WO2025163683A1

WO2025163683A1 - Pharmaceutical compositions of 5-alpha reductase inhibitors

Info

Publication number: WO2025163683A1
Application number: PCT/IN2025/050126
Authority: WO
Inventors: Pranav Patel; Gunjan TRIVEDI; Manoranjan SHARMA; Kiran Hothur; Harilal PATEL; Abhijit Chatterjee; Vipul Doshi
Original assignee: Zydus Lifesciences Ltd
Current assignee: Zydus Lifesciences Ltd
Priority date: 2024-02-02
Filing date: 2025-02-03
Publication date: 2025-08-07
Anticipated expiration: 2026-08-02

Abstract

The present invention relates to pharmaceutical compositions of 5-alpha reductase inhibitors and minoxidil. The invention also relates to processes for preparing such compositions. The invention also relates to methods of treating or preventing hair loss, androgenic alopecia or stimulating hair growth in a patient in need thereof by topically administering the said compositions.

Description

PHARMACEUTICAL COMPOSITIONS OF 5-ALPHA REDUCTASE INHIBITORS

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

5 -alpha-reductase inhibitors class of drugs includes dutasteride, finasteride, epristeride etc. This class of drugs inhibits conversion of testosterone (T) to dihydrotestosterone (DHT). This class of drugs involves side effects like impotence, decreased libido, decreased volume of ejaculation, breast tenderness and/or enlargement, etc.

U.S. PG-Publication No. 2010/0048598 Al discloses topical compositions comprising 5-alpha reductase inhibitors. It discloses examples of dutasteride gel, microemulsion in gel, dermal stick, ointment, cream, lotion, spray, flammable composition, and microsphere-in-gel.

U.S. Patent No. 10,993,934 B2 discloses topical compositions of dutasteride. It discloses examples of dutasteride solution.

International Publication No. (PCT) WO 2012/148174 discloses compositions for topical application for preventing hair loss and stimulating hair growth having a 5a- reductase suppressant and minoxidil. It discloses examples of external preparation compositions of finasteride, dutasteride, and dutasteride and minoxidil combination. There is still a need for alternate pharmaceutical compositions of 5-alpha reductase inhibitors having improved stability, better aesthetic appearance, improved drug exposure, residence time, ease of application, lesser side effects etc.

SUMMARY OF THE INVENTION

In one general aspect, the present invention provides a pharmaceutical composition of a 5-alpha reductase inhibitor and minoxidil, and one or more pharmaceutically acceptable excipients. In an another aspect, the present invention provides a pharmaceutical composition, for example, an emulsion comprising an oil phase comprising dutasteride, an aqueous phase comprising minoxidil, and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition has improved parameters, such as good aesthetic appearance, for example, in terms of transparency, opacity and colour, ease of application at the required site (for example, scalp area, eyebrow area, beard area, mustache area, etc.), for example, in terms of spreadability, convenience for application, low potential for interpersonal transfer of drug(s), low potential for transfer from the application site to other skin site(s), optimized pharmaceutical and physicochemical parameters, for example, droplet size, viscosity, pH, physical and chemical stability at long term and accelerated conditions, higher drug (5-alpha reductase inhibitor and minoxidil) exposure and/or residence time at the local application site, less systemic drug (5- alpha reductase inhibitor and minoxidil) exposure in systemic circulation / blood stream, less or no itching, burning, irritation, dryness, redness, and/or hypersensitivity reaction after application at the required application site, noninferior or superior efficacy for the treatment of alopecia (for example, androgenic alopecia), and / or less or no side effects, like, loss of libido / decreased libido, impotence, decreased volume of ejaculation, etc.

Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the composition may further comprise one or more emulsifiers, one or more viscosity modifying or gelling agents, one or more humectants, one or more solubilizers, one or more vehicles, one or more antioxidants, one or more preservatives, one or more chelating / complexing agents, and/or one or more pH adjusting agents. The pharmaceutical composition comprises one or more drugs (5-alpha reductase inhibitor(s) and minoxidil), one or more emulsifiers, one or more viscosity modifying or gelling agents, one or more humectants, one or more solubilizers, one or more vehicles, one or more antioxidants, one or more preservatives, one or more chelating / complexing agents, and/or one or more pH adjusting agents, wherein the composition is for application at the required application site.

In another general aspect, the invention provides a process for preparing a pharmaceutical composition comprising one or more 5-alpha reductase inhibitors and minoxidil, wherein the process comprises the steps of (a) preparing an aqueous phase comprising minoxidil, (b) preparing an oil phase comprising one or more 5- alpha reductase inhibitors, and (c) mixing the aqueous phase and the oil phase to provide an emulsion.

In another general aspect, the invention provides a suitable packaging material to supply the emulsion, optionally provided along with an applicator. The packaging material may be a laminated or aluminium tube with dispenser cap, bottle pack with /without metered pump, bottle pack with non-metered dispenser, metered airless pump pack, etc. The applicator may be of a suitable design and shape to provide convenience for composition application and to avoid any interpersonal transfer.

