A topical aqueous NANO-dispersion composition of antifungal agents and implementations thereof

Abstract

The present invention provides a topical aqueous nano-dispersion composition comprising at least one antifungal agent and lipid carrier particles, wherein the at least one antifungal agent is entrapped within the lipid carrier particles in molecular form. The nano-dispersion has drug entrapment efficiency in the range of 70 to 97%. The present invention further provides process of preparing the composition, method of treating / preventing a fungal infection and use thereof.

Description

A TOPICAL AQUEOUS NANO-DISPERSION COMPOSITION OF ANTIFUNGAL AGENTSAND IMPLEMENTATIONS THEREOFFIELD OF THE INVENTION

[0001] The present invention relates to topical aqueous nano-dispersion composition, in particular relates to topical aqueous nano-dispersion composition comprising antifungal agents entrapped in lipid carriers. The compositions are designed for enhanced skin permeation, resistance prevention, and improved antifungal activity while being free from harmful solvents, and ensuring long-term stability.BACKGROUND OF THE INVENTION

[0002] Fungal infections of the skin are prevalent dermatological conditions affecting all age groups, with common examples including seborrheic dermatitis, athlete’s foot, candidiasis, and pityriasis versicolor. These infections are caused by fungi such as *Malassezia*, *Candida*, and *Tinea*, which initially target the skin surface but can invade deeper layers over time, utilizing skin fatty acids for nourishment. Effective treatment requires direct and sustained delivery of antifungal agents to the site of infection, which is optimally achieved through topical formulations.

[0003] Topical delivery offers higher drug concentration at the infection site, minimizes systemic toxicity, and avoids pre-systemic metabolism. Common topical antifungals include ketoconazole, luliconazole, and clotrimazole. These azole-type agents work by inhibiting the synthesis of ergosterol, a critical component of the fungal cell membrane, via the enzyme lanosterol demethylase. This inhibition results in a compromised and dysfunctional fungal cell membrane. Due to their water-insoluble nature, these antifungals often require micronization to improve solubility and enhance skin delivery. However, micronized formulations face challenges with dose uniformity and reduced active availability.

[0004] Recent advancements in topical drug delivery systems have focused on improving the efficacy and stability of therapeutic agents through nano-dispersions.Conopco Inc. has developed a method for producing oil-continuous nano-emulsions. Their technique involves utilizing two macro emulsions with distinct pH levels: a first macro emulsion at pH 10 to 14 containing an active, and a second macro emulsion at pH 2 to 5 without the active. By mixing and shearing these macro emulsions, they achieve nano emulsions with droplets ranging from 150 to 900 nm, incorporating 0.15 to 5%w / w by weight of the active. This method ensures precise control over pH and particle size, thereby enhancing the delivery and stability of the active.

[0005] US8226965B2, discloses treatment of fungal infections with nanoemulsions featuring droplets smaller than 400 nm. This formulation includes soybean oil, surfactants, ethanol, and antifungal agents such as Bifonazole and Clotrimazole.

[0006] W02019070221 Al provides a luliconazole emulsion with particles smaller than 20 pm. This describes emulsion comprising various excipients like miconazole and isopropyl myristate and a preparation process involving dissolving ingredients in benzyl alcohol and hydrating with other compounds, which may impact the formulation’s performance.

[0007] IN202221004921 A involves nanostructured lipid carriers for posaconazole, aimed at enhancing its dissolution and bioavailability. The stable composition includes solid and liquid lipids, surfactants, and pH adjusters, but the approach does not fully address topical application needs or optimal drug delivery.

[0008] CN1931165A describes an econazole nitrate emulsion designed to treat fungal infections. The preparation method includes mixing, dissolving, and adding water to form the emulsion.

[0009] However there is still a need in the state of art for antifungal compositions to address the limitations of existing compositions, provide high drug entrapment efficiency with improved permeation and resistance prevention.SUMMARY OF THE INVENTION

[0010] In an aspect of the present disclosure, there is provided a topical aqueous nano-dispersion composition comprising: a) at least one antifungal agent in anamount of 1% to 5% by weight; and b) lipid carrier particles, the lipid carrier particles comprising: (i) at least one lipid in an amount of 0.5% to 22% by weight; (ii) at least one solvent in an amount of 1% to 12% by weight; (iii) at least one emulsifier / surfactant in an amount of 1% to 4.5% by weight; (iv) at least one skin permeation enhancer in an amount of 0.1% to 15% by weight; (v) at least one charge modifier in an amount of 0.1% to 3% by weight; and (vi) optionally, at least one transient bio-membrane modulating agent present in an amount of 0% to 10% by weight, wherein the at least one antifungal agent is entrapped within the lipid carrier particles in molecular form.

[0011] In another aspect of the present disclosure, there is provided a process of preparation of the topical aqueous nano-dispersion composition as disclosed herein, the process comprising: (a) preparing a drug phase by: (i) mixing the at least one antifungal agent with the at least one skin permeation enhancer, at least one charge modifier, at least one surfactant / emulsifier, at least one solvent, and optionally the at least one transient bio-membrane modulating agent using a high shear mixer; and (ii) adding the at least one lipid to the mixture of step (i) and homogenizing to obtain a homogeneous drug phase; (b) preparing an aqueous phase by dissolving the at least one emulsifier / surfactant, at least one chelating agent, optionally at least one buffering agent, and optionally at least one preservative in purified water; (c) adding the drug phase to the aqueous phase and homogenizing using high-pressure homogenization at optimized conditions to form a carrier-drug dispersion; (d) optionally preparing a gel phase by dispersing at least one gelling agent in a mixture of at least one humectant / wetting agent and purified water using a high shear mixer -until a uniform gel is formed; (e) optionally slowly adding the carrier-drug dispersion to the gel phase while continuing to mix; (f) optionally adding desired colorants and fragrances; and (g) homogenizing the mixture to obtain the topical aqueous nano-dispersion composition.

[0012] In yet another aspect of the present disclosure, there is provided a method of treating a fungal infection in a subject, comprising topically applying to an affected area of the subject a therapeutically effective amount of the composition as disclosed herein.

[0013] In yet another aspect of the present disclosure, there is provided a method of preventing recurrence of fungal infections in a subject, comprising topically applying to previously affected areas a therapeutically effective amount of the composition as disclosed herein as a prophylactic treatment.

[0014] In one another aspect of the present disclosure, there is provided a method of treating multiple fungal infections simultaneously in a subject, comprising topically applying to multiple affected areas a therapeutically effective amount of the composition disclosed herein, wherein the composition demonstrates broadspectrum antifungal activity.

[0015] In one another aspect of the present disclosure, there is provided a method of treating fungal infections in immunocompromised subjects, comprising topically applying to affected areas a therapeutically effective amount of the composition as disclosed herein, wherein the enhanced drug delivery system provides effective treatment despite compromised immune function.

[0016] In one aspect, the present invention involves the development of a topical aqueous nano-dispersion formulation containing antifungal drugs or APIs and pharmaceutically acceptable topical excipients, including skin penetration enhancers (SPEs) and / or transient bio-membrane modulating agents (TBMAs). This formulation is based on a platform technology "PERMIACTIVE TECHNOLOGY" that enables high entrapment efficiency of the antifungal drug(s) in nano-carrier particles, enhancing drug delivery and providing effective treatment of fungal infections.

[0017] These and other features, aspects, and advantages of the present subject matter will be better understood with reference to the following detailed description and appended claims. This summary is provided to introduce a selection of concepts in a simplified form. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS

[0018] The following drawings form a part of the present specification and are included to further illustrate aspects of the present disclosure. The disclosure may be better understood by reference to the drawings in combination with the detailed description of the specific embodiments presented herein.

[0019] Figure 1 depicts a graphical representation of the effect of TBMA concentration (decyl-rac-glycerol) on zeta potential (mV) of compositions of ketoconazole at initial time point T=0 and after 12M at room temperature, in accordance with an embodiment of the present disclosure.

[0020] Figure 2 depicts a graphical representation of effect of docusate sodium (charge modifier) concentration on zeta potential of compositions of ketoconazole at initial time point T=0 and after 24M at room temperature, in accordance with an embodiment of the present disclosure.

[0021] Figure 3 depicts effect of docusate sodium (charge modifier) on physical (Appearance) dispersion stability of compositions of ketoconazole after 24M storage at room temperature, in accordance with an embodiment of the present disclosure.

[0022] Figure 4 depicts graphical representation of the effect of lipid (type and concentration) on drug entrapment efficiency of compositions of ketoconazole, in accordance with an embodiment of the present disclosure.

[0023] Figure 5 depicts (A) and (B) comparative light microscopic images, and (C) and (D) physical appearance in glass bottles at room temperature of ketoconazole dispersion prepared by homogenizer process (A & C) and high pressure homogenization process (B & D), respectively, in accordance with an embodiment of the present disclosure.

[0024] Figure 6 depicts transmission electron microscopic (TEM) image of ketoconazole topical nano-dispersion composition, in accordance with an embodiment of the present disclosure.

[0025] Figure 7 depicts antifungal activity (MIC Assay) of compositions (A) Control -Ketoconazole solution, (B & C) Examples 2 and 10 ketoconazole nano-dispersions respectively, against Malassezia furfur by Dixon’s Agar Plate Method, in accordance with an embodiment of the present disclosure.DETAILED DESCRIPTION OF THE INVENTION

[0026] Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such steps, features, compositions, and compounds referred to or indicated in this specification, individually or collectively, and any, all combinations of any or more of such steps or features. Definitions

[0027] For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are delineated here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.

