anidulafungin (LY303366), pimaricin, griseofulvin, haloprogin, tolnaftate, undecylenate, and any combination thereof. Furthermore, this patent application specifically discloses antifungal compositions containing terbinafine or terbinafine hydrochloride, but does not teach or disclose vaginal compositions of miconazole and luliconazole.

[0015] U.S. Pat. No. 5,514,698 discloses a long-lasting viscous antifungal vaginal cream composition containing an imidazole antifungal selected from miconazole, econazole, terconazole, saperconazole, itraconazole, ketoconazole, and clotrimazole, but does not teach or disclose vaginal compositions of miconazole and luliconazole.

[0016] WO 2011 / 121604 discloses a liquid vaginal spray comprising a therapeutically effective amount of at least one antifungal agent and lactic acid, the antifungal agent being selected from miconazole, ketoconazole, clotrimazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, griseofulvin, fluconazole, fosfluconazole, itraconazole, posaconazole, voriconazole, amorolfine, butenafine, naftifine, terbinafine, natamycin, nystatin, amphotericin B, thiabendazole, anidulafungin, caspofungin, micafungin, and flucytosine, but does not teach or disclose vaginal compositions of miconazole and luliconazole.

[0017] Currently, products available on the market for the treatment of vaginal fungal infections include butoconazole nitrate (2% vaginal cream), clotrimazole (1% topical cream), miconazole (4% vaginal cream, 100mg and 200mg suppositories), terconazole (0.4% and 0.8% cream, 80mg suppository), and fluconazole (50mg, 100mg, 150mg and 200mg tablets).

[0018] The most common side effects of existing luliconazole products are application site reactions, while those of miconazole are allergic contact dermatitis, cellulitis, rash, burning sensation, and maceration, making these products incompatible with patients in the treatment of vaginal fungal infections.

[0019] Since there is no combination of miconazole and luliconazole on the market, there is an unmet need to develop a vaginal pharmaceutical composition containing a combination of miconazole or a salt thereof and luliconazole or a salt thereof.

[0020] Vaginal infections are very common because there are many factors that disrupt the vaginal flora, which reduces the vagina's resistance to infections, including but not limited to bacterial and fungal infections. Therefore, the inhibition of harmful bacteria and fungi has important clinical implications for the prevention and treatment of genital tract infections.

[0021] Therefore, there is an unmet need in the art to develop a vaginal pharmaceutical composition for treating vaginal infections that comprises miconazole and luliconazole, has minimal side effects, a broad spectrum of antifungal activity, is effective in treating vaginal fungal infections, and provides better patient compliance.

[0022] Therefore, the applicant of the present invention has invented a novel vaginal pharmaceutical composition for treating vaginal infections, comprising miconazole or its salt and luliconazole or its salt, which is effective, has a broad therapeutic spectrum against vaginal infections, has few side effects and is well tolerated by patients.

[0023] Object of the invention An object of the present invention is to provide a vaginal pharmaceutical composition comprising miconazole or a salt thereof, luliconazole or a salt thereof, and one or more pharma- ceutically acceptable excipients.

[0024] An object of the present invention is to provide a vaginal pharmaceutical composition for treating vaginal infections, comprising miconazole or a salt thereof and luliconazole or a salt thereof.

[0025] An object of the present invention is to provide a vaginal pharmaceutical composition for treating vaginal infections, comprising miconazole or a salt thereof, luliconazole or a salt thereof, and one or more pharma- ceutically acceptable excipients.

[0026] The object of the present invention is to i) 0.1 to 10% by weight of miconazole or a salt thereof, ii) 0.01 to 5% by weight of luliconazole or a salt thereof, iii) 0.1 to 15% by weight of a lubricant; iv) 0.1 to 25% by weight of an emulsifier; v) 0.1 to 10% by weight of a co-emulsifier; vi) 0.001 to 6% by weight of a preservative, and vii) A suitable amount of drug vehicle. The present invention provides a vaginal pharmaceutical composition for treating vaginal infections, comprising:

[0027] The object of the present invention is to i) 0.1 to 10% by weight of miconazole or a salt thereof, ii) 0.01 to 5% by weight of luliconazole or a salt thereof, iii) 0.1 to 15% by weight of a lubricant; iv) 0.1 to 25% by weight of an emulsifier; v) 0.1 to 10% by weight of an auxiliary emulsifier; vi) 0.001 to 6% by weight of a preservative, and vii) A suitable amount of drug solvent The present invention provides a vaginal pharmaceutical composition comprising the compound

[0028] It is a further object of the present invention to provide a vaginal pharmaceutical composition for treating vaginal infections comprising miconazole or a salt thereof and luliconazole or a salt thereof, which has a broad spectrum of antifungal activity in the treatment of vaginal fungal infections.