In another general aspect, the invention provides a method of treating or preventing hair loss, alopecia, for example, androgenic alopecia or stimulating hair growth in a patient, comprising applying pharmaceutical compositions comprising one or more 5-alpha reductase inhibitors and minoxidil at the required site (for example, scalp area, eyebrow area, beard area, mustache area, etc.) of a human being in need thereof, wherein the composition is an emulsion. The application of the composition is directed to the required site through human fingers/hand, and/or through an applicator or a device. The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 - Images of Group 1 : placebo control mice; Group 2 F9: test product (emulsion - F035); Group 3: Inbilt®-F commercial product (solution); and group 4: normal control mice.

DETAILED DESCRIPTION OF THE INVENTION

The inventors of the present invention have found that when 5-alpha reductase inhibitor and minoxidil are formulated as a pharmaceutical composition, for example, emulsion, the composition having improved parameters can be obtained. The emulsion composition having one or more improved parameters, such as good aesthetic appearance, ease of application at scalp area, optimized pharmaceutical and physicochemical parameters, higher drug exposure at the local application site and lower drug exposure in the systemic circulation (for 5-alpha reductase inhibitor and/or minoxidil), non-inferior or superior efficacy for the prevention or treatment of hair fall, alopecia, for example, androgenic alopecia, and/or stimulating hair growth, can be obtained.

The inventors have also found that when the dutasteride and minoxidil emulsion is used along with an applicator or a device, a better application of the composition and user convenience can be obtained.

In one embodiment, the invention provides a topical pharmaceutical composition comprising 5-alpha reductase inhibitor, minoxidil, and one or more pharmaceutically acceptable excipients. In an another embodiment, the invention provides an emulsion comprising an oil phase comprising dutasteride, an aqueous phase comprising minoxidil, and one or more pharmaceutically acceptable excipients. The one or more pharmaceutically acceptable excipients can comprise an emulsifier, a viscosity modifying agent, a humectant, a solubilizer, a vehicle, an antioxidant, or a pH adjusting agent. The one or more pharmaceutically acceptable excipients may further comprise a preservative, a chelating / complexing agent. The pharmaceutical composition, for example, an emulsion, can comprise one or more drugs (5-alpha reductase inhibitor and minoxidil), one or more emulsifiers, one or more viscosity modifying or gelling agents, one or more humectants, one or more solubilizers, one or more vehicles, one or more antioxidants, one or more preservatives, one or more chelating / complexing agents, and/or one or more pH adjusting agents.

The term “pharmaceutical composition” as used herein, unless and otherwise explicitly mentioned, refers to compositions comprising one or more active agents together with one or more pharmaceutically acceptable excipients as required to prepare a dosage form for the effective delivery of the active agent. Such pharmaceutical compositions can be in the form of solutions, emulsions, ointments, creams, gels, lotions, suspensions, sprays, foams, microspheres, microemulsions, nanoemulsions, nanoparticles, nanosuspensions, dermal sticks, roll-ons, pumps, patches, tapes, and the like.

The term “topical pharmaceutical composition” as used herein, unless and otherwise explicitly mentioned, refers to a pharmaceutical composition that is applied onto the skin surface. Such “topical” pharmaceutical composition may act ‘locally’ to provide higher drug exposure at the local application site, for example, in terms of mean skin concentration and may not be / may be less absorbed systemically to provide lower systemic drug (dutasteride and/or minoxidil) exposure in systemic circulation / blood stream, for example, in terms of mean serum concentration.

Examples of suitable drug which can be included in the emulsion composition of the invention can include, but not limited to, dutasteride, finasteride, epristeride, and minoxidil. The drug, for example, dutasteride, can be present in the composition in a concentration of between about 0.01 % w/w and about 1 % w/w, for example, about 0.025 % w/w, 0.05 % w/w, or about 0.10 % w/w. The drug, for example, minoxidil, can be present in the composition in a concentration of between about 1 % w/w and about 20 % w/w, for example, between about 5 % w/w and about 15 % w/w, or at about 5 % w/w.

The term “about” in quantitative terms, as used herein, unless and otherwise explicitly mentioned, refers to plus or minus 30 %, for example, plus or minus 20 %, plus or minus 10 %, or plus or minus 5 %. For example, “about 5 %” would encompass 3.5-6.5 % and “about 10 %” would encompass 7-13 %. Moreover, where “about” is used herein in conjunction with a quantitative term it is understood that in addition to the value plus or minus 30 %, the exact value of the quantitative term is also contemplated and described. For example, the term "about 5 %" expressly contemplates, describes and includes exactly 5 %.

Examples of suitable emulsifiers can include, but are not limited to, polyoxyethylene sorbitan fatty acid esters (polysorbate(s)), for example, polyoxyethylene 20 sorbitan monolaurate (polysorbate 20), polyoxyethylene 20 sorbitan monopalmitate (polysorbate 40), polyoxyethylene 20 sorbitan monostearate (polysorbate 60), or polyoxyethylene 20 sorbitan monooleate (polysorbate 80), or any combination thereof; sorbitan esters (sorbitan fatty acid esters), for example, sorbitan monolaurate (span 20), sorbitan monopalmitate (span 40), sorbitan monostearate (span 60), or sorbitan monooleate (span 80), or any combination thereof; cetostearyl alcohol; polyoxyethylene alkyl ethers, for example, various grades of commercially available Brij® and/or Laureth®; polyoxyethylene castor oil derivatives, for example, PEG-35 castor oil; stearalkonium hectorite; carbomers, for example, Pemulen® (various grades thereof); and the like. The polysorbate, for example, polysorbate 60, can be present in the composition in a concentration of between about 1 % w/w and about 15 % w/w, for example, at about 5 % w/w. The sorbitan fatty acid ester, for example, commercially available span 80, can be present in the composition in a concentration of between about 0.5 % w/w and about 10 % w/w, for example, at about 3 % w/w.