[0028] The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

[0029] The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.

[0030] Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of elements or steps but not the exclusion of any other element or step or group of elements or steps.

[0031] The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.

[0032] The term “w / w,” as used herein, refers to percentage by weight, relative to the weight of the total composition, unless otherwise specified.

[0033] The term “emulsifier / surfactant” as used herein are amphiphilic molecules and are thus absorbed in the interface. At the interface, they align themselves such that they reduce the surface or interfacial tension. Surfactants contemplated in the present invention include but are not limited to anionic surfactants, amphoteric surfactants, non-ionic surfactants, and macromolecular surfactants. The surfactants are selected from fatty acid esters of sorbitan (polyol esters / span series), polyoxyl hydrogenated castor oil, polyoxyethylene esters, polysorbates, fatty acid esters, polyglycerol esters, propylene glycol fatty acid esters, sulfate-based surfactants, sulfonate-based surfactants, or combinations thereof. Examples of fatty acid esters of sorbitan include but not limited to polyol esters and span series compounds. Examples of polysorbates series include but not limited to polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, and polysorbate 85. Examples of polyoxyl hydrogenated castor oil include but not limited to polyoxyl 40 hydrogenated castor oil, and polyoxyl 35 hydrogenated castor oil. The surfactants include but not limited to polyoxyl hydrogenated castor oil surfactants, fatty esters of sorbitan, polyoxyethylene esters, poloxamers, fatty acid esters of glycerol, polyglycerol esters, polyethylene glycol esters, propylene glycol fatty esters, sucrose esters, sulfate-type surfactants, sulfonate-type surfactants, salts of fatty acids such as sodium oleate, potassium oleate, sodium stearate, and combinations thereof.

[0034] The term “skin permeation enhancer” or “SPE” as used herein refers to compounds that increase the permeability of the skin to allow drugs or other active compounds to pass through the skin barrier more easily, and SPEs also improve the topical absorption of medications.

[0035] The term “charge modifier” as used herein refers to an ingredient that would alter the surface charge of the compositions. This can influence how the drug or its compositions or its dispersions interacts with the skin and how effectively it penetrates. It can also stabilize the compositions or dispersions. Examples include, anionic charge modifiers: compounds with anionic charge, anionic functional groups, such as sulfate, sulfonate, phosphate, and carboxylates, sodium salts of fatty acids and fatty sulfates, sodium, potassium, or ammonium salts of fatty sulfonates,bile salts, docusate sodium, docusate potassium, sodium dodecyl sulphate, sodium laureth sulphate, sodium oleate, and sodium stearate; Cationic Charge Modifiers: compounds with cationic charge, cationic functional groups, pH-dependent primary, secondary, or tertiary amines, stearyl amine, oleyl amine, DOTAP, benzalkonium chloride, cetyl pyridinium chloride, and quaternary ammonium compounds; Zwitterionic Charge Modifiers: Zwitterionic (ampholytic / amphoteric) compounds have both cationic and anionic centers / charges, zwitterionics have a phosphate anion with an amine or ammonium, such as the phospholipids, phosphatidylserine, phosphatidylethanolamine, sphingomyelins, lauryldimethylamine oxide and myristamine oxide of the tertiary amine oxides structural type and other topically acceptable charge modifiers.

[0036] The term “transient bio-membrane modulating agent” or “TBMA” as used herein refers to ingredients that would temporarily and reversibly alter the structure or function of biological membranes, such as the skin barrier, other biological membranes (fungal membranes), to enhance the absorption of drug and to facilitate drug penetration through the biological membrane. Examples include, C5-C24 alkyl glycerol’s, 1-0-alkyl-sn-glycerols, glycerol ether lipids, their other derivatives and other topically acting TBMAs.

[0037] The term “drug entrapment efficiency” or “DEE” as used herein refers to the percentage of the drug (antifungal agent) successfully entrapped within the carrier particles relative to the total amount of drug used in the formulation process. It is a critical parameter in drug delivery systems, particularly for nano-dispersion formulations or nano-carrier formulations, as it directly impacts drug efficacy and stability. High DEE ensures a substantial portion of the drug reaches the target site, enhancing therapeutic outcomes and reducing drug wastage. High DEE is desirable in topical formulations as it maximizes the active ingredient's delivery to the infection site, improving treatment efficacy and reducing resistance risk. Drug entrapment efficiency is measured by Diafiltration or cross-flow filtration method. Unentrapped free drug in formulation (nano-dispersion) was separated using optimised Diafiltration method (separation technique), using an appropriate molecular weight cut-off membrane, and both ‘Retentate’ & ‘Filtrate’ werecollected separately. The Retentate contains the entrapped drug in nano carrier particle while all un-entrapped free drug will be found in the filtrate. Drug content is estimated in both Retentate and filtrate using validated HPLC method. Following formula was used to calculate the entrapment efficiency (% Drug Entrapment) of nano-dispersion (formulation):% Drag entrapment = Amount of Drug in Retentate X 100Total amount of Ding in Formulation

[0038] The terms “composition(s)”, “formulation(s)”, “dispersion(s)”, “nanodispersion^)” are used interchangeably and refers to composition comprising one or more said components / ingredients as defined herein.

[0039] As used herein, the term "pharmaceutically acceptable salts and derivatives" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, regarded as safe for consumption, acceptable to use through specified route of administration, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit-risk ratio. Several pharmaceutically acceptable ingredients are known in the art and in official publications; for example, Inactive Ingredient database and the United States Pharmacopeia describe the analytical criteria to assess the pharmaceutical acceptability of numerous ingredients of interest.

[0040] As used herein, the terms "preferred" and "preferably" refer to embodiments of the invention that may afford certain benefits under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful and is not intended to exclude other embodiments from the scope of the invention.

[0041] Ratios, concentrations, amounts, and other numerical data may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not onlythe numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.

[0042] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described.

[0043] As discussed in the background, there is a need for antifungal compositions for topical applications with high drug entrapment efficiency. Accordingly the compositions of the present disclosure provides high drug entrapment efficiency, ensuring that the antifungal agents are entrapped in their molecular form within lipid carriers. This high entrapment efficiency is achieved through optimal size of the carrier particles and through a specific weight ratio of excipients relative to the drug (antifungal agents). The composition of the present disclosure comprises at least one excipient such as gelling agents / thickening agents, chelating agents, preservatives, chemical stabilizers, biodegradable polymers, humectant / wetting agents, buffering agents, and combinations thereof. Further, the composition is prepared by a unique process and the process not only enhances the stability of the composition but also ensures that the drug remains in a molecular form, preventing crystallization and improving skin permeability. Furthermore, the composition integrates skin permeation enhancers (SPEs) and transient bio-membrane modulating agents (TBMAs), which transiently open skin and fungal cell membranes, significantly enhancing drug penetration and efficacy. This combination of high entrapment efficiency, precise excipient weight ratios, use of SPEs / TBMAs and a unique process provides a robust and effective solution for treating fungal infections, offering notable improvements over existing technologies. Advantageously, the composition of the present invention is characterized by being alcohol-free (ethanol and isopropanol), thus avoiding the skin dryness and irritation often associated with alcohol-based products, and use oflow surfactant content (NMT 5%w / w) making it suitable for long-term use without causing skin toxicity.

[0044] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition comprising: (a) at least one antifungal agent in an amount of 1% to 5% by weight; and (b) lipid carrier particles, the lipid carrier particles comprising: (i) at least one lipid in an amount of 0.5% to 22% by weight; (ii) at least one solvent in an amount of 1% to 12% by weight; (iii) at least one emulsifier / surfactant in an amount of 1% to 4.5% by weight; (iv) at least one skin permeation enhancer in an amount of 0.1% to 15% by weight; (v) at least one charge modifier in an amount of 0.1% to 3% by weight; and (vi) optionally, at least one transient bio-membrane modulating agent present in an amount of 0% to 10% by weight, wherein the at least one antifungal agent is entrapped within the lipid carrier particles in molecular form.

[0045] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition comprising: (a) at least one antifungal agent in an amount of 1% to 5% by weight; and (b) lipid carrier particles, the lipid carrier particles comprising: (i) at least one lipid in an amount of 0.5% to 22% by weight; (ii) at least one solvent in an amount of 1% to 12% by weight; (iii) at least one emulsifier / surfactant in an amount of 1% to 4.5% by weight; (iv) at least one skin permeation enhancer in an amount of 0.1% to 15% by weight; (v) at least one charge modifier in an amount of 0.1% to 3% by weight; and (vi) at least one transient biomembrane modulating agent present in an amount of 0% to 10% by weight, wherein the at least one antifungal agent is entrapped within the lipid carrier particles in molecular form with a drug entrapment efficiency in the range of 70 to 97%.

[0046] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition comprising: (a) at least one antifungal agent in an amount of 1% to 5% by weight; and (b) lipid carrier particles having an average particle size in a range of 25 nm to 5 pm, the lipid carrier particles comprising: (i) at least one lipid in an amount of 0.5% to 22% by weight; (ii) at least one solvent in an amount of 1% to 12% by weight; (iii) at least one emulsifier / surfactant in an amount of 1% to 4.5% by weight; (iv) at least one skinpermeation enhancer in an amount of 0.1% to 15% by weight; (v) at least one charge modifier in an amount of 0.1% to 3% by weight; and (vi) optionally, at least one transient bio-membrane modulating agent present in an amount of 0% to 10% by weight, wherein the at least one antifungal agent is entrapped within the lipid carrier particles in molecular form.

