WO2021080527A1 - Topical pharmaceutical compositions containing difluocortolone and isoconazole - Google Patents

Topical pharmaceutical compositions containing difluocortolone and isoconazole Download PDF

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Publication number
WO2021080527A1
WO2021080527A1 PCT/TR2019/050896 TR2019050896W WO2021080527A1 WO 2021080527 A1 WO2021080527 A1 WO 2021080527A1 TR 2019050896 W TR2019050896 W TR 2019050896W WO 2021080527 A1 WO2021080527 A1 WO 2021080527A1
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Prior art keywords
ethanol
weight
difluocortolone
isoconazole
topical pharmaceutical
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PCT/TR2019/050896
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French (fr)
Inventor
Abdulhaluk SANCAK
Ayşe Figen ONUK GÖREN
Başak ACAR KARAKÖY
Hakan Gürpinar
Koray YILMAZ
Serkan SOLMAZ
Suna BEYOĞLU
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Pharmacti̇ve İlaç Sanayi̇ Ve Ti̇caret A.Ş.
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Priority to PCT/TR2019/050896 priority Critical patent/WO2021080527A1/en
Publication of WO2021080527A1 publication Critical patent/WO2021080527A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to the preparation of pharmaceutical compositions comprising difluocortolone and isoconazole; and also relevant excipients, useful for the treatment of dermatological disorder such as fungal infections.
  • fungi Many types of fungal germs (fungi) live outdoors in soil and on plants as well as on many indoor surfaces and on human skin. Fungal infections are often caused by microscopic fungi that are common in the environment.
  • Diflucortolone is classed as a potent topical corticosteroid. Topical corticosteroids are also referred to as topical steroids. Difluocortolone is used as a topical treatment of the symptoms of inflammatory skin disorders like eczema, seborrheic eczema, lichen planus and psoriasis. All these disorders present as a common characteristic the occurrence of symptoms as itching, swelling, redness and scaling. Diflucortolone relieves the symptoms of a flare-up by reducing inflammation, itching and redness.
  • Diflucortolone valerate is a potent corticosteroid esterified with valeric acid. It is insoluble in water, freely soluble in dichloromethane, 1,4-dioxane, slightly soluble in methanol, and sparingly soluble in ether.
  • Difluocortolone valerate has a chemical name as (6a, 1 1 b, 16a)-6,9-Di fluoro- 1 1 -hydroxy- 16- methyl-3,20-dioxopregna-l,4-dien-21-yl valerate and its chemical structure is shown in the Figure I.
  • Isoconazole is structurally related to miconazole and econazole and was synthesized by Janssen Pharmaceutica.
  • Isoconazole is an azole antifungal agent for the treatment of infections. It can be used an antifungal agent and also antibacterial drug.
  • Isoconazole has broad-spectrum activity in vitro against dermatophytes, pathogenic yeasts, pathogenic filamentous fungi, gram-positive bacteria, and trichomonads.
  • Isoconazole nitrate has a chemical name as l- ⁇ 2-[(2,6-Dichlorobenzyl)oxy]-2-(2,4- dichlorophenyl)ethyl ⁇ -lH-imidazole nitrate (1:1) and its chemical structure is shown in the Figure 2.
  • Difluocortolone valerate / Isoconazole nitrate is marketed under the trademark “Travocort 0.1 + 1% w/w Cream” by Bayer. It is used to treat fungal infections of the skin where inflammation (redness, swelling, soreness) is also a problem. Isoconazole nitrate treats fungal diseases of the skin and diflucortolone valerate suppresses inflammation of the skin and soothes complaints such as itching, burning and pain. Travocort contains two active substances, isoconazole nitrate and diflucortolone valerate. Travocort includes white soft paraffin, liquid paraffin, cetostearyl alcohol, polysorbate 60, sorbitan stearate, disodium edetate dihydrate and purified water.
  • Present invention relates to a topical pharmaceutical spray composition
  • a topical pharmaceutical spray composition comprising; a) difluocortolone valerate and b) isoconazole nitrate, c) ethanol, preferably ethanol %95, and d) propylene glycol.
  • the weight ratio of ethanokpropylene glycol is between 4,0:1 to 2,0:1 (w/w), preferably 3,5:1 to 2,5:1 (w/w). More preferably the weight ratio of ethanokpropylene glycol is 2,95:1, 3,0:1 or 3,05:1 (w/w).
  • the present invention also relates to a process for preparing a topical pharmaceutical spray composition and uses of the composition.
  • topical as used herein is meant to encompass any condition, disease or disorder manifested on body surfaces such as the skin or mucosal membranes; such as the vagina, anus, throat, eyes and ears, including any tissue covering a body of a mammalian subject consisting of the outer, thinner epidermis (epithelial tissue) and the inner, thicker dermis (connective tissue), that is anchored to the subcutaneous layer.
  • composition or kit of the invention is intended for dermatological use on any type of skin area, being an exterior exposed area (such as for example areas of the skin, scalp, hair, and nails), an interior skin area such as a mucosal membrane (such as for example mucosal membrane around and on the nostrils, the lips, the ears, the genital area, and the anus) or any vicinal areas in close proximity with the treated skin or mucosal membrane areas wherein said composition and agents comprised in said composition may reach via any kind of diffusion mechanisms to a skin area or mucosal membrane.