[0029] A further object of the present invention is to provide a method for preparing a vaginal pharmaceutical composition comprising miconazole or a salt thereof and luliconazole or a salt thereof, the method comprising the steps of: (a) Aqueous phase: Dissolve the preservative in purified water, mix, and heat at an appropriate temperature; (b) Lipid phase: Mix co-emulsifier, emulsifier, lubricant, and preservative and heat at an appropriate temperature; (c) cooling the lipid phase of step (b) to a suitable temperature and mixing with both the active pharmaceutical ingredients (APIs) for 5 to 10 minutes; (d) adding the product of step (c) to the product of step (a) and emulsifying by mixing for 10 minutes; and (e) slowly mixing the cream obtained in step (d) and cooling it at room temperature; This includes: Summary of the Invention

[0030] In a main aspect, the present invention discloses a vaginal pharmaceutical composition comprising miconazole or a salt thereof, luliconazole or a salt thereof, and one or more pharma- ceutically acceptable excipients.

[0031] In one embodiment, the present invention discloses a vaginal pharmaceutical composition for treating vaginal infections, comprising miconazole or a salt thereof and luliconazole or a salt thereof.

[0032] In another aspect, the present invention relates to a vaginal pharmaceutical composition for treating a vaginal infection, comprising miconazole or a salt thereof, luliconazole or a salt thereof, and one or more pharma- ceutically acceptable excipients.

[0033] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: i) 0.1 to 10% by weight of miconazole or a salt thereof, ii) 0.01 to 5% by weight of luliconazole or a salt thereof, iii) 0.1 to 15% by weight of a lubricant; iv) 0.1 to 25% by weight of an emulsifier; v) 0.1 to 10% by weight of an auxiliary emulsifier; vi) 0.001 to 6% by weight of a preservative, and vii) A suitable amount of drug solvent The present invention relates to a vaginal pharmaceutical composition for treating vaginal infections, comprising:

[0034] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: i) 0.1 to 10% by weight of miconazole or a salt thereof, ii) 0.01 to 5% by weight of luliconazole or a salt thereof, iii) 0.1 to 15% by weight of a lubricant; iv) 0.1 to 25% by weight of an emulsifier; v) 0.1 to 10% by weight of an auxiliary emulsifier; vi) 0.001 to 6% by weight of a preservative, and vii) A suitable amount of drug solvent The present invention relates to a vaginal pharmaceutical composition comprising the compound

[0035] In another aspect, the present invention provides a method for preparing a vaginal pharmaceutical composition comprising miconazole or a salt thereof and luliconazole or a salt thereof, the method comprising: (a) Aqueous phase: Dissolve the preservative in purified water, mix, and heat at an appropriate temperature; (b) Lipid phase: Mix co-emulsifier, emulsifier, lubricant, and preservative and heat at an appropriate temperature; (c) cooling the lipid phase of step (b) to a suitable temperature and mixing with both the active pharmaceutical ingredients (APIs) for 5 to 10 minutes; (d) adding the product of step (c) to the product of step (a) and emulsifying by mixing for 10 minutes; and (e) slowly mixing the cream obtained in step (d) and cooling it at room temperature; This includes:

[0036] Another aspect of the present invention provides a vaginal pharmaceutical composition for treating a vaginal infection comprising miconazole or a salt thereof and luliconazole or a salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] As used herein, the terms "composition," "pharmaceutical composition," "vaginal pharmaceutical composition," or "topical pharmaceutical composition" are synonymous and include dosage forms such as topicals, creams, ointments, and the like.

[0038] The terms "infection", "vaginal infection", "fungal infection", "yeast infection", "vaginal yeast infection", or "vaginal fungal infection" are used interchangeably herein.

[0039] In the following specification and claims, use a number of terms which are defined to have the following meanings: The singular forms "a," "an," and "the" include the plural referents unless the context clearly indicates otherwise.