The term "between" as used herein for the purpose of defining range is inclusive of the lower and upper number of the range.

Examples of suitable viscosity modifying or gelling agents can include, but are not limited to xanthan gum, cyclomethicone, acacia gum, HEC 250 HX, cetyl alcohol, glycerol, polyethylene glycol (PEG), PEG-stearate, cellulose and its derivatives, such as sodium carboxymethyl celluloses and hydroxyalkyl and alkyl celluloses, carbomers such as Carbopol™ and their derivatives, carob, carregeenans and derivatives, sclerane gum, long chain alkanolamides, bentone and derivatives, kaolin, green clay, bentonite, magnesium aluminum silicate (Veegum™), guar gums (such as Jaguar™ HP- 120), cross-linked acrylic acid polymers, and the like, including any mixtures thereof. The viscosity modifying or gelling agents can be present in the composition in a concentration of between about 0.05 % w/w to about 10 % w/w. For example, the xanthan gum can be present in the composition in a concentration of between about 0.05 % w/w and about 1 % w/w, between about 0.1 % w/w and about 0.5 % w/w, for example, at about 0.2 % w/w.

Examples of suitable humectants can include, but are not limited to, glycerin, sodium hyaluronate, sorbitol, methyl gluceth-20 (Glucam® E20), and the like. The glycerin can be present in the composition in a concentration of between about 0.1 % w/w and about 10.0 % w/w, for example, at about 5 % w/w.

Examples of suitable solubilizers can include, but are not limited to, castor oil, propylene glycol, ethanol / dehydrated alcohol, olive oil, medium chain triglycerides, isopropyl myristate, diisopropyl adipate, isopropyl palmitate, coconut oil, light mineral oil, diethylene glycol monoethylether (Transcutol®), diethyl sebacate, benzyl alcohol, cyclomethicone, polyethylene glycol, dimethyl isosorbide, and the like. The castor oil can be present in the composition in a concentration of between about 1 % w/w and about 30 % w/w, for example, between about 5 % w/w and about 20 % w/w, or at about 14 % w/w. The propylene glycol can be present in the composition in a concentration of between about 1 % w/w and about 20 % w/w, for example, between about 5 % w/w and about 15 % w/w, or at about 10 % w/w. The ethanol / dehydrated alcohol can be present in the composition in a concentration of between about 1 % w/w and about 20 % w/w, for example, between about 5 % w/w and about 15 % w/w, or at about 8 % w/w.

Examples of suitable vehicle can include, but is not limited to, water, and the like. The vehicle can be present in the composition in a concentration to provide quantity sufficient to 100 % of the composition.

Examples of suitable anti-oxidants can include, but are not limited to tocopherol succinate, ascorbic acid, propyl gallate, vitamin E, butylated hydroxytoluene, butylated hydroxyanisole, sodium pyrosulfite, kojic acid, cysteine, hydroquinone, and the like, including any mixtures thereof. The butylated hydroxytoluene can be present in the composition in a concentration of between about 0.05 % w/w and about 1 % w/w, for example, between about 0.1 % w/w and about 0.5 % w/w, or at about 0.2 % w/w.

Examples of suitable preservatives may include, but are not limited to diazolidinyl urea and imidazolidinyl urea, as well as methyl, ethyl, propyl and butyl esters of p- hydroxybenzoic acid (parabens), isothiazolones, and the like, including any mixtures thereof.

Examples of suitable chelating or complexing agents may include, but are not limited to ethylenediaminetetraacetic acid (EDTA) and its derivatives, thioglycolic acid, thiolactic acid, thioglycerol, and the like, including mixtures thereof.

Examples of suitable pH adjusting agents can include, but are not limited to, sodium hydroxide, lactic acid, hydrochloric acid, ammonium hydroxide, potassium hydroxide, aminomethyl propanol, tetrahydroxypropyl ethylenediamine, triethanolamine, tromethamine, diisopropanolamine, triisopropanolamine, citric acid, fumaric acid, succininc acid, adipic acid and maleic acid, and the like. The pH adjusting agent(s) is/are added in the composition / emulsion in a sufficient amount to produce the composition pH between about 4.0 and about 7.0, for example, between about 4.5 and about 5.5, or about 5.0.

The topical pharmaceutical composition of the invention, for example, an emulsion can comprise dutasteride, minoxidil, glycerin, polysorbate, sorbitan fatty acid ester, castor oil, butylated hydroxytoluene, propylene glycol, alcohol / ethanol, lactic acid, sodium hydroxide, and water. The emulsion can comprise an oil phase comprising dutasteride, castor oil, polysorbate, sorbitan monooleate, and butylated hydroxytoluene, and an aqueous phase comprising minoxidil, glycerin, propylene glycol, ethanol, lactic acid, sodium hydroxide, and water. The emulsion can comprise dutasteride in a concentration of about 0.05 % w/w, castor oil in a concentration of about 14 % w/w, polysorbate in a concentration of about 5 % w/w, sorbitan fatty acid ester in a concentration of about 3 % w/w, butylated hydroxytoluene in a concentration of about 0.2 % w/w, minoxidil in a concentration of about 5 % w/w, glycerin in a concentration of about 5 % w/w, propylene glycol in a concentration of about 10 % w/w, ethanol in a concentration of about 8 % w/w, one or more pH adjusting agents in an amount sufficient to provide a pH of the emulsion composition between about 4.5 and about 5.5, or about 5.0, and water in a concentration sufficient to make the quantity 100 % w/w.