[0047] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition comprising: (a) at least one antifungal agent in an amount of 1% to 5% by weight; and (b) lipid carrier particles having an average particle size in a range of 25 nm to 5 pm, the lipid carrier particles comprising: (i) at least one lipid in an amount of 0.5% to 22% by weight; (ii) at least one solvent in an amount of 1% to 12% by weight; (iii) at least one emulsifier / surfactant in an amount of 1% to 4.5% by weight; (iv) at least one skin permeation enhancer in an amount of 0.1% to 15% by weight; (v) at least one charge modifier in an amount of 0.1% to 3% by weight; and (vi) optionally, at least one transient bio-membrane modulating agent present in an amount of 0% to 10% by weight, wherein the at least one antifungal agent is entrapped within the lipid carrier particles in molecular form with a drug entrapment efficiency in the range of 70 to 97%.

[0048] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the composition is free from ethanol and has a total surfactant content of not more than 5% by weight.

[0049] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the composition demonstrates enhanced skin permeation ability characterized by: (a) penetration of the antifungal agent to deeper skin layers beyond the stratum comeum; (b) achievement of therapeutic drug concentrations at the site of fungal infection; (c) sustained drug release maintaining therapeutic levels for extended periods; and (d) superior permeation compared to conventional topical antifungal formulations due to the nano-sized lipid carrier particles and the presence of skin penneation enhancers and transient bio-membrane modulating agents. In another embodimentof the present disclosure, wherein the enhanced skin permeati on ability is achieved through: (a) nano-sized lipid carrier particles having a particle size of 25 nm to 350 nm that facilitate transport through skin layers; (b) skin permeation enhancers that temporarily and reversibly reduce stratum corneum barrier properties; (c) transient bio-membrane modulating agents that transiently open both the bio-membranes : skin (helps permeation into deeper layers of skin where fungus is lodged) and fungal cell membranes (further helps to enter into fungi crossing the fungal cell membrane) to effectively kill fungi there by achieving / addressing fungal resistance; and (d) optimized surface charge properties providing favourable skin interaction.

[0050] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the lipid carrier particles have an average particle size in a range of 25 nm to 5 pm. In another embodiment of the present disclosure, wherein the lipid carrier particles have an average particle size in a range of 25 nm to 350 nm.

[0051] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one antifungal agent is entrapped within the lipid carrier particles in molecular form with a drug entrapment efficiency in the range of 70 to 97%.

[0052] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the composition comprises water as a continuous aqueous phase. In another embodiment of the present disclosure, the continuous aqueous phase comprises purified water.

[0053] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one antifungal agent is selected from ketoconazole, luliconazole, clotrimazole, bifonazole, tioconazole, eberconazole, fenti conazole, fluconazole, econazole, miconazole, efinaconazole, oxiconazole, voriconazole, sertaconazole, sulconazole, terbinafine, butenafine, nystatin, naftifine, tavaborole, tolciclate, tolnaftate, ciclopirox, amoroffine, haloprogin, their pharmaceutically acceptable salts or derivatives thereof. In another embodiment of the present disclosure, the antifungal agent is selected from from the group consisting of ketoconazole, luliconazole,clotrimazole, their pharmaceutically acceptable salts and derivatives thereof. In one another embodiment of the present disclosure, the antifungal agent is selected from ketoconazole, luliconazole, or clotrimazole.

[0054] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one lipid is selected from medium chain triglycerides (MCTs), long chain triglycerides (LCTs), fatty acid esters (Ci-Cse), alkanoic acid esters, oils, phospholipids, phosphatidylcholines, lecithin, soybean oil, castor oil, natural oils, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, cholesterol, glyceryl monoesters, triglyceride esters, their derivatives, or combinations thereof. In another embodiment of the present disclosure, the at least one lipid is selected from medium chain triglycerides (MCTs), soybean oil, cetostearyl alcohol, phospholipids, lecithin or combinations thereof.

[0055] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one lipid is selected from medium chain triglycerides (MCT), soybean oil, phospholipids, cetostearyl alcohol, or combinations thereof.

[0056] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one solvent is selected from carboxylic acids, saturated C6-C26 fatty acids, unsaturated C6-C26 fatty acids, phenylcarbinol, polyols, butanol, butylene glycol, di ethylene glycol monoethyl ether, propylene glycol and its derivatives, polyethylene glycol and its derivatives, glycol ethers, aprotic solvents or combinations thereof. In another embodiment of the present disclosure, the aprotic solvents include but not limited to N-methyl pyrrolidone, dimethyl sulfoxide and so on.

[0057] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one solvent is selected from caprylic acid, phenylcarbinol, palmitic acid, stearic acid, polyols, or combinations thereof.

[0058] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least oneemulsifier / surfactant is selected from polyoxyl hydrogenated castor oil surfactants, fatty esters of sorbitan, polyoxyethylene esters, poloxamers, fatty acid esters of glycerol, polyglycerol esters, polyethylene glycol esters, propylene glycol fatty esters, sucrose esters, sulfate-type surfactants, sulfonate-type surfactants, salts of fatty acids, or combinations thereof. In another embodiment of the present disclosure, the salts of fatty acids include but not limited to sodium oleate, potassium oleate, or sodium stearate and so on.

[0059] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one emulsifier / surfactant is selected from polyoxyl -40-hydrogenated castor oil, poloxamers, fatty esters of sorbitan, or combinations thereof.

[0060] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one skin permeation enhancer is selected from monounsaturated omega-9 fatty acids, C4-C24 fatty alcohols, alkyl alcohols including oleyl alcohol and octyl dodecanol, bile salts including sodium deoxycholate, sodium deoxyglycolate, sodium glycocholate, sodium caprate, and sodium taurocholate, glycerol esters, cocoyl capryl ocaprate, dimethylacetamide, terpenes, glycols, aromatic oils, their derivatives, or combinations thereof. In another embodiment of the present disclosure, the aromatic oils include but not limited to lemon oil, clove oil, eucalyptus oil, cinnamon oil, mint oil orange oil, sandalwood oil and so on.

[0061] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one skin permeation enhancer is selected from oleyl alcohol, transcutol, oleic acid, limonene, lemon oil, or combinations thereof.

[0062] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one charge modifier is selected from sodium alkyl ether sulfates, sodium dodecyl sulfate, other topically acceptable anionic / cationic / zwitterionic charge modifiers, or combinations thereof.

[0063] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one charge modifier is selected from docusate sodium, sodium dodecyl sulfate, or combinations thereof.

[0064] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one transient bio-membrane modulating agent is selected from C5-C24 alkyl glycerols or 1-O-alkyl-sn-glycerols, glycerol ether lipids, their derivatives, or combinations thereof.

[0065] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one transient bio-membrane modulating agent is selected from 1-o-dodecyl-rac- glycerol, 1-o-decyl-rac-glycerol, or combinations thereof.

[0066] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the antifungal agent and solvent are in a weight ratio range of 1 :0.2 to 1 : 12.

[0067] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the antifungal agent and lipid are in a weight ratio range of 1 :0.1 to 1 :22.

[0068] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the antifungal agent and transient bio-membrane modulating agent are in a weight ratio range of 1 :0.02 to 1 : 10.

[0069] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the antifungal agent and charge modifier are in a weight ratio range of 1 :0.02 to 1 :3.

[0070] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the antifungal agent and surfactant are in a weight ratio range of 1 :0.2 to 1 :4.5.

[0071] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the antifungal agent and skin permeation enhancer are in a weight ratio range of 1 :0.02 to 1 : 15.

[0072] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the composition further comprises an excipient selected from at least one gelling agent / thickening agent, at least one chelating agent, at least one preservative, at least one chemical stabilizer, at least one biodegradable polymer, at least one humectant / wetting agent, at least one buffering agent, and combinations thereof.

[0073] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one gelling agent / thickening agent is present in an amount of 0% to 3% by weight; the at least one chelating agent is present in an amount of 0.01% to 0.1% by weight; the at least one preservative is present in an amount of 0% to 2% by weight; the at least one chemical stabilizer is present in an amount of 0.01% to 3% by weight; the at least one biodegradable polymer is present in an amount of 0% to 5% by weight; the at least one humectant / wetting agent is present in an amount of 0% to 5% by weight; and the at least one buffering agent is present in an amount of 0.01% to 1% by weight.

[0074] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one gelling agent / thickening agent is selected from cellulose derivatives, hydroxypropyl methylcellulose (HPMC), methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carbomers, polymeric gelling agents, gelatin, povidones, natural polymers, xanthan gum, guar gum, carrageenan, alginates, gellan gum, chitosans, polyacrylamides, waxes, silicas, clays, or combinations thereof. In another embodiment of the present disclosure, wherein the gelling agent is selected from natural polymers, xanthan gum, or combinations thereof.

[0075] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one chelating agent is selected from disodium EDTA, tetrasodium EDTA, calciumdisodium EDTA, ethylene glycol tetraacetic acid (EGTA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), phosphonic acid derivatives, or combinations thereof. In another embodiment of the present disclosure, wherein the chelating agent is selected from disodium EDTA, tetrasodium EDTA, or combinations thereof.

[0076] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one preservative is selected from potassium sorbate, sodium sorbate, sorbic acid, sodium benzoate, benzoic acid, methylparaben, ethylparaben, propylparaben, butylparaben, phenoxyethanol, benzyl alcohol, chlorhexidine, benzalkonium chloride, cetylpyridinium chloride, or combinations thereof. In another embodiment of the present disclosure, wherein the preservative is selected from sodium sorbate, potassium sorbate, or combinations thereof.