[0040] The present invention relates to a vaginal pharmaceutical composition comprising miconazole or a salt thereof, luliconazole or a salt thereof, and one or more pharma- ceutically acceptable excipients.

[0041] The present invention relates to a vaginal pharmaceutical composition for treating vaginal infections, comprising miconazole or a salt thereof and luliconazole or a salt thereof.

[0042] The miconazole and luliconazole of the present invention may be present in the form of a free base or a pharma- ceutically acceptable salt thereof.

[0043] The term "miconazole" is used broadly to include not only "miconazole" itself, but also its pharma- ceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, isomers, polymorphs, prodrugs, and its various crystalline and amorphous forms.

[0044] The salt of miconazole can be selected from the group consisting of nitrate, maleate, hemifumarate, and hemisuccinate, with miconazole nitrate being preferred.

[0045] The concentration of miconazole or a salt thereof is at least 0.1%, preferably ranging from 0.1% to 10%, more preferably from 0.25% to 5% by weight of the total composition.

[0046] The term "luliconazole" is used in a broad sense to include not only "luliconazole" itself, but also pharma- ceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, isomers, polymorphs, and prodrugs thereof, as well as various crystalline and amorphous forms thereof.

[0047] The salt of luliconazole may be selected from formic acid, acetic acid, citric acid, tartaric acid, bitartaric acid, benzoic acid, lactic acid, malic acid, fumaric acid, succinic acid, gluconic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, and the like.

[0048] The concentration of luliconazole or a salt thereof is at least 0.01% by weight of the composition, preferably in the range of 0.01% to 5%, more preferably 0.1% to 4%.

[0049] The term "fungal infection" as used in the present invention may be selected from the group consisting of vaginal candidiasis (Candida), monilia, or Molinia vaginitis caused by fungus-like yeasts of the genus Candida (formerly Monilia), and fungal infections caused in particular by species including C. albicans, C. tropicalis, C. psuedotropicalis, C. glabrata, C. parapsilosis, C. krusei, and C. stellatoidea.

[0050] The vaginal infection treated in the present invention may also be selected from the group consisting of yeast infection, bacterial vaginosis, trichomoniasis, sexually transmitted infections (STIs), chlamydia infection, gonorrhea, viral vaginitis (herpes), trichomoniasis, non-infectious vaginitis and atrophic vaginitis.

[0051] The antifungal activity of miconazole nitrate covers a wide range of fungi, including yeasts and dermatophytes, particularly against Candida (C. guilliermondii and C. tropicalis), Trichophyton (Trichophyton mentagrophytes and Trichophyton rubrum), Epidermophyton (E. floccosum), Microsporum (M. canis), Pityrosporon orbiculare (Malassezia furfur), but also has some activity against gram-positive bacteria (Staphylococcus aureus).

[0052] The antifungal activity of luliconazole covers a range of dermatophytes, yeasts and some other fungi, particularly against Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans, Trichophyton verrucosum, Trichophyton violaceum, Microsporum canis, Trichophyton gypseum, Epidermophyton floccosum, Candida albicans, Malassezia furfur, Malassezia restricta, Malassezia slooffiae and Malassezia sympodialis.

[0053] The miconazole and luliconazole of the present invention act as antifungal agents to suppress / prevent vaginal mycosis.

[0054] Miconazole inhibits 14α-demethylation of lanosterol and, as a result, inhibits ergosterol synthesis in fungal cell membranes. Furthermore, miconazole has been shown to induce reactive oxygen species in fungal biofilms and has a minimum growth concentration (MIC) of 256 μM or higher against Candida spp.

[0055] Luliconazole inhibits lanosterol demethylase, thereby inhibiting the synthesis of ergosterol. When azoles inhibit the activity of this enzyme, the amount of ergosterol that constitutes the fungal cell membrane decreases, and lanosterol accumulates.

[0056] The vaginal pharmaceutical composition comprises miconazole or a salt thereof and luliconazole or a salt thereof, which provide strong antifungal activity, efficacy and patient compliance in the treatment of vaginal fungal infections.

[0057] The vaginal pharmaceutical composition for treating vaginal infections comprising miconazole or a salt thereof and luliconazole or a salt thereof according to the present invention provides an extended therapeutic spectrum, an increased rate or extent of antifungal or antibacterial activity, and reduced toxicity for the treatment of vaginal fungal infections.

[0058] In one embodiment, the present invention provides a vaginal pharmaceutical composition comprising miconazole or a salt thereof, luliconazole or a salt thereof, and one or more pharma- ceutically acceptable excipients.