The topical pharmaceutical composition of the invention, for example, an emulsion can comprise dutasteride, minoxidil, glycerin, xanthan gum, polysorbate, sorbitan fatty acid ester, castor oil, propylene glycol, butylated hydroxytoluene, alcohol / ethanol, lactic acid, sodium hydroxide, and water. The emulsion comprising an oil phase comprising dutasteride, castor oil, polysorbate, sorbitan monooleate, and butylated hydroxytoluene, and an aqueous phase comprising minoxidil, glycerin, propylene glycol, ethanol, xanthan gum, lactic acid, sodium hydroxide, and water. The emulsion can comprise dutasteride in a concentration of about 0.05 % w/w, castor oil in a concentration of about 14 % w/w, polysorbate in a concentration of about 5 % w/w, sorbitan fatty acid ester in a concentration of about 3 % w/w, butylated hydroxytoluene in a concentration of about 0.2 % w/w, minoxidil in a concentration of about 5 % w/w, glycerin in a concentration of about 5 % w/w, propylene glycol in a concentration of about 10 % w/w, ethanol in a concentration of about 8 % w/w, xanthan gum in a concentration of about 0.2 % w/w, one or more pH adjusting agents in an amount sufficient to provide a pH of the emulsion composition between about 4.5 and about 5.5, or about 5.0, and water in a concentration sufficient to make the quantity 100 % w/w.

In an embodiment, the invention provides a topical pharmaceutical composition, for example, an emulsion composition comprising dutasteride, minoxidil, and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients comprise an emulsifier, a viscosity modifying agent, a humectant, a solubilizer, a vehicle, an antioxidant, or a pH adjusting agent, and wherein the weight ratio of the dutasteride to the solubilizer is between about 1 :50 and about 1 :500 and weight ratio of the minoxidil to the solubilizer is between about 1 : 1 and about 1 : 10.

In one another embodiment, the invention provides a topical pharmaceutical composition, for example, an emulsion composition comprising dutasteride, minoxidil, and castor oil, wherein weight ratio of dutasteride to castor oil is between about 1 :50 and about 1 :500.

In an another embodiment, the invention provides a topical pharmaceutical composition, for example, an emulsion composition comprising dutasteride, minoxidil, and ethanol, wherein weight ratio of minoxidil to ethanol is between about 1 : 1 and about 1 : 10. In an embodiment, the invention provides a topical pharmaceutical composition for example, an emulsion comprising dutasteride, minoxidil and a pharmaceutically acceptable excipient, wherein either dutasteride or minoxidil or both can be present in the composition partly in solubilized and partly in particulate form.

In one embodiment, the invention provides a topical pharmaceutical composition, for example, an emulsion comprising dutasteride and minoxidil, having improved aesthetic appearance, for example, in terms of transparency, opacity, and colour.

In an another embodiment, the invention provides a topical pharmaceutical composition, for example, an emulsion comprising dutasteride and minoxidil which upon applying using hand or an applicator can provide ease and convenience of application at the required site, for example, in terms of spreadability, avoid or has low likelihood/potential of interpersonal transfer of drug(s), and avoid or has low likelihood/potential of transfer from the application site to other skin site(s).

In one another embodiment, the invention provides a topical pharmaceutical composition, for example, an emulsion comprising dutasteride and minoxidil having optimized pharmaceutical and physicochemical parameters, for example, globule size distribution, particle size distribution, viscosity, pH, physical stability and, chemical stability in terms of higher drug assay and reduced levels of known, unknown and total impurities, when exposed to different storage conditions including at long term and accelerated conditions.

In another embodiment, the invention provides a topical pharmaceutical composition, for example, an emulsion comprising an oil phase comprising 5-alpha reductase inhibitor, an aqueous phase comprising minoxidil, and one or more pharmaceutically acceptable excipients. The emulsion is an oil-in-water emulsion and comprises oil globules. The oil globules have a globule size distribution of Dio, D50, and D90 not more than 50 micrometers, for example, not more than 25 micrometers, not more than 15 micrometers, not more than 10 micrometers, or not more than 5 micrometers. The undissolved drug can be present in the emulsion in form of suspended particles having a particle size distribution of Dw, D50, and D90 not more than 50 micrometers, for example, not more than 25 micrometers, not more than 15 micrometers or not more than 10 micrometers. D90 means 90 % of the total globules are smaller than the mentioned numerical value / mentioned size.

In an embodiment, the emulsion comprising dutasteride and minoxidil can provide viscosity value of between about 1 cps and about 5000 cps, for example, between about 10 cps and about 2000 cps, between about 200 cps and about 1500 cps, or between about 1000 cps and about 1500 cps as determined by the brookfield viscometer (for example, model: LVDV-3T, Spindle: SC4-27, RPM-5). The emulsion can retain its viscosity value in the mentioned range after storage for more than 1 month, for example, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, or 36 months at controlled room temperature i.e., 20°C to 25°C (68°F to 77°F).