[0077] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one chemical stabilizer is selected from alpha-tocopherol, tocopherol acetate, mixed tocopherols, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tertiary butylhydroquinone (TBHQ), ascorbic acid, ascorbyl palmitate, sodium ascorbate, sodium metabisulfite, sodium sulfite, citric acid, their derivatives, or combinations thereof. In another embodiment of the present disclosure, wherein the chemical stabilizer is selected from alphatocopherol, tocopherol acetate, mixed tocopherols, propyl gallate, butylated hydroxytoluene (BHT), or combinations thereof.

[0078] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one biodegradable polymer is selected from polyvinylpyrrolidones (PVPs), polyethylene glycols (PEGs), polyvinyl alcohol (PVA), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), chitosan, hyaluronic acid, or combinations thereof. In another embodiment of the present disclosure, wherein the biodegradable polymer is selected frompolyvinylpyrrolidones (PVPs), polyethylene glycols (PEGs), polyvinyl alcohol (PVA), or combinations thereof.

[0079] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the at least one buffering agent is selected from citric acid, sodium citrate, phosphoric acid, sodium phosphate, potassium phosphate, acetic acid, sodium acetate, triethanolamine, diethanolamine, monoethanolamine, tri s(hydroxymethyl)aminom ethane (Tris), sodium hydroxide, potassium hydroxide, hydrochloric acid, or combinations thereof. In another embodiment of the present disclosure, wherein the buffering agent is selected from of citric acid, sodium citrate, phosphoric acid, sodium phosphate, triethanolamine, or combinations thereof.

[0080] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the composition has an average particle size of in a range of 60 to 350 nm; a poly dispersity index (PDI) of less than 0.5; and a zeta potential ranging from -45 mV to +4 mV.

[0081] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the antifungal drug entrapped within the lipid carrier has a specific surface area of not less than 750 m2 / kg.

[0082] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the composition is stable when stored for up to 2 years at 25°C ± 2°C / 60% RH ± 5% RH.

[0083] In an embodiment of the present disclosure, there is provided a topical aqueous nano-dispersion composition as disclosed herein, wherein the composition is in the form of a dispersion, emulsion, gel, lotion, cream, ointment, spray, or liquid.

[0084] In an embodiment of the present disclosure, there is provided a process of preparation of the topical aqueous nano-dispersion composition, the process comprising: (a) preparing a drug phase by: (i) mixing the at least one antifungal agent with the at least one skin permeation enhancer, at least one charge modifier, at least one surfactant / emulsifier, at least one solvent, and optionally the at least one transient bio-membrane modulating agent using a high shear mixer; and (ii)adding the at least one lipid to the mixture of step (i) and homogenizing to obtain a homogeneous drug phase; (b) preparing an aqueous phase by dissolving the at least one emulsifier / surfactant, at least one chelating agent, optionally at least one buffering agent, and optionally at least one preservative in water; (c) adding the drug phase to the aqueous phase and homogenizing using high-pressure homogenization at optimized conditions to form a carrier-drug dispersion; (d) optionally preparing a gel phase by dispersing at least one gelling agent in a mixture of at least one humectant / wetting agent and water using a high shear mixer -until a uniform gel is formed; (e) optionally slowly adding the carrier-drug dispersion to the gel phase while continuing to mix; (f) optionally adding desired colorants and fragrances; and (g) homogenizing the mixture to obtain the topical aqueous nanodispersion composition.

[0085] In an embodiment of the present disclosure, there is provided a process of preparation of the topical aqueous nano-dispersion composition as disclosed herein, wherein the high-pressure homogenization in step (c) is conducted at a pressure in a range of 8000-15000 psi for 3-7 cycles at a temperature in a range of 15-30°C. In another embodiment of the present disclosure, wherein the high-pressure homogenization in step (c) is conducted at a pressure in a range of 8000-15000 psi for 3-7 cycles at a product temperature in a range of 15-30°C and a flow rate from 0.05L to 25L per minute depending on scale of manufacturing. In another embodiment of the present disclosure, wherein the high-pressure homogenization in step (c) is conducted at a pressure in a range of 8000-12000 psi for 3-6 cycles at a product temperature in a range of 18-20°C and a flow rate from 130 to 170 mL per minute.

[0086] In an embodiment of the present disclosure, there is provided a process of preparation of the topical aqueous nano-dispersion composition as disclosed herein, wherein the high shear mixer used in steps (a)(i) and (d) operates at a tip speed in the range of 1-30 m / s.

[0087] In an embodiment of the present disclosure, there is provided a process of preparation of the topical aqueous nano-dispersion composition as disclosed herein,wherein the aqueous phase preparation in step (b) includes adjusting the pH to a range of 4.5-7.5 using at least one buffering agent.

[0088] In an embodiment of the present disclosure, there is provided a process of preparation of the topical aqueous nano-dispersion composition as disclosed herein, wherein the homogenization in step (g) is conducted using equipment selected from rapid mixers, anchor mixer, high-shear / high-speed homogenizers, or high-pressure homogenizers. In another embodiment of the present disclosure, wherein the homogenization in step (g) is conducted using high-shear / high-speed homogenizers, or high-pressure homogenizers.

[0089] In an embodiment of the present disclosure, there is provided a method of treating a fungal infection in a subject, the method comprises topically applying to an affected area of the subject a therapeutically effective amount of the composition as disclosed herein.

[0090] In an embodiment of the present disclosure, there is provided a method of treating a fungal infection in a subject as disclosed herein, wherein the fungal infection is selected from the group consisting of dermatophytosis, candidiasis, tinea infections, Malassezia infection, seborrheic dermatitis, and combinations thereof.

[0091] In an embodiment of the present disclosure, there is provided a method of treating a fungal infection in a subject as disclosed herein, wherein the composition is applied once or twice daily to the affected area.

[0092] In an embodiment of the present disclosure, there is provided a method of treating a fungal infection in a subject as disclosed herein, wherein the subject is a human.

[0093] In an embodiment of the present disclosure, there is provided a method of preventing recurrence of fungal infections in a subject, comprising topically applying to previously affected areas a therapeutically effective amount of the composition as disclosed herein as a prophylactic treatment.

[0094] In an embodiment of the present disclosure, there is provided a method of treating multiple fungal infections simultaneously in a subject, comprising topically applying to multiple affected areas a therapeutically effective amount of thecomposition as disclosed herein, wherein the composition demonstrates broadspectrum antifungal activity.

[0095] In an embodiment of the present disclosure, there is provided a method of treating fungal infections in immunocompromised subjects, comprising topically applying to affected areas a therapeutically effective amount of the composition as disclosed herein, wherein the enhanced drug delivery system provides effective treatment despite compromised immune function.

[0096] In an embodiment of the present disclosure, there is provided topical use of the composition as disclosed herein for treating fungal infections in immunocompromised subjects.

[0097] In an embodiment of the present disclosure, there is provided topical use of the composition as disclosed herein for treating multiple fungal infections simultaneously in a subject.

[0098] In an embodiment of the present disclosure, there is provided topical use of the composition as disclosed herein for preventing recurrence of fungal infections in a subject.

[0099] In an embodiment of the present disclosure, there is provided topical use of the composition as disclosed herein as a medicament for treating and / or preventing fungal infections.

[0100] In an embodiment of the present disclosure, there is provided use of the composition as disclosed herein in the manufacture of a medicament for the treatment and prevention of dandruff.

[0101] In an embodiment of the present disclosure, there is provided use of the composition as disclosed herein for treating athlete's foot, ringworm, candidiasis, jock itch, and tinea versicolor, tine corporis caused by dermatophytes such as Trichophyton rubrum, Microsporum gypseum, and Epidermophyton floccosum.

[0102] Although the subject matter has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the subject matter, will become apparent to persons skilled in the art upon reference to the description of the subject matter. It is thereforecontemplated that such modifications can be made without departing from the spirit or scope of the present subject matter as defined.EXAMPLES

[0103] The disclosure will now be illustrated with following examples, which is intended to illustrate the stable of disclosure and not intended to take restrictively to imply any limitations on the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the disclosed methods and compositions, the exemplary methods, devices and materials are described herein. It is to be understood that this disclosure is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary.EXAMPLE IPreparation of the composition

[0104] The composition according to the invention was prepared by preparing drug phase, aqueous phase and optionally gel phase, and mixing said phases by homogenizing under high pressure.

[0105] In an example, the process of preparing the composition comprises preparing a drug phase by mixing the at least one antifungal agent with the at least one skin permeation enhancer, at least one charge modifier, at least one surfactant / emulsifier, at least one solvent, and optionally the at least one transient biomembrane modulating agent using a high shear mixer; and adding the at least one lipid to the mixture of step (i) and homogenizing to obtain a homogeneous drug phase. Followed by preparing an aqueous phase by dissolving the at least one emulsifier / surfactant, at least one chelating agent, optionally at least one buffering agent, and optionally at least one preservative in water; and adding the drug phase to the aqueous phase and homogenizing using high-pressure homogenization at optimized conditions to form a carrier-drug dispersion. A gel phase was thenprepared by dispersing at least one gelling agent in a mixture of at least one humectant / wetting agent and water or purified water using a high shear mixer -until a uniform gel is formed; and optionally slowly adding the carrier-drug dispersion to the gel phase while continuing to mix; and optionally adding desired colorants and fragrances; and homogenizing the mixture to obtain the topical aqueous nanodispersion composition.Prepartion of compositions 1 to 5 - Examples 1 to 5

[0106] Drug Phase or lipid phase: Ketoconazole (antifungal agent) along with caprylic acid (solvent), oleic acid (Example 4, skin permeation enhancer), phenyl carbinol(solvent), alpha-tocopherol (chemical stabilizer), propyl gallate(chemical stabilizer), and docusate sodium (charge modifier, Example 2, 3, 4 & 5) were mixed together using a high shear mixer. Oleyl alcohol (skin permeation enhancer), poloxamer 407(emulsifier / surfactant), and medium chain triglycerides (MCT, lipid) were then added and mixed to obtain the drug phase.