[0059] In one embodiment, the present invention discloses a vaginal pharmaceutical composition for treating vaginal infections, comprising miconazole or a salt thereof and luliconazole or a salt thereof.

[0060] In one embodiment, the present invention discloses a vaginal pharmaceutical composition for treating vaginal infections, comprising miconazole or a salt thereof, luliconazole or a salt thereof, and one or more pharma- ceutically acceptable excipients.

[0061] The vaginal pharmaceutical composition for treating vaginal infections comprising miconazole or a salt thereof and luliconazole or a salt thereof according to the present invention is formulated into a dosage form selected from the group consisting of pessaries, vaginal rings, irrigators, suppositories, tablets, soft capsules, tampons, foams, sprays, gels, creams, intrauterine devices (IUDs), ointments, pastes, lotions, solutions, tinctures, powders, mousses, washes, and mucoadhesive vaginal films.

[0062] A vaginal pharmaceutical composition for treating a vaginal infection comprises miconazole or a salt thereof, luliconazole or a salt thereof, and one or more pharma- ceutically acceptable excipients.

[0063] The vaginal pharmaceutical composition for treating vaginal infection containing miconazole or a salt thereof and luliconazole or a salt thereof may contain one or more pharma- ceutically acceptable excipients selected from the group consisting of bases, emollients, lubricants, thickening stabilizers, thickeners, surfactants, solubilizers, emulsifiers, emulsifiers, co-emulsifiers, preservatives, antioxidants, moisturizers, absorbents, penetration enhancers, opacifying agents, chelating agents, gelling agents, acidifying agents, alkalizing agents, buffers, flavors, fragrances, antifoaming agents, adhesives, bioadhesive polymers, drug solvents, and other excipients known in the art for producing pharmaceutical compositions.

[0064] Examples of bases in the present invention include, but are not limited to, carnauba wax, cetyl alcohol, cetyl ester wax, emulsifying wax, hydrolyzed lanolin, lanolin, lanolin alcohol, vegetable oils, animal fats, coconut oil, beeswax, olive oil, spermaceti wax, sesame oil, almond oil, alcohol, acid, ester, oleic acid, oleyl alcohol, palmitic acid, lauryl alcohol, lauric acid, myristyl alcohol, ethyl oleate, isopropyl myristate, ethylene glycol, hydrogenated and sulfated oils, hydrogenated castor oil, cottonseed oil, hydrogenated sulfated castor oil, microcrystalline wax, liquid paraffin, petrolatum, polyethylene glycol, stearic acid, stearyl alcohol, white wax, yellow wax, and combinations thereof.

[0065] Examples of emollients in the present invention include waxes, lipids, caprylic / capric triglyceride, castor oil, ceteareth-20, ceteareth-30, cetearyl alcohol, ceteth 20, cetostearyl alcohol, cetyl alcohol, cetylstearyl alcohol, cocoa butter, diisopropyl adipate, glycerin, glyceryl monooleate, glyceryl stearate, isopropyl myristate, isopropyl palmitate, lanolin, lanolin alcohol, hydrogenated lanolin, liquid paraffin, linoleic acid, mineral oil, oleic acid, white petrolatum, polyethylene glycol, polyoxyethylene glycol fatty alcohol ether, polyoxypropylene 15-stearyl ether, propylene glycol stearate, squalane, steareth-2, steareth-100, squalane ... The groups include, but are not limited to, stearic acid, urea; naturally occurring oils such as almond oil, coconut oil, olive oil, palm oil, and peanut oil; fatty acids such as lauric acid, myristic acid, palmitic acid, and stearic acid; monohydric alcohol esters of fatty acids such as ethyl laurate, isopropyl laurate, ethyl myristate, n-propyl myristate, ethyl palmitate, methyl palmitate, methyl stearate, ethyl stearate, isopropyl stearate, butyl stearate, isobutyl stearate, amyl stearate, and isoamyl stearate; glycols such as ethylene glycol, diethylene glycol, and polyethylene glycol; branched aliphatic alcohols such as lauryl alcohol, myristyl alcohol, and stearyl alcohol, and combinations thereof.