In an embodiment, the emulsion comprising dutasteride and minoxidil shows at least not less than 90 % drug(s) assay (% assay), for example, at least 95 % drug(s) assay (% assay) or at least 100 % drug(s) assay (% assay) for both dutasteride and minoxidil as determined by HPLC (High-performance liquid chromatography) or UV (Ultraviolet) visible spectroscopy. The emulsion of the invention remains stable and retains at least not less than 90 % drug(s) assay (% assay), for example, at least 95 % drug(s) assay (% assay) or at least 100 % drug(s) assay (% assay) for both dutasteride and minoxidil as determined by HPLC (High-performance liquid chromatography) or UV (Ultraviolet) visible spectroscopy after storage for 1 or more months, for example, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, or 36 months, at -20°C (Degree Centigrade / Celsius) to -15°C, or at 2°C to 8°C, or at controlled room temperature, i.e., 20°C to 25°C and 60 %RH (Relative Humidity), or at 30°C and 75 %RH, or at 40°C and 75 %RH. In an embodiment, the emulsion comprising dutasteride and minoxidil shows not more than 3 %, for example, not more than 2 %, not more than 1 %, not more than 0.5 %, not more than 0.1 %, or 0 % of any of the known, unknown or the total impurities, as determined by HPLC (High-performance liquid chromatography) or UV (Ultraviolet) visible spectroscopy. The emulsion comprising dutasteride and minoxidil remains stable and shows not more than 3 %, for example, not more than 2 %, not more than 1 %, not more than 0.5 %, not more than 0.1 %, or 0 % of any of the known, unknown or the total impurities, as determined by HPLC (High- performance liquid chromatography) or UV (Ultraviolet) visible spectroscopy after storage for 1 or more months, for example, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, or 36 months, at -20°C (Degree Centigrade / Celsius) to -15°C, or at 2°C to 8°C, or at controlled room temperature, i.e., 20°C to 25°C and 60 %RH (Relative Humidity), or at 30°C and 75 %RH, or at 40°C and 75 %RH.

In another embodiment, the emulsion comprising dutasteride and minoxidil remains free of any defect such as, phase separation, phase inversion, flocculation, coalescence, creaming, ostwald ripening, cracking, air bubbles, voids or lumps after its storage for 1 or more months, for example, 3 months, 6 months, 12 months, 18 months, 24 months, 30 months, or 36 months, at -20°C to -15°C, or at 2°C to 8°C, or at controlled room temperature, i.e., 20°C to 25°C and 60 %RH, or at 30°C and 75 %RH, or at 40°C and 75 %RH.

In one another embodiment, the invention provides a topical pharmaceutical composition, for example, an emulsion comprising dutasteride and minoxidil having higher exposure of the dutasteride at the local application site, for example, in terms of mean skin concentration, and having a lower exposure of dutasteride in systemic circulation, for example, in terms of mean serum concentration.

In an embodiment, mean skin concentration of Dutasteride after 5 hours of topical administration is more than 1000 ng/g, for example, is more than 2000 ng/g, more than 3000 ng/g, more than 4000 ng/g, more than 5000 ng/g, more than 6000 ng/g, more than 7000 ng/g, more than 8000 ng/g, or more than 8500 ng/g and the mean skin concentration of the Dutasteride after 24 hours of topical administration is more than 500 ng/g, for example, more than 700 ng/g, more than 900 ng/g, more than 1000 ng/g, more than 1200 ng/g, or more than 1500 ng/g.

In an embodiment, mean serum concentration of Dutasteride after 5 hours of topical administration is less than 2500 ng/mL, for example, less than 2000 ng/mL, less than 1500 ng/mL, less than 1000 ng/mL, less than 800 ng/mL, or less than 600 ng/mL, and the mean serum concentration of the Dutasteride after 24 hours of topical administration is less than 2500 ng/mL, for example, less than 2000 ng/mL, less than 1500 ng/mL, less than 1000 ng/mL, less than 800 ng/mL, or less than 700 ng/mL.

In an embodiment, the ratio of mean skin concentration (ng/g) of dutasteride to mean serum concentration (ng/mL) of dutasteride after 5 hours of topical administration, is from about 1 :3 to about 15: 1, for example, from about 1 :2 to about 14: 1, from about 1 : 1 to about 13: 1, from about 2: 1 to about 12: 1, from about 3 : 1 to about 11 : 1, from about 4: 1 to about 10: 1, from about 5: 1 to about 9: 1, or from about 6: 1 to about 8: 1.

In an another embodiment, the invention provides a topical pharmaceutical composition, for example, an emulsion comprising dutasteride and minoxidil which shows non-inferior or superior efficacy for the treatment or prevention of hair loss, alopecia (for example, androgenic alopecia) and/or stimulating hair growth, when evaluated, for example, in terms of changes in skin / hair characteristics before and after treatment, including change in hair thickness, change in hair numbers, hair growth score, skin colour score.

In an another embodiment, the invention provides a topical pharmaceutical composition, for example, an emulsion comprising dutasteride and minoxidil for topically administering to a patient for the treatment or prevention of hairl loss, alopecia, for example, androgenic alopecia, and/or stimulating hair growth, wherein change in skin colour score after 14 days of treatment with the emulsion of the invention, in comparison to the normal control group is less than 2.5, for example, less than 2.5, 2.3, 2.1, 2.0, 1.9, or 1.7.