[0107] Aqueous Phase: Polyoxyl 40 hydrogenated castor oil (Surfactant), docusate sodium (charge modifier, Example 1), disodium EDTA(chelating agent), and potassium sorbate (preservative) were dissolved in purified water to obtain the aqueous phase. The drug phase and aqueous phase were high-pressure homogenized (High-pressure homogenization at 8000-12000 psi for 3-6 cycles with a flow rate of 130-170 ml / min) at 18 to 20°C to obtain a carrier-drug dispersion.

[0108] Gel Phase: Xanthan gum (gelling agent) was dispersed in glycerol(humectant / wetting agent) and purified water and mixed using a high shear mixer to obtain the uniform gel phase. The carrier-drug dispersion (Example 3 and 4) was added slowly to this gel-phase while continuing mixing. Appropriate colour and fragrance were added, and the contents were mixed / homogenized until a homogeneous composition was obtained.

[0109] Table 1 provides the components and their corresponding weight % taken to obtain compositions 1 to 5 (Examples 1 to 5).Table 1: Examples 1 to 5

[0110] Similarly examples 6 to 13 (E.g. 6 to E.g.13) were prepared by varying concentration of transient bio-membrane modulating agent (TMBA, 1-o-decyl-rac- glycerol / l-o-dodecyl-rac-glycerol) and the corresponding compositions are shown in Table 2.Table 2: Examples 6 to 13Process of Preparation for Examples 6 to 13:

[0111] Drug Phase (Lipid phase): Ketoconazole along with caprylic acid, phenyl carbinol, alpha-tocopherol, propyl gallate, docusate sodium, 1-o-decyl-rac-glycerol or 1-o-dodecyl-rac-glycerol, oleyl alcohol, pol oxamer 407, and MCT were mixed together using a high shear mixer to obtain the drug phase.

[0112] Aqueous Phase: Polyoxyl 40 hydrogenated castor oil, disodium EDTA, and potassium sorbate were dissolved in purified water to obtain the aqueous phase. Thedrug phase and aqueous phase were high-pressure homogenized (High-pressure homogenization at 8000-12000 psi for 3-6 cycles with a flow rate of 130-170 ml / min) at 18 to 20°C to obtain a carrier-drug dispersion.

[0113] Gel Phase: Xanthan gum was dispersed in glycerol and purified water and mixed using a high shear mixer to obtain the uniform gel phase. The carrier-drug dispersion was added slowly to this gel-phase while continuing mixing. The contents were mixed / homogenized until a homogeneous formulation was obtained.Preparation of Examples 14 to 46

[0114] Similarly compositions 14 to 46 were prepared by the process as described above. Ketoconazole along with Caprylic acid (Except in E.g. 14), Phenyl carbinol (Except in E.g. 18), Alpha Tocopherol, propyl gallate and Docusate sodium (Except in E.g. 23), were mixed together using high speed mixer. Oleyl alcohol (except in E.g. 31), Poloxamer 407 (Except in E.g.44) and MCT (Except in E.g. 36), Soy bean oil (E.g. 41, 42 and 43) were added and mixing continued to yield a clear drug phase. Aqueous phase and Dispersion preparation method is same as given in Examples 1 to 5. Tables 3 to 9 provide the components of the compositions with corresponding weight % of the components.Table 3: Examples 14 to 18Table 4: Examples 19 to 22Table 5: Examples 23 to 30Table 6: Examples 31 to 35Table 7: Examples 36 to 40Table 8: Examples 41 to 43Table 9: Examples 44 to 46Preparation of Examples 47 to 58:

[0115] Similar to Examples 1 to 5, the compositions 47 to 58 were prepared. Ketoconazole along with Oleic acid (Except in E.g. 47, 48), Caprylic acid (Except in E.g. 55, 56, 57, 58), Phenyl carbinol, Alpha Tocopherol, propyl gallate, Palmitic acid (E.g. 47), Stearic acid (E.g. 48) and Docusate sodium were mixed together using high speed / shear mixer. Oleyl alcohol (E.g. 49, 55, 58), Poloxamer 407 and MCT were added and mixing continued to yield a clear drug phase. Aqueous phase, Dispersion preparation and Gel phase method is same as given in Example 1 to 5. Tables 10 and 11 provide the components of the compositions with corresponding weight % of the components.Table 10: Examples 47 and 48Table 11: Examples 49 to 58Preparation of Examples 59 and 60:

[0116] Preparation method of compositions 59 and 60 are same as given for Examples 14 to 46. Method of preparation of gel phase is similar as given for Examples 1 to 5.Table 12: Examples 59 and 60Preparation of Examples 61 to 63:

[0117] Ketoconazole along with caprylic acid, phenyl carbinol, alpha tocopherol (except in Example 63), butylated hydroxy toluene (except in Example 63), propyl gallate and docusate sodium were mixed together using high speed / shear mixer, oleyl alcohol, poloxamer 407 and MCT were added and mixing continued to yield a clear drug phase. Aqueous phase was prepared by adding polyoxyl 40 hydrogenated castor oil, potassium sorbate, disodium EDTAto weighed quantity of Purified water and mixed. Dispersion preparation method is same as given in Example 1 to 5.Table 13: Examples 61 to 63Preparation of Examples 64 to 69:

[0118] Drug phase: Luliconazole along with caprylic acid, phenyl carbinol, alpha tocopherol, propyl gallate, docusate sodium, 1-o-dodecyl-rac-glycerol (example 67, 68 and 69) and mixed using high shear mixer, oleyl alcohol, poloxamer 407 and met were added and mixed to obtain drug phase.

[0119] Aqueous phase: Polyoxyl 40 hydrogenated castor oil, disodium edta and potassium sorbate (except in e.g. 66) were dissolved in purified water to obtain aqueous phase, drug phase and aqueous phase were together homogenized (high pressure homogenization at 8000-12000psi pressure for 3-6 cycles with a flow rate of 130-170ml / min) at 18 to 20°c temperature to obtain carrier-drug dispersion.

[0120] Xanthan gum was dispersed in glycerol and purified water and mixed using high shear mixer to obtain gel phase. Carrier-drug dispersion (Example 65, 66, 67) was added slowly to this gel-phase whilst continuing mixing. Appropriate fragrance was added, and the contents were mixed / homogenized until the homogeneous formulation (Final Product) was obtained.Table 14: Examples 64 to 69Preparation of Examples 70 to 76: Preparation method of Examples 70 to 76 is same as given for Examples 64 to 69 and details of the compositions are shown in Tables 15 to 17.Table 15: Examples 70 to 72Table 16: Examples 73 and 74Table 17: Examples 75 to 76Preparation of Example 77 to Example 80:

[0121] Drug phase: Luliconazole along with caprylic acid (except in E.g. 80), phenyl carbinol, alpha Tocopherol, propyl gallate, docusate sodium, stearic acid (E.g. 77), palmitic acid (E.g. 78) and oleic acid (E.g. 79, 80) were added and mixed using high shear mixer. Oleyl alcohol, poloxamer 407 and MCT were added and mixed to obtain drug phase.

[0122] Aqueous phase: Polyoxyl 40 hydrogenated castor oil, disodium EDTA and potassium sorbate were dissolved in purified water to obtain aqueous phase.

[0123] Preparation method of Dispersion and gel are same as that of given for E.g. 64 to 69. Table 18 provides the components and their corresponding weight % taken to obtain compositions 77 to 80.Table 18: Examples 77 to 80General method of preparation for Examples 81 to 82:

[0124] Clotrimazole, phospholipid 90G / lecithin, phenylcarbinol, BHT and cetostearyl alcohol, oleic acid, Lemon oil / Limonene, soybean oil and Oleyl alcohol (Example 82) were mixed together using high shear mixer to obtain drug phase. Tween 80, glycerol, sodium dodecyl sulphate (Example 81), triethanolamine (Example 81), transcutol (Example 82) and EDTA (Example 82) were dissolved in purified water to obtain aqueous phase. Drug phase and aqueous phase were together homogenized (High pressure Homogenization at 8000-12000psi pressure for 3-6 cycles with a flow rate of 130-170ml / min) at 18 to 20°C temperature to obtain the carrier-drug dispersion and thus the composition. Table 19 provides thecomponents and their corresponding weight % taken to obtain compositions 81 to82.Table 19: Examples 81 and 82EXAMPLE II

[0125] The prepared compositions were analyzed for particle size, zeta potential and drug entrapment efficiency. Particle size was measured using Zetasizer (Malvern, UK) or Mastersizer 3000 (Malvern, UK), Zeta Potential was measured using Zetasizer (Malvern, UK) and Drug Entrapment Efficiency was tested using optimised diafiltration technique using appropriate ultrafiltration membranes and drug was analysed using fit-for-purpose HPLC method. The results are tabulated below in Tables 20 to 54.Table 20: Particle size, Zeta potential and Entrapment data of Topical Compositions of Ketoconazole (Example 1 to 5)Table 21: Particle size, Zeta potential and % drug Entrapment data of TopicalCompositions of Ketoconazole (Examples 6 to 9)Table 22: Particle size, Zeta potential and %w / w Drug entrapment ofTopical Compositions of Ketoconazole (Examples 10 to 13)