[0066] Examples of lubricants in the present invention include, but are not limited to, the group consisting of castor oil, mineral oil, paraffin oil, ispagol mucilage, vitamin D, talc, and any mixtures thereof. The amount of lubricant present in the composition is about 0.1-15%, preferably about 0.5-12%, more preferably about 1-10% by weight of the composition.

[0067] Examples of thickening stabilizers or thickeners in the present invention include, but are not limited to, the group including carbomer, hydrogenated castor oil, methylcellulose, sodium carboxymethylcellulose, carrageenan, colloidal silicon dioxide; natural gums such as gelatin, tragacanth gum, guar gum, etc.; hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene oxide, alginic acid, paraffin, cetostearyl alcohol, PEG200, PEG300, PEG400, PEG600, monoethanolamine, triethanolamine, glycerol, propylene glycol, polyoxyethylene sorbiton monooleate, poloxamer, polyvinylpyrrolidone; various alcohols such as polyvinyl alcohol, ethanol, isopropyl alcohol, etc.; fumed silica, and combinations thereof.

[0068] Examples of surfactants in the present invention include, but are not limited to, the group consisting of ionic surfactants, cationic surfactants, nonionic surfactants, and mixtures thereof, and further include polysorbate, polysorbate 20, polysorbate 40, polysorbate 80, polysorbate 60, poloxamer, sorbitan monostearate, sorbitan monooleate, sodium lauryl sulfate, propylene glycol monostearate, dodecylbenzenesulfonate, polyethylene glycol, PEG 100 stearate, polyethylene glycol distearate, and the like. and combinations thereof.

[0069] Examples of solubilizers, emulsifiers, or emulsifiers in the present invention include, but are not limited to, the group consisting of apricot kernel oil PEG-6 ester, pegoxol-7 stearate, polysorbate 20, polysorbate 80, polysorbate 60, poloxamer, emulsifying wax, sorbitan monostearate, sorbitan monooleate, sodium lauryl sulfate, propylene glycol monostearate; natural gums such as acacia, tragacanth; mono- and divalent soaps, lanolin, cholesterol, cholesterol esters, triethanolamine and its salts, dodecylbenzenesulfonate, diethylene glycol monoethyl ether, sodium docusate, and mixtures thereof. The amount of solubilizer, emulsifier, or emulsifier present in the composition is about 0.1-25%, preferably 1-22%, by weight of the composition.

[0070] Examples of auxiliary emulsifiers in the present invention include, but are not limited to, the group consisting of apricot kernel oil PEG-6 ester, propylene glycol stearate, hydroxyethylcellulose cetyl, poloxamer 407, polyglyceryl-2 stearate, and combinations thereof. The amount of auxiliary emulsifier present in the composition is about 0.1-10%, preferably 0.05-8%, by weight of the composition.

[0071] Examples of preservatives in the present invention include, but are not limited to, the group consisting of chlorocresol, benzoic acid, butylated hydroxyanisole, phenylmercuric nitrate, benzyl alcohol, benzoic acid and its salts, boric acid, methylparaben, propylparaben, sodium acetate trihydrate, anhydrous sodium acetate, chlorhexidine, formaldehyde, glutaraldehyde, imidazolidinyl urea, triclosan, benzalkonium chloride, chloroxylenol, and combinations thereof. The amount of preservative present in the composition is about 0.001-6%, preferably about 0.001-5%, more preferably about 0.005-4.5% by weight of the composition.

[0072] Examples of antioxidants in the present invention include butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate; polyols such as sorbitol, xylitol, and maltitol; natural extracts such as quillaja, lactic acid, urea, lithium chloride, ascorbic acid, sodium metabisulfite, carotenoids; carotenes such as α-carotene, β-carotene, and lycopene; chlorogenic acid, tocopherol, uric acid, ZnO, ZnSO 4 and combinations thereof.

[0073] Examples of moisturizing agents in the present invention include, but are not limited to, the group consisting of glycerin, glyceryl triacetate, propylene glycol, polyethylene glycol, sorbitol solution, 1,2,6-hexanetriol, isopropyl myristate, petrolatum, isopropyl palmitate, hydrogenated castor oil, mineral oil, polyoxymethylene urea, potassium sorbate, and combinations thereof.

[0074] Examples of absorbents in the present invention include, but are not limited to, the group consisting of magnesium carbonate, calcium carbonate, starch, cellulose and its derivatives, and combinations thereof.