In one another embodiment, the invention provides a topical pharmaceutical composition, for example, an emulsion comprising dutasteride and minoxidil, which shows less or no itching, burning, irritation, dryness, redness, and/or hypersensitivity reaction after application at the required application site, and / or has less or no side effects, like, loss of libido / decreased libido, impotence, decreased volume of ejaculation, etc.

In one embodiment, an emulsion comprising dutasteride and minoxidil can be prepared by steps comprising:

(a) preparing an aqueous phase comprising minoxidil,

(b) preparing an oil phase comprising one or more 5 -alpha reductase inhibitors, and

(c) mixing the aqueous phase and the oil phase to provide an emulsion.

In another embodiment, an emulsion comprising dutasteride and minoxidil can be prepared by steps comprising:

(a) mixing water, glycerin, and propylene glycol to provide an aqueous phase,

(b) mixing minoxidil, alcohol (ethanol), and water to provide an aqueous minoxidil phase,

(c) mixing dutasteride, castor oil, and one or more emulsifiers, to provide a dutasteride oil phase,

(d) mixing the dutasteride oil phase with the aqueous phase obtained at step (a) above, to provide a primary emulsion, and (e) mixing the primary emulsion with the aqueous minoxidil phase obtained at step (b) above, to provide the emulsion comprising dutasteride and minoxidil.

In another embodiment, an emulsion comprising dutasteride and minoxidil can be prepared by steps comprising of:

(a) mixing water, viscosity modifying agent and glycerin to provide an aqueous phase,

(b) mixing minoxidil, propylene glycol, alcohol (ethanol), and water to provide an aqueous minoxidil phase,

(c) mixing dutasteride, castor oil, butylated hydroxytoluene, and one or more emulsifiers, to provide a dutasteride oil phase,

(d) mixing the dutasteride oil phase with the aqueous phase obtained at step (a) above, to provide a primary emulsion, and

(e) mixing the primary emulsion with the aqueous minoxidil phase obtained at step (b) above, to provide the emulsion comprising dutasteride and minoxidil.

The emulsion comprising dutasteride and minoxidil is suitable to undergo process of filling into suitable package, to provide a packaged emulsion composition.

In one embodiment, the emulsion composition of the invention is supplied/provided in a suitable primary packaging material, for example, laminated or aluminium tube with dispenser cap, bottle pack with/without metered pump, bottle pack with nonmetered dispenser, metered airless pump pack, etc.

In another embodiment, the emulsion composition of the invention is supplied/provided, as a kit, where an applicator is either already attached to the primary packaging material or an applicator is provided separately to be attached to the primary packaging material before application of the composition. The applicator device may contain various constituent parts/portions, for example, a portion providing a hold/grip, a portion for delivery of the composition, and the like.

In one embodiment, the invention provides a method of treating or preventing hair loss, alopecia, for example, androgenic alopecia and/or stimulating hair growth in a patient, comprising applying topically to a human being in need thereof a topical pharmaceutical composition, for example, an emulsion comprising dutasteride and minoxidil. The method may involve application of the emulsion composition to the required application site using human fmgers/palm, and/or using an applicator device.

All Product/Brand names are the trademarks of their respective owners.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Example 1: Composition of dutasteride and minoxidil emulsion:

Emulsion comprising an oil phase comprising dutasteride, an aqueous phase comprising minoxidil and one or more pharmaceutically acceptable excipients were prepared as per the Table 1 below. Table 1:

Manufacturing Process (For F9):

Stepl : Preparation of aqueous phase

Purified water (partial quantity), glycerin and xanthan gum were added and mixed in a stainless steel container to form a clear aqueous phase.

Step 2: Preparation of aqueous minoxidil phase

Purified water (partial quantity), propylene glycol and alcohol (ethanol) were added and mixed in a stainless steel container. Minoxidil was added and mixed by stirring. Lactic acid was added to adjust the pH between 5.0 and 5.50 to obtain aqueous minoxidil phase.

Step 3 : Preparation of dutasteride oil phase

Castor oil, polysorbate 60, butylated hydroxytoluene, and span 80 were added and mixed in a stainless steel container at temperature between 75°C and 85°C. Dutasteride was added and mixed by stirring with maintenance of the temperature. The bulk dutasteride oil phase was allowed to cool below 30°C under stirring.

Step 4: Preparation of primary emulsion

The dutasteride oil phase of step 3 was transferred to the aqueous phase obtained at step 1. The bulk was homogenized for 20 minutes to obtain a primary emulsion. Step 5: Preparation of the dutasteride and minoxidil emulsion

The aqueous minoxidil phase obtained at step 2 was added to the primary emulsion obtained at step 4 and homogenized for 20 minutes to obtain white to off-white bulk dispersion. The pH of the bulk dispersion was adjusted between 4.5 and 5.5 by adding 10% w/w NaOH solution and/or lactic acid. The weight of the bulk was checked and made to 100% by adding remaining quantity of purified water.

All other composition from F1-F10 were prepared by the process described above.