[0126] Figure 1 depicts the effect of TBMA concentration (decyl-rac-glycerol) on Zeta Potential (ZP) of the compositions (Nano dispersion). Increase in Decyl-rac- glycerol from 0% to 1% (E.g. 2, 10 and 11) resulted in increase in ZP (Solid-line) and with further increase in concentration of decyl-rac-glycerol the ZP slightlydecreased and there after it remained unchanged. Similar ZP trend was observed in compositions (nano-dispersion) even after 12M storage at room temperature (dotted line), where in ZP values (12M) are similar to that of initial ZP values clearly indicated the surface orientation of TBMA.Table 23: Particle size, Zeta potential and %w / w Drug entrapment ofTopical Compositions of Ketoconazole at T=0 (Examples 14 to 18)Table 24: Particle size, Zeta potential and %w / w Drug entrapment of Topical Compositions of Ketoconazole at Initial time point (T=0) (Examples 19 to 22)

[0127] From Table 23 and Table 24 it could be observed that the composition Examples 14 and 19 without any skin permeation enhancer was recrystallized and the composition Examples 18 and 22 comprising higher amount of solvent exhbited creaming after 10 days. Thus, to maintain physical stability it is essential that the composition comprises components in said weight ranges as disclosed herein.Table 25: Effect of Docusate sodium concentration (charge modifier) on Particle size, Zeta potential and Physical appearance / stability (after 24Months at room temperature) of the dispersion for topical compositions of ketoconazole (Examples 2, 23 to 30)

[0128] From Table 25, it could be determined that charge modifiers played significant role in stabilizing the composition and the weight % in the range of 0.1 to 3% was found to be critical for prolonged stability and enhanced performance.

[0129] Figure 2 depicts initial (T=0) Zeta potential of topical (nano-dispersion) formulations which changed from +2.623mV (E.g. 23: with no docusate sodium) to -40.2mV (Example 30: with 5.0% docusate sodium), out of which formulations (nano-dispersions) with 0.15% (E.g. 2), 0.3% (E.g. 27), 0.6% (E.g. 28) and 3.0% (E.g. 29) docusate sodium were found to be ‘stable’ when stored at room temperature for 24 months and these compositions (nano-dispersions) have shown similar Zeta potential values as that of T=0 values, suggested the critical role of docusate sodium (charge modifier) and its concentration on long-term physical stability via surface charge stabilization of particles in these topical compositions.

[0130] Figure 3 depicts effect of docusate sodium (charge modifier) on physical (appearance) dispersion stability of topical compositions of ketoconazole after 24M storage at room temperature. Concentration of docusate sodium was varied from 0% to 5%w / w (E.g. 2, 23 to 30). Figure 3 images show clear phase separation in nanodispersion compositions (Examples: 23, 24, 25 and 30) and creaming in Example 26 after 24 months storage at room temperature, whereas nano-dispersion compositions (Examples: 2, 27, 28, 29) were found to be ‘stable’ and uniformly dispersed even after 24Months storage at room temperature, suggested the critical role of docusate sodium (charge modifier) and its concentration on the long-term physical stability of topical nano-dispersion compositions.Table 26: Particle size, Zeta potential and %w / w Drug entrapment of Topical Compositions of Ketoconazole at Initial time point (T=0) (Example 31 to 35)

[0131] The composition Example 31 prepared without skin permeation enhancer exhibited phase separation after 12 hours, thereby confirmed the critical role of skin permeation enhancer in the stability of the compositions in addition to its role in skin permeation.Table 27: Particle size, Zeta potential and %w / w Drug entrapment of TopicalCompositions of Ketoconazole at Initial time point (T=0) (Example 36 to 40)

[0132] Also the composition Example 36 prepared without lipid was found unstable and showed phase separation after 12 hours.Table 28: Particle size, Zeta potential and %w / w Drug entrapment of Topical Compositions of Ketoconazole at Initial time point (T=0) (Example 41 to 43)

[0133] Figure 4 depicts graphical representation of the effect of lipid (type and concentration) on percent drug entrapment efficiency of topical compositions of ketoconazole (Examples: 36 to 43). Figure 4 shows the increase in % drug (ketoconazole) entrapment from 65.0% to 87.0% with increase in MCT oil concentration from 0% to 5% followed by slight decline in entrapment from 87.0% to 74.0% with further increase in MCT concentration from 5% to 22% (solid-line). The dotted-line shows slight increase in % drug entrapment from 82% to 84% with increase in Soybean oil concentration from 5% to 7.5% and slight decrease in % drug entrapment to 80% with further increase in soybean oil concentration to 10%.The results suggested the critical role of lipid and concentration on drug entrapment efficiency of topical compositions of ketoconazole.Table 29: Particle size, Zeta potential and %w / w Drug entrapment of Topical Compositions of Ketoconazole at Initial time point (T=0) (Example 44 to 46)Table 30: Particle size, Zeta potential and %w / w Drug entrapment of Topical Compositions of Ketoconazole at Initial time point (T=0) (Example 47 and 48)Table 31: Particle size, Zeta potential and %w / w Drug entrapment of Topical Compositions of Ketoconazole at Initial time point (T=0) (Example 49 to 58)(Oleic acid concentration effect with and without caprylic acid)Table 32: Particle size and Zeta potential of Topical Compositions of Ketoconazole at Initial time point (T=0) (Example 59 to 60)Table 33: Particle size, Zeta potential and %w / w Drug entrapment of Topical Compositions of Ketoconazole at Initial time point (T=0) (Example 61 to 63)Table 34: Stability data of Ketoconazole Topical Nano Formulation (Example 3) at Accelerated Conditions (40°C / 75%RH) up to 6M and at 25°C / 60%RH for up to 24M: Bench-Scale batch data.Table 35: Stability data of Example 3 at Accelerated Conditions (40°C / 75%RH) up to 6M and at 25°C / 60%RH for up to 24M: Pilot-Lab ScaleTable 36: Stability data of Ketoconazole Topical Nano Formulation [Example 11 (Finished gel product)] at Accelerated Condition (40°C / 75%RH) up to 6M and at 25°C / 60%RH for up to 24MTable 37: Stability data of Ketoconazole Topical Nano Formulation (Example 4) at Accelerated Conditions (40°C / 75%RH) for up to 6 months and up to 24M at 25°C / 60%RH.Table 38: Stability data of Ketoconazole Topical Nano Formulation (Example 49) at Accelerated Conditions for up to 3 months at 40°C / 75%RH and 25°C / 60%RH.Table 39: Stability data of Ketoconazole Topical Nano Formulation (Example 59, Finished Gel product) at Accelerated Conditions (40°C / 75%RH) for up to 6 months and up to 12M at 25°C / 60%RH.Table 40: Stability data of Luliconazole Topical nano Formulation (Example 65) for up to 6 months at 40°C / 75%RH.Table 41: Stability data of Luliconazole Topical nano Formulation (Example 65) for up to 24M at 25°C / 60%RH and 30°C / 75%RH.Table 42: Stability data of Luliconazole Topical nano Formulation (Example 66) for up to 6months at 40°C / 75%RH and 25°C / 60%RH.Table 43: Stability data of Luliconazole Topical nano Formulation (Example 67) for up to 6 months at 40°C / 75%RH.Table 44: Stability data of Luliconazole Topical nano Formulation (Example 67) for up to 24M at 30°C / 75%RH & 25°C / 60%RH.Table 45: Particle size and Zeta potential of Topical Compositions ofLuliconazole at Initial time point (T=0) (Example 67 to 69).Table 46: Particle size and Zeta potential of Topical Compositions ofLuliconazole at Initial time point (T=0) (Example 70 to 72)Table 47: Particle size, Zeta potential and %w / w Drug entrapment of TopicalCompositions of Luliconazole at Initial time point (T=0) (Example 73 to 74)Table 48: Particle size, Zeta potential and %w / w Drug entrapment of TopicalCompositions of Luliconazole at Initial time point (T=0) (Example 75 to 76)Table 49: Particle size, Assay and %w / w Drug entrapment of Topical Compositions of Luliconazole for up to 3 / 6 months at 40°C / 75%RH (Example 77 to 80)Table 50: Particle size distribution at T=0 (Initial time point) of Topical Compositions of Clotrimazole (Example 81 and 82).

[0134] The above illustrated examples of topical compositions of ketoconazole revealed the effect of various components (such as skin permeation enhancers, charge modifiers, surfactants), their weight %, process of preparation and the effect on particle size, zeta potential, and drug entrapment efficiency. Drug entrapment efficiency varied widely, with values ranging from 70.0% to 97.0%, and few compositions such as 14, 18, 19, 22 to 26, 30, 31, 36, 44 and 71 that are outside of the invention showed recrystallization or phase separation over time. Further, it could be inferred that the inclusion of transient bio-membrane modulating agents (TBMAs) and different ratios of such agents also affected the particle size and improved drug entrapment efficiency.