[0075] Examples of penetration enhancers in the present invention include, but are not limited to, the group consisting of propylene glycol, ethanol, isopropyl alcohol, oleic acid, polyethylene glycol, phospholipids, cyclodextrin, piper nigrum, pyrrolidone, dimethyl sulfoxide (DMSO), decyl methyl sulfoxide (DCMS), terpenes (cineole, eugenol, d-limonene, menthol, menthone), urea, and combinations thereof.

[0076] Examples of opacifying agents in the present invention include, but are not limited to, the group consisting of higher fatty alcohols such as cetyl alcohol, stearyl alcohol, cetostearyl alcohol, arachidyl alcohol, behenyl alcohol, etc.; solid esters such as cetyl palmitate, glyceryl laurate, etc.; various fatty acid derivatives such as propylene glycol esters and polyethylene glycol esters; inorganic materials such as magnesium aluminum silicate, zinc oxide, titanium dioxide, etc.; other light-blocking agents, and combinations thereof.

[0077] Examples of chelating agents in the present invention include, but are not limited to, the group consisting of ethylenediaminetetraacetate, dimercaprol, dimercaptosuccinic acid, penicillamine, deferoxamine, deferasirox, citric acid, maleic acid, phosphoric acid, and combinations thereof.

[0078] Examples of gelling agents in the present invention include, but are not limited to, the group consisting of carbomer / carbopol, pemulen; cellulose derivatives such as methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, and the like; glycerol or propylene glycol gelled with a suitable agent such as natural gums such as xanthan gum and tragacanth; fenugreek mucilage, pectin, poloxamer (pluronic), alginates, gelatin, starch, polyvinyl alcohol, povidone, and combinations thereof.

[0079] Examples of acidifying agents, alkalizing agents or buffering agents in the present invention include, but are not limited to, the group consisting of anhydrous citric acid, citric acid monohydrate, phosphoric acid, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium sorbate, sodium phosphate monobasic, sodium phosphate dibasic, triethanolamine and combinations thereof.

[0080] Examples of fragrances or fragrances in the present invention include, but are not limited to, the group consisting of lavender, lemon, gardenia, hypoallergenic fragrances, menthol, and combinations thereof.

[0081] Examples of anti-foaming agents in the present invention include, but are not limited to, the group consisting of cyclomethicone, dimethicone, simethicone, and combinations thereof.

[0082] Examples of adhesive agents in the present invention include, but are not limited to, the group consisting of natural gums (gum arabic, algae gum, guar gum, tragacanth gum, xanthan gum, pectin, dextran) and combinations thereof.

[0083] Examples of bioadhesive polymers in the present invention include, but are not limited to, the group consisting of ethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, and combinations thereof.

[0084] Examples of the drug solvent in the present invention include, but are not limited to, the group consisting of purified water, hexylene glycol, propylene glycol, oleyl alcohol, propylene carbonate, mineral oil, almond oil, cottonseed oil, ethyl oleate, isopropyl myristate, isopropyl palmitate, myristyl alcohol, octyldodecanol, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, squalene, polyethylene glycol, diethylene glycol monoethyl, glycofurol, benzyl alcohol, labrasol, benzyl benzoate, ethyl oleate, diethylene glycol monoethyl ether, ethyl alcohol, cremophor ELP, solutol, transcutol, capmul, captex, and mixtures thereof.Preferably, the drug solvent is water.The drug solvent in the present invention may be an amount that makes up the appropriate volume.

[0085] In one embodiment, the present invention provides i) 0.1 to 10% by weight of miconazole or a salt thereof, ii) 0.01 to 5% by weight of luliconazole or a salt thereof, iii) 0.1 to 15% by weight of a lubricant; iv) 0.1 to 25% by weight of an emulsifier; v) 0.1 to 10% by weight of an auxiliary emulsifier; vi) 0.001 to 6% by weight of a preservative, and vii) A suitable amount of drug solvent The present invention provides a vaginal pharmaceutical composition for treating vaginal infections, comprising:

[0086] In one embodiment, the present invention provides i) 0.1 to 10% by weight of miconazole or a salt thereof, ii) 0.01 to 5% by weight of luliconazole or a salt thereof, iii) 0.1 to 15% by weight of a lubricant; iv) 0.1 to 25% by weight of an emulsifier; v) 0.1 to 10% by weight of an auxiliary emulsifier; vi) 0.001 to 6% by weight of a preservative, and vii) A suitable amount of drug solvent The present invention provides a vaginal pharmaceutical composition comprising:

[0087] In one embodiment, the present invention provides a method for preparing a vaginal pharmaceutical composition comprising miconazole or a salt thereof and luliconazole or a salt thereof, the method comprising: (a) Aqueous phase: Dissolve the preservative in purified water, mix, and heat at an appropriate temperature; (b) Lipid phase: Mix co-emulsifier, emulsifier, lubricant, and preservative and heat at an appropriate temperature; (c) cooling the lipid phase of step (b) to a suitable temperature and mixing with both the active pharmaceutical ingredients (APIs) for 5 to 10 minutes; (d) adding the product of step (c) to the product of step (a) and emulsifying by mixing for 10 minutes; and (e) slowly mixing the cream obtained in step (d) and cooling it at room temperature; This includes:

[0088] A vaginal pharmaceutical composition for treating a vaginal infection comprises miconazole or a salt thereof and luliconazole or a salt thereof, and said vaginal pharmaceutical composition may be applied at least once a day or as directed by a healthcare provider.

[0089] The vaginal pharmaceutical composition according to the present invention can be applied to the affected area by hand or with a suitable applicator.

[0090] The vaginal pharmaceutical composition for treating vaginal infections containing miconazole or a salt thereof and luliconazole or a salt thereof contains other pharma- ceutical acceptable polymers that are primarily used to maintain an appropriate viscosity of the formulation.

[0091] The vaginal pharmaceutical composition for treating vaginal infections containing miconazole or a salt thereof and luliconazole or a salt thereof according to the present invention can be manufactured by trituration method, levigation method, fusion method, chemical reaction method, emulsification method, cold method, dispersion method, molding method, compression method, hand-rolling method, casting method, wet granulation method, dry granulation method or direct compression method.

[0092] The concentrations of the active ingredients miconazole or a salt thereof, luliconazole or a salt thereof, and other excipients as well as the manufacturing process are optimized to ensure that the composition exerts maximum therapeutic efficacy in treating vaginal fungal infections, has minimal or no side effects, and improves patient compliance.

[0093] Miconazole or a salt thereof and luliconazole or a salt thereof according to the present invention have a synergistic effect in the treatment of vaginal fungal infections, thereby broadening the therapeutic spectrum, enhancing the speed or degree of antifungal or antibacterial activity, and reducing toxicity.

[0094] The vaginal pharmaceutical composition containing miconazole or a salt thereof and luliconazole or a salt thereof is evaluated by measuring pH, primary skin irritation test, appearance, viscosity, spreadability, stability test, rheology test, thermal behavior, saponification value and acid value.

[0095] The vaginal pharmaceutical composition for treating vaginal infections containing miconazole or a salt thereof and luliconazole or a salt thereof according to the present invention can be used in a stability test based on the ICH guideline.

[0096] The vaginal pharmaceutical composition for treating vaginal infections containing miconazole or its salt and luliconazole or its salt according to the present invention can be packaged in a collapsible tube, jar, pot, bottle, or single-dose sachet. The container material or packaging material of the present invention does not affect the quality of the formulation and does not allow any diffusion across the container material into the formulation.

[0097] The vaginal pharmaceutical composition for treating vaginal infections containing miconazole or a salt thereof and luliconazole or a salt thereof according to the present invention can be labeled based on the requirements of Good Manufacturing Practice (GMP). EXAMPLES

[0098] The following examples are intended to illustrate embodiments of the present invention and are not intended to limit the scope of the invention.

[0099] Example 1: Test with cream base TIFF2025507426000003.tif61153 qs: moderate amount

[0100] Manufacturing process: 1. Aqueous phase: Benzoic acid was dissolved in purified water, mixed and heated at 65-75°C. 2. Lipid phase: Apricot kernel oil PEG-6 ester, pegoxol-7 stearate, mineral oil, and butyl hydroxyanisole were mixed and heated at 65-75°C. 3. The phase from step 2 was cooled to 65°C and mixed with the active pharmaceutical ingredients (APIs) miconazole nitrate and luliconazole for 5-10 minutes. 4. The product of step 3 was added to the product of step 1 and emulsified by stirring for 10 minutes. 5. The produced cream was slowly mixed and cooled at room temperature.