Example 2: Evaluation of optical and aesthetic properties of emulsion:

The emulsion of composition F9 was further evaluated for preliminary optical and aesthetic properties like transparency, opacity, colour, spreadability, convenience for application, potential for interpersonal transfer, and potential for transfer from the application site to other skin site(s). The results are summarized in the Table 2 below.

Table 2:

Example 3: Evaluation of pharmaceutical properties of emulsion:

The emulsion of composition F9 was further evaluated for various pharmaceutical properties like microscopic analysis in terms of globule size distribution and particle size distribution, rheological analysis i.e. viscosity and emulsion pH at 25

° C ± 2°C. The results are shown in the Table 3 below.

Table 3:

Example 4: Accelerated stability analysis

The emulsion of composition F9 was evaluated for accelerated stability analysis as per ICH guidelines. The emulsion was packed in amber colour glass vials and was exposed to 40 °C for a period of 3 months. The results in the table 4 below, shows that the emulsion remained physically and chemically stable in terms of retaining the assay of both dutasteride and minoxidil and did not show any presence of any known or unknown or total impurities.

Table 4:

Example 5: Evaluation of changes in skin characteristics after treatment Twenty-three male C57 mice were depilated and randomized into four groups. Androgenic Alopecia (AGA) was induced in eighteen mice (3 groups with six in each) by subcutaneously administering testosterone propionate (0.5%) in an amount of 100 pL per mouse. Group 1 was treated by topically applying placebo for composition F9 of Example 1 (without dutasteride and minoxidil) termed as placebo control group. Group 2 was treated by topically applying dutasteride and minoxidil test product (emulsion) prepared according to composition F9 of Example 1. Group 3 was treated by topically applying commercial product (Inbilt®- F; Finasteride 0.1% and Minoxidil 5% solution; marketed in India by Glenmark Pharmaceuticals Ltd). The products applied at all the groups were once a day. At each application, amount of the product applied was 100 microliter (pL)/mouse. Group 4 comprised of five mice which received neither testosterone propionate nor any treatment is termed as normal control group. After 14 days of treatment, the skin color score was measured for all the groups by grading on a scale of 1-6 using the following parameters: l=pink; 2=pinky white; 3=white; 4=greyish white; 5=grey; 6=dark grey. The results are reported in the Table 5 and the images in Figure 1. Then the mice were sacrificed to collect blood for serum and skin tissue for measurement of drug level (example 6).

Table 5:

* represents P value <0.05 measured using one-way ANOVA followed by Dunnet’s psot-hoc test.

It is evident from the results reported in the Table 5 and images provided at Figure 1 that the test product (emulsion) provides marked improvement in skin color score compared to commercial product (solution). The skin colour score in the test product group was significantly ( <0.05) improved as compared to the placebo control group in the testosterone-induced androgenic alopecia model in mice. Whereas, the commercial product did not show significant improvement in skin color when compared to the placebo control group. The emulsion as per the invention showed superior efficacy as compared to the placebo and/or the marketed composition containing minoxidil and finasteride.

Example 6: Evaluation of exposure of dutasteride at the site of application and in systemic circulation

The exposure of dutasteride at the site of application and in systemic circulation was evaluated in terms of the mean skin concentration (ng/g) and mean serum concentration (ng/mL). The test product emulsion of composition F9 was applied topically on the mouse skin at a dose of 100 pL per mouse. The mean skin concentration and the mean serum concentration were evaluated after 5 hours and 24 hours. The results are summarized in the Table 6 below.

The estimation of dutasteride in serum and skin were performed using a sensitive and specific liquid chromatography-tandem mass spectrometry method (LC-

MS/MS). The method was developed and validated as fit for purpose. The extraction of dutasteride and internal standard in serum and skin samples were carried out by Liquid-Liquid Extraction method. Table 6:

The above results show that the prepared emulsion of composition F9 was successful in retaining dutasteride to the mouse skin and had reduced systemic drug exposure.

Claims

We Claim:

1. An emulsion comprising an oil phase comprising dutasteride, an aqueous phase comprising minoxidil, and one or more pharmaceutically acceptable excipients.

2. The emulsion of claim 1, wherein the dutasteride is present in a concentration of between about 0.01 % w/w and about 1 % w/w and the minoxidil is present in a concentration of between about 1% w/w and about 20 % w/w of the emulsion.

3. The emulsion of claim 1, wherein the emulsion is an oil-in-water emulsion, comprising oil globules and wherein the oil globules have D90 not more than 50 micrometers.

4. The emulsion of claim 1, wherein the one or more pharmaceutically acceptable excipients comprise an emulsifier, a viscosity modifying agent, a humectant, a solubilizer, a vehicle, an antioxidant, or a pH adjusting agent.

5. The emulsion of claim 4, wherein the emulsifier comprises a polyoxyethylene sorbitan fatty acid ester, a sorbitan fatty acid ester, cetostearyl alcohol, a polyoxyethylene alkyl ether, a polyoxyethylene castor oil derivative, stearalkonium hectorite, or a carbomer.

6. The emulsion of claim 5, wherein the polyoxyethylene sorbitan fatty acid ester comprises polyoxyethylene 20 sorbitan monolaurate (polysorbate 20), polyoxyethylene 20 sorbitan monopalmitate (polysorbate 40), polyoxyethylene 20 sorbitan monostearate (polysorbate 60), polyoxyethylene 20 sorbitan monooleate (polysorbate 80), or any combination thereof, and wherein the polyoxyethylene sorbitan fatty acid ester is present in a concentration of between about 1 % w/w and about 15 % w/w of the emulsion.