[0135] For luliconazole topical nano-formulations (Examples 65 to 67) with and without TBMAs, stability data (at Accelerated & Long-term ICH conditions) indicated that particle size, drug entrapment, drug-assay, pH, viscosity - remainedwell within acceptable limits across different storage conditions. Notably, formulations with higher initial drug entrapment and lower particle sizes showed better long-term stability. Additionally, the examples revealed the significance of components, excipients, concentrations, weight ratios with respect to particle size, PDI, zeta potential, and drug entrapment.EXAMPLE IIIVarying process of preparation of compositions

[0136] The composition (Example 2) was prepared using different processes such as by hand mixing, using lab stirrer, homogenizer or by high pressure homogenization as shown in Table 51 below. The obtained compositions were tested and the results as shown in Tables 52, 53 and 54. The observations confirmed that high pressure homogenization resulted in stable dispersion and was appropriate for preparing compositions of the present invention.Table 51: Ketoconazole composition (Example 2) prepared using different processes:composition (Example 2), prepared using different processes at T=0 (At RT immediately after preparation): Measured Using Master Sizer 3000.Table 53: Particle size distribution and surface area of Ketoconazole composition (Example 2, with HPH Process) measured using Master Sizer 3000 at 25°C / 75%RH for up to 22 MonthsTable 54: Particle size distribution of Ketoconazole composition (Example 2, with HPH Process) measured using Zeta Sizer at 25°C / 75%RH for up to 22 Months.

[0137] Further, the composition (Example 2) prepared via different processes showed significant differences in product characteristics. Hand mixing and labstirring produced coarse dispersions with noticeable phase separation within minutes to hours, while high shear homogenization resulted in a fine dispersion with phase separation occurring after 24 hours. The high-pressure homogenization (HPH) process with set optimized parameters, yielded a colloidal, semi-transparent, uniform dispersion that maintained stability for 22 months at room temperature, without phase separation.

[0138] The particle size distribution (PSD) and specific surface area measurements (by Zetasizer and Mastersizer 3000) highlighted that high-pressure homogenization (HPH) process provided the smallest particle sizes (D10: 0.0244 pm, D50: 0.0475 pm, D90:0.0911 pm) and largest surface area (136,500 m2 / kg), compared to larger particle sizes and lower surface areas from other processes. Over 22 months at 25°C / 60%RH, the HPH-processed formulation showed minimal changes in particle size and specific surface area, with a slight increase in particle size from 103.6 nm to 111.2 nm and a decrease in specific surface area from 136,500 m2 / kg to 110,300 m2 / kg.

[0139] Figure 5A depicts light microscopic image of Example 2 prepared using High speed / shear homogenizer, it showed large particles of micrometre size [Particle size: D (90) = 4.75 pm, Measured at T=0 by Malvern Mastersizer 3000], Figure 5B depicts light microscopic image of Example 2 prepared using High pressure homogenizer optimised process, no particle was visible on the image as very small particles of nanometre size range were formed which were out of visible range of light microscope [Particle size: D(90) = 0.0911 pm, Measured at T=0 by Malvern Mastersizer 3000],

[0140] Figure 5C depicts physical appearance (in glass bottle) of Example 2 prepared using high speed / shear homogenizer, phase separation (physical instability) was observed after 24 hours at room temperature. Figure 5D depicts physical appearance (in glass bottle) of Ketoconazole dispersion formulation (Example 2) prepared using High pressure homogenizer optimised process, uniform colloidal dispersion is formed (no phase separation or any physical instability wasobserved) even after 22 months when stored at room temperature. Figure 6 depicts electron microscopic image (TEM) of composition (Example 2).EXAMPLE IVAntifungal Activity (MIC / MFC Assay)

[0141] Antifungal Activity (MIC / MFC Assay) of the prepared compositions (Example 2 and Example 10) against Malassezia furfur was determined by Dixon’s Agar Plate Method. Malassezia furfur is lipodependent yeast like fungus that causes superficial mycoses such as pityriasis versicolor and dandruff. Malassezia furfur is streaked horizontally at the center of Dixons agar plate.

[0142] As shown in Figure 7, at 300nM concentration, when compared to control i.e., ketoconazole solution in dimethyl sulfoxide [Figure 7A] which showed growth, both the compositions according to the invention: Example 2 [Figure 7B] and Example 10 [Figure 7C] showed the consistent growth inhibition of Malassezia furfur, and the antifungal activity (growth inhibition) of Example 10 was found better than that of Example 2. ‘Positive control’ plate was inoculated with Malassezia furfur but without ketoconazole (Drug).

[0143] Thus, the topical aqueous nano-dispersion compositions of antifungal agents described in this invention are suitable for the treatment of various fungal infections, providing enhanced efficacy and safety for patients. The compositions are designed to be user-friendly, with minimal side effects, making them ideal for widespread clinical use.ADVANTAGES OF THE PRESENT DISCLOSURE

[0144] The compositions of the present invention exhibit enhanced drug delivery efficiency: The nano-dispersion composition of the present invention achieves superior drug entrapment efficiency through optimized use of components in corresponding weight ranges and ensures maximum therapeutic payload delivery. The entrapment of actives within nano-carrier particles, further facilitates sustained drug release. This sustained release mechanism results in a long-lasting therapeutic effect and enhanced efficacy in eradicating fungal infections, thereby preventing antifungal resistance. The composition of the present invention is alcohol freethereby eliminates skin dryness and irritation. The composition of the present invention demonstrates excellent long-term stability as evidenced by maintained zeta potential values within the optimal range of +4 to -45 mV, preventing particle aggregation and maintaining consistent performance over time. The inclusion of skin permeation enhancers in effective concentrations significantly improves transdermal drug delivery, overcoming the barrier properties of the skin for enhanced bioavailability. Additionally, the incorporation of transient bio-membrane modulating agents (TBMAs) helps transiently open skin layers and fungal cell membranes, aiding in targeted delivery and eradication of fungal infections while preventing resistance. The composition achieves consistent nano-scale particle size distribution, ensuring uniform drug distribution and predictable release characteristics. The defined component ranges (surfactant, solvent, lipid, and charge modifier) provide a reliable framework for developing various drug formulations while maintaining efficacy and stability.

[0145] The validated diafiltration method enables precise measurement of drug entrapment efficiency, allowing for consistent quality control and formulation optimization. The optimized solvent concentration prevents formulation instability while maintaining effective drug solubilization, reducing potential toxicity concerns. The formulation parameters of the present invention are designed to be reproducible at commercial scale, facilitating translation from laboratory to manufacturing environments.

Claims

I / We claim:

1. A topical aqueous nano-dispersion composition comprising:(a) at least one antifungal agent in an amount of 1% to 5% by weight; and(b) lipid carrier particles, the lipid carrier particles comprising:(i) at least one lipid in an amount of 0.5% to 22% by weight;(ii) at least one solvent in an amount of 1% to 12% by weight;(iii) at least one emulsifier / surfactant in an amount of 1% to 4.5% by weight;(iv) at least one skin permeation enhancer in an amount of 0.1% to 15% by weight;(v) at least one charge modifier in an amount of 0.1% to 3% by weight; and(vi) optionally, at least one transient bio-membrane modulating agent present in an amount of 0% to 10% by weight, wherein the at least one antifungal agent is entrapped within the lipid carrier particles in molecular form.

2. The topical aqueous nano-dispersion composition as claimed in claim 1, wherein the lipid carrier particles have a particle size in a range of 25 nm to 5 pm.

3. The topical aqueous nano-dispersion composition as claimed in claim 1, wherein the at least one antifungal agent is entrapped within the lipid carrier particles in molecular form with a drug entrapment efficiency in the range of 70 to 97%.

4. The topical aqueous nano-dispersion composition as claimed in claim 1, wherein the composition comprises water as a continuous aqueous phase.

5. The topical aqueous nano-dispersion composition as claimed in claim 1, wherein the at least one antifungal agent is selected from ketoconazole, luliconazole, clotrimazole, bifonazole, tioconazole, eberconazole, fenti conazole, fluconazole, econazole, miconazole, efinaconazole, oxiconazole, voriconazole, sertaconazole, sulconazole, terbinafine, butenafine, nystatin, naftifine, tavaborole, tolciclate, tolnaftate, ciclopirox, amorolfme, haloprogin, their pharmaceutically acceptable salts, their derivatives or combinations thereof.

6. The topical aqueous nano-dispersion composition as claimed in claim 1, wherein the at least one lipid is selected from medium chain triglycerides (MCTs), long chain triglycerides (LCTs), fatty acid esters (Ci-Cse), alkanoic acid esters, oils,phospholipids, phosphatidylcholines, lecithin, soybean oil, castor oil, natural oils, lemon oil, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, cholesterol, glyceryl monoesters, triglyceride esters, their derivatives, or combinations thereof.

7. The topical aqueous nano-dispersion composition as claimed in claim 6, wherein the at least one lipid is selected from medium chain triglycerides (MCT), soybean oil, phospholipids, lecithin, cetostearyl alcohol, or combinations thereof.

8. The topical aqueous nano-dispersion composition as claimed in claim 1, wherein the at least one solvent is selected from carboxylic acids, saturated C6-C26 fatty acids, unsaturated C6-C26 fatty acids, phenylcarbinol, polyols, butanol, butylene glycol, diethylene glycol monoethyl ether, propylene glycol and its derivatives, polyethylene glycol and its derivatives, glycol ethers, aprotic solvents, or combinations thereof.

9. The topical aqueous nano-dispersion composition as claimed in claim 6, wherein the at least one solvent is selected from caprylic acid, phenylcarbinol, palmitic acid, stearic acid, polyol, or combinations thereof.