[0101] Physical parameters TIFF2025507426000004.tif35153

[0102] Example 2: Testing cream bases with different emulsifiers and preservatives TIFF2025507426000005.tif61153 qs: moderate amount

[0103] manufacturing process 1. Aqueous phase: Benzoic acid was dissolved in purified water, mixed and heated at 65-75°C. 2. Lipid phase: Apricot kernel oil PEG-6 ester, pegoxol-7 stearate, and mineral oil were mixed and heated at 65-75°C. 3. The phase from step 2 was cooled to 65°C and mixed with the active pharmaceutical ingredients (APIs) miconazole nitrate and luliconazole for 5-10 minutes. 4. The product of step 3 was added to the product of step 1 and emulsified by stirring for 10 minutes. 5. The produced cream was slowly mixed and cooled at room temperature.

[0104] Physical parameters TIFF2025507426000006.tif35153

Claims

1. Vaginal pharmaceutical composition for treating vaginal infections, comprising miconazole or a salt thereof, luliconazole or a salt thereof, and one or more pharma- ceutically acceptable excipients

2. 2. A vaginal pharmaceutical composition for treating vaginal infections according to claim 1, comprising: i) 0.1 to 10% by weight of miconazole or a salt thereof; ii) 0.01 to 5% by weight of luliconazole or a salt thereof; iii) 0.1 to 15 wt. % of a lubricant; iv) 0.1 to 25 wt. % of an emulsifier; v) 0.1 to 10% by weight of a co-emulsifier; vi) 0.001 to 6% by weight of a preservative, and vii) A suitable amount of drug solvent A vaginal pharmaceutical composition comprising:

3. 2. A vaginal pharmaceutical composition for treating vaginal infections according to claim 1, comprising: A vaginal pharmaceutical composition, wherein the vaginal infection is selected from the group consisting of yeast infection, bacterial vaginosis, trichomoniasis, sexually transmitted infection (STI), chlamydia infection, gonorrhea, viral vaginitis (herpes), trichomoniasis, non-infectious vaginitis, atrophic vaginitis, and the like.

4. i) miconazole or a salt thereof, ii) luliconazole or a salt thereof, and iii) one or more pharma- ceutically acceptable excipients; A vaginal pharmaceutical composition comprising:

5. 5. The vaginal pharmaceutical composition according to claim 4, i) 0.1 to 10% by weight of miconazole or a salt thereof; ii) 0.01 to 5% by weight of luliconazole or a salt thereof; iii) 0.1 to 15 wt. % of a lubricant; iv) 0.1 to 25% by weight of an emulsifier; v) 0.1 to 10% by weight of a co-emulsifier; vi) 0.001 to 6% by weight of a preservative, and vii) A suitable amount of drug solvent A vaginal pharmaceutical composition comprising:

6. 5. The vaginal pharmaceutical composition according to claim 1 or 4, The one or more pharma- ceutically acceptable excipients are selected from the group consisting of bases, emollients, lubricants, thickening agents, viscosity enhancers, surfactants, solubilizers, emulsifiers, emulsifiers, co-emulsifiers, preservatives, antioxidants, humectants, absorbents, penetration enhancers, opacifying agents, chelating agents, gelling agents, acidifying agents, alkalizing agents, buffers, flavors, fragrances, antifoaming agents, adhesives, bioadhesive polymers, drug solvents, and the like.

7. 5. The vaginal pharmaceutical composition according to claim 1 or 4, The vaginal pharmaceutical composition is formulated into a dosage form selected from the group consisting of a pessary, a vaginal ring, a water fountain, a suppository, a tablet, a softgel, a tampon, a foam, a spray, a gel, a cream, an intrauterine device (IUD), an ointment, a paste, a lotion, a solution, a tincture, a mousse, a wash, and a mucoadhesive vaginal film.

8. A method for preparing a vaginal pharmaceutical composition containing miconazole or a salt thereof and luliconazole or a salt thereof, comprising the steps of: (a) Water phase: Dissolve the preservative in purified water, mix and heat to an appropriate temperature; (b) Lipid phase: Mix co-emulsifier, emulsifier, lubricant, and preservative and heat at appropriate temperature; (c) cooling the lipid phase of step (b) to a suitable temperature and mixing with both the active pharmaceutical ingredients (APIs) for 5-10 minutes; (d) adding the product of step (c) to the product of step (a) and emulsifying by mixing for 10 minutes; and (e) The cream obtained in step (d) is slowly mixed and cooled at room temperature. A preparation method comprising:

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