7. The emulsion of claim 5, wherein the sorbitan fatty acid ester comprises sorbitan monolaurate (span 20), sorbitan monopalmitate (span 40), sorbitan monostearate (span 60), sorbitan monooleate (span 80), or any combination thereof, and wherein the sorbitan fatty acid ester is present in a concentration of between about 0.5 % w/w and about 10 % w/w of the emulsion.

8. The emulsion of claim 4, wherein the viscosity modifying agent comprises xanthan gum, cetyl alcohol, glycerol, polyethylene glycol (PEG), or PEG- stearate, and wherein the viscosity modifying agent is present in a concentration of between about 0.05 % w/w and about 1 % w/w of the emulsion.

9. The emulsion of claim 4, wherein the humectant comprises glycerin, sodium hyaluronate, sorbitol, or methyl gluceth-20, and wherein the humectant is present in a concentration of between about 0.1 % w/w and about 10.0 % w/w of the emulsion.

10. The emulsion of claim 4, wherein the solubilizer comprises castor oil, propylene glycol, ethanol, olive oil, medium chain triglycerides, isopropyl myristate, diisopropyl adipate, isopropyl palmitate, coconut oil, light mineral oil, diethylene glycol monoethylether, diethyl sebacate, benzyl alcohol, cyclomethicone, polyethylene glycol, or dimethyl isosorbide, and wherein the solubilizer is pesent in a concentration of between about 1 % w/w and about 40.0 % w/w of the emulsion.

11. The emulsion of claim 4, wherein the antioxidant comprises tocopherol succinate, ascorbic acid, propyl gallate, vitamin E, butylated hydroxytoluene, butylated hydroxyanisole, sodium pyrosulfite, kojic acid, cysteine, or hydroquinone and wherein the antioxidant is present in a concentration of between about 0.05 % w/w and about 1 % w/w of the emulsion.

12. The emulsion of claim 4, wherein the pH adjusting agent comprises sodium hydroxide, lactic acid, hydrochloric acid, ammonium hydroxide, potassium hydroxide, aminomethyl propanol, tetrahydroxypropyl ethylenediamine, triethanolamine, tromethamine, diisopropanolamine, triisopropanolamine, citric acid, fumaric acid, succininc acid, adipic acid, or maleic acid, and wherein the pH adjusting agent is added in the emulsion in an amount sufficient to produce the emulsion pH between about 4.0 and about 7.0.

13. The emulsion of claim 4, wherein weight ratio of the dutasteride to the solubilizer is between about 1 :50 and about 1 :500 and weight ratio of the minoxidil to the solubilizer is between about 1 : 1 and about 1 : 10.

14. An emulsion comprising an oil phase comprising dutasteride, castor oil, polysorbate, sorbitan monooleate, and butylated hydroxytoluene, and an aqueous phase comprising minoxidil, glycerin, propylene glycol, ethanol, xanthan gum, lactic acid, sodium hydroxide, and water.

15. The emulsion of claim 14, wherein the oil phase comprises dutasteride in a concentration of about 0.05 % w/w, castor oil in a concentration of about 14 % w/w, polysorbate in a concentration of about 5 % w/w, sorbitan monooleate in a concentration of about 3 % w/w, and butylated hydroxytoluene in a concentration of about 0.2 % w/w, and wherein the aqueous phase comprises minoxidil in a concentration of about 5 % w/w, glycerin in a concentration of about 5 % w/w, propylene glycol in a concentration of about 10 % w/w, ethanol in a concentration of about 8 % w/w and xanthan gum in a concentration of about 0.2 % w/w, lactic acid, and sodium hydroxide in an amount sufficient to provide a pH between about 5.0 and about 6.0, and water.

16. The emulsion of claim 14, wherein the emulsion remains physically and chemically stable, does not show a phase separation and flocculation, retains more than 90 % of the dutasteride and the minoxidil, and does not show increase in known, unknown, or total impurities when stored at 40 ° C for a period of 3 months.

17. An emulsion comprising dutasteride and minoxidil prepared by steps comprising:

(a) mixing water, glycerin, and xanthan gum to provide an aqueous phase,

(b) mixing minoxidil, propylene glycol, ethanol, and water to provide an aqueous minoxidil phase,

(c) mixing dutasteride, castor oil, butylated hydroxytoluene, Polyoxyethylene 20 Sorbitan Monostearate, and Sorbitan Monooleate to provide a dutasteride oil phase,

18. A method of treating or preventing hair loss, androgenic alopecia, and/or stimulating hair growth in a patient in need thereof, by topically administering an emulsion comprising an oil phase comprising dutasteride, an aqueous phase comprising minoxidil, and one or more pharmaceutically acceptable excipients.

19. The method of treatment of claim 18, wherein the emulsion provides a higher exposure of dutasteride at local application site, a higher mean skin concentration of dutasteride, a lower exposure of dutasteride in systemic circulation, a lower mean serum concentration of dutasteride, and improves skin color score in comparison to placebo.

20. A kit comprising an emulsion comprising an oil phase comprising dutasteride, an aqueous phase comprising minoxidil, and one or more pharmaceutically acceptable excipients, and an applicator.