10. The topical aqueous nano-dispersion composition as claimed in claim 1, wherein the at least one emulsifier / surf actant is selected from polyoxyl hydrogenated castor oil surfactants, fatty esters of sorbitan, polyoxyethylene esters, poloxamers, fatty acid esters of glycerol, polyglycerol esters, polyethylene glycol esters, propylene glycol fatty esters, sucrose esters, sulfate-type surfactants, sulfonate-type surfactants, salts of fatty acids, or combinations thereof.

11. The topical aqueous nano-dispersion composition as claimed in claim 10, wherein the at least one emulsifier / surfactant is selected from polyoxyl -40-hydrogenated castor oil, poloxamers, fatty esters of sorbitan, or combinations thereof.

12. The topical aqueous nano-dispersion composition as claimed in claim 1, wherein the at least one skin permeation enhancer is selected from monounsaturated omega- 9 fatty acids, C4-C24 fatty alcohols, alkyl alcohols including oleyl alcohol and octyl dodecanol, bile salts including sodium deoxycholate, sodium deoxyglycolate, sodium glycocholate, sodium caprate, and sodium taurocholate, glycerol esters, cocoyl caprylocaprate, dimethylacetamide, terpenes, glycols, aromatic oils, their derivatives, or combinations thereof.

13. The topical aqueous nano-dispersion composition as claimed in claim 12, wherein the at least one skin permeation enhancer is selected from oleyl alcohol, limonene, transcutol, oleic acid, or combinations thereof.

14. The topical aqueous nano-dispersion composition as claimed in claim 1, wherein the at least one charge modifier is selected from sodium, alkyl ether sulfates, sodium dodecyl sulfate, other topically acceptable anionic / cationic / zwitterionic charge modifiers, or combinations thereof.

15. The topical aqueous nano-dispersion composition as claimed in claim 14, wherein the at least one charge modifier is selected from docusate sodium, sodium dodecyl sulfate, or combinations thereof.

16. The topical aqueous nano-dispersion composition as claimed in claim 1, wherein the at least one transient bio-membrane modulating agent is selected from C5-C24 alkyl glycerol, glycerol ether lipids, their derivatives, or combinations thereof.

17. The topical aqueous nano-dispersion composition as claimed in claim 16, wherein the at least one transient bio-membrane modulating agent is selected from l-o- dodecyl-rac-glycerol, 1-o-decyl-rac-glycerol, ot combinations thereof.

18. The topical aqueous nano-dispersion composition as claimed in any one of the claims 1-17, further comprises an excipient selected from at least one gelling agent / thickening agent, at least one chelating agent, at least one preservative, at least one chemical stabilizer, at least one biodegradable polymer, at least one humectant / wetting agent, at least one buffering agent, or combinations thereof.

19. The topical aqueous nano-dispersion composition as claimed in claim 18, wherein(a) the at least one gelling agent / thickening agent is present in an amount of 0% to 3% by weight;(b) the at least one chelating agent is present in an amount of 0.01% to 0.1% by weight;(c) the at least one preservative is present in an amount of 0% to 2% by weight;(d) the at least one chemical stabilizer is present in an amount of 0.01% to 3% by weight;(e) the at least one biodegradable polymer is present in an amount of 0% to 5% by weight;(f) the at least one humectant / wetting agent is present in an amount of 0% to 5% by weight; and(g) the at least one buffering agent is present in an amount of 0.01% to 1% by weight.

20. The topical aqueous nano-dispersion composition as claimed in claim 18, wherein the at least one gelling agent / thickening agent is selected from cellulose derivatives, hydroxypropyl methylcellulose (HPMC), methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carbomers, polymeric gelling agents, gelatin, povidones, natural polymers, xanthan gum, guar gum, carrageenan, alginates, gellan gum, chitosans, polyacrylamides, waxes, silicas, clays, or combinations thereof.

21. The topical aqueous nano-dispersion composition as claimed in claim 18, wherein the at least one chelating agent is selected from disodium EDTA, tetrasodium EDTA, calcium disodium EDTA, ethylene glycol tetraacetic acid (EGTA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), phosphonic acid derivatives, or combinations thereof.

22. The topical aqueous nano-dispersion composition as claimed in claim 18, wherein the at least one preservative is selected from potassium sorbate, sodium sorbate, sorbic acid, sodium benzoate, benzoic acid, methylparaben, ethylparaben, propylparaben, butylparaben, phenoxyethanol, benzyl alcohol, chlorhexidine, benzalkonium chloride, cetylpyridinium chloride, or combinations thereof.

23. The topical aqueous nano-dispersion composition as claimed in claim 18, wherein the at least one - chemical stabilizer is selected from alpha-tocopherol, tocopherol acetate, mixed tocopherols, propyl gallate, butylated hydroxytoluene (BEIT), butylated hydroxyanisole (BHA), tertiary butylhydroquinone (TBHQ), ascorbic acid, ascorbyl palmitate, sodium ascorbate, sodium metabisulfite, sodium sulfite, citric acid, their derivatives, or combinations thereof.

24. The topical aqueous nano-dispersion composition as claimed in claim 18, wherein the at least one biodegradable polymer is selected from polyvinylpyrrolidones (PVPs), polyethylene glycols (PEGs), polyvinyl alcohol (PVA), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), chitosan, hyaluronic acid, or combinations thereof.

25. The topical aqueous nano-dispersion composition as claimed in claim 18, wherein the at least one buffering agent is selected from itric acid, sodium citrate, phosphoric acid, sodium phosphate, potassium phosphate, acetic acid, sodium acetate, triethanolamine, diethanolamine, monoethanolamine, tris (hydroxymethyl) aminomethane (Tris), sodium hydroxide, potassium hydroxide, hydrochloric acid, or combinations thereof.

26. The topical aqueous nano-dispersion composition as claimed in any one of the claims 1-25, wherein the antifungal drug entrapped within the lipid carrier has a specific surface area of not less than 750 m2 / kg.

27. The topical aqueous nano-dispersion composition as claimed in any one of the claims 1 -26, wherein the composition is stable when stored for up to 2 years at 25°C ± 2°C / 60% RH ± 5% RH.

28. The topical aqueous nano-dispersion composition as claimed in any one of claims 1-27, wherein the composition is in the form of a dispersion, emulsion, gel, lotion, cream, ointment, spray, or liquid.

29. A process of preparation of the topical aqueous nano-dispersion composition as claimed in any one of the claims 1-28, the process comprising:(a) preparing a drug phase by:(i) mixing the at least one antifungal agent with the at least one skin permeation enhancer, at least one charge modifier, at least one surfactant / emulsifier, at least one solvent, and optionally the at least one transient bio-membrane modulating agent using a high shear mixer; and(ii) adding the at least one lipid to the mixture of step (i) and homogenizing to obtain a homogeneous drug phase;(b) preparing an aqueous phase by dissolving the at least one emulsifier / surfactant, at least one chelating agent, optionally at least one buffering agent, and optionally at least one preservative in water;(c) adding the drug phase to the aqueous phase and homogenizing using high- pressure homogenization at optimized conditions to form a carrier-drug dispersion;(d) optionally preparing a gel phase by dispersing at least one gelling agent in a mixture of at least one humectant / wetting agent and water using a high shear mixer -until a uniform gel is formed;(e) optionally slowly adding the carrier-drug dispersion to the gel phase while continuing to mix;(f) optionally adding desired colorants and fragrances; and(g) homogenizing the mixture to obtain the topical aqueous nano-dispersion composition.

30. The process as claimed in claim 29 wherein the high-pressure homogenization in step (c) is conducted at a pressure in a range of 8000-15000 psi for 3-7 cycles at a temperature in a range of 15-30°C and flow rate from 0.05L to 25L per minute depending on scale of manufacturing.

31. The process claimed in claim 29, wherein the high shear mixer used in steps (a)(i) and (d) operates at a tip speed in the range of 1-30 m / s.

32. The process as claimed in claim 29, wherein the aqueous phase preparation in step (b) includes adjusting the pH to a range of 4.5-7.5 using at least one buffering agent.

33. The process as claimed in claim 29, wherein the homogenization in step (g) is conducted using equipment selected from rapid mixers, anchor mixer, high- shear / high-speed homogenizers, or high-pressure homogenizers.

34. A method of treating a fungal infection in a subj ect, comprising topically applying to an affected area of the subject a therapeutically effective amount of the composition as claimed in any one of the claims 1-28.

35. The method as claimed in claim 34, wherein the fungal infection is selected from the group consisting of dermatophytosis, candidiasis, tinea infections, Malassezia infection, seborrheic dermatitis, and combinations thereof.

36. The method as claimed in any one of the claims 34-35, wherein the composition is applied once or twice daily to the affected area.

37. The method as claimed in claim 34, wherein the subject is a human.

38. A method of preventing recurrence of fungal infections in a subject, comprising topically applying to previously affected areas a therapeutically effective amount of the composition as claimed in any one of the claims 1 -28 as a prophylactic treatment.

39. A method of treating multiple fungal infections simultaneously in a subject, comprising topically applying to multiple affected areas a therapeutically effective amount of the composition as claimed in any one of the claims 1-28, wherein the composition demonstrates broad-spectrum antifungal activity.

40. A method of treating fungal infections in immunocompromised subjects, comprising topically applying to affected areas a therapeutically effective amount of the composition as claimed in any one of the claims 1-28, wherein the enhanced drug delivery system provides effective treatment despite compromised immune function.

41. Use of the composition as claimed in any one of the claims 1-28, as a medicament for topical applications.

42. Use of the composition as claimed in any one of the claims 1-28, for treating and / or preventing fungal infections.

Images