  • an exterior exposed area such as for example areas of the skin, scalp, hair, and nails
  • an interior skin area such as a mucosal membrane (such as for example mucosal membrane around and on the nostrils, the lips, the ears, the genital area, and the anus) or any vicinal areas in close proximity with the treated skin or mucosal membrane areas wherein said composition and agents comprised in said composition may reach via any kind of diffusion mechanisms to a skin
  • Difluocortolone valerate and isoconazole nitrate combination product may be used more effectively, comparing with single activity of difluocortolone valerate due to possible fungal infection, so as to provide a pharmaceutical form for the desired therapeutic effect.
  • the success of a dermotological drug depends on the ability of the drug to penetrate through skin in sufficient quantities to achieve the desired therapeutic effect.
  • the present invention provides to increase the rate of percutaneous penetration, thereby shortening the time period in which the active agents can show their effect.
  • the components of the pharmaceutical composition according to the present invention are brought together into a spray for topical administration according to standard practice and procedures well known to one of ordinary skill in the art using conventional composition and manufacturing techniques.
  • Another object is to provide improved manufacturing processes which is simple, cost-effective and time saving for preparing the topical spray compositions of difluocortolone valerate and isoconazole nitrate.
  • the present invention may be used for the treatment of inflammatory or eczematous skin conditions which are accompanied by fungal infections.
  • the present invention shows well physical properties depends on its solubility characteristics in appropriate excipients for topical compositions. It shows good properties to provide basic physical stability.
  • compositions of difluocortolone valerate and isoconazole nitrate comprise one or more pharmaceutically acceptable excipient(s).
  • Pharmaceutically acceptable excipients comprise, but are not limited to, polymers, emollients, solvents, pH adjusting agents, preservatives, fragrances, stabilizers, penetration enhancers, moisturizers, and mixtures thereof.
  • Emollients can be selected from the group, but are not limited to, liquid vaseline, paraffinum liquidum, petrolatum, propylene glycol, fatty acid esters, mineral oil including dimethicone, waxes including white wax, spermacetic wax, squalene, cetearyl alcohol, cetostearyl alcohol, stearyl alcohol, 2-Octyldodecanol, mineral oil USP, light mineral oil NF, liquid paraffin BP, light liquid paraffin BP, candellilla wax, sweet almond oil, apricot oil, emu oil, argan oil, glycerin, coconut oil, grape seed oil, honey, lanolin and other materials known to one of ordinary skill in the art and mixtures thereof.
  • the preferred emollient is propylene glycol.
  • Solvents/cosolvents can be selected from the group, but not limited to, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, purified water and other materials known to one of ordinary skill in the art and mixtures thereof.
  • the preferred solvent is ethanol.
  • the present inventions provide pharmaceutical compositions comprising difluocortolone valerate and isoconazole nitrate and relevant excipients, characterized by i) to control / program the release of the active ingredient according to desired therapeutical needs, and ii) a simple and competitive manufacturing process.
  • Present invention relates to a topical pharmaceutical spray composition comprising; a) difluocortolone valerate and b) isoconazole nitrate, c) ethanol, preferably ethanol %95, and d) propylene glycol. wherein the weight ratio of ethanohpropylene glycol is between 4,0:1 to 2,0:1 (w/w).
  • the weight ratio of ethanol and propylene glycol is between 3,5:1 to 2,5:1 (w/w). More preferably the weight ratio of ethanol and propylene glycol is 2,95:1, 3,0:1 or 3,05:1 (w/w).
  • the invention also relates to the use of a topical pharmaceutical spray composition as described above for the treatment of inflammatory skin conditions such as eczema and dermatitis, and also relieving the symptoms of a flare-up, itching and redness.
  • the present invention also relates to a specific topical pharmaceutical spray composition
  • a specific topical pharmaceutical spray composition comprises a.0,01 to 1,00 % by weight of difluocortolone valerate, b.0,10 to 5,00 % by weight of isoconazole nitrate, c.60,00 to 90,00 % by weight of ethanol, preferably ethanol %95, d.8,00 to 40,00 % by weight of propylene glycol, wherein the weight ratio of ethanol and propylene glycol is between 4,0: 1 to 2,0: 1 (w/w), preferably 3,5:1 to 2,5:1 (w/w). More preferably the weight ratio of ethanol and propylene glycol is 2,95:1, 3,0:1 or 3,05:1 (w/w).
  • the present invention also relates to a specific topical pharmaceutical spray composition
  • a specific topical pharmaceutical spray composition comprises a.0,01 to 1,00 % by weight of difluocortolone valerate, b.0,10 to 5,00 % by weight of isoconazole nitrate, c.70,00 to 80,00 % by weight of ethanol, preferably ethanol %95, d.20,00 to 35,00 % by weight of propylene glycol, wherein the weight ratio of ethanol and propylene glycol is between 4,0: 1 to 2,0: 1 (w/w), preferably 3,5:1 to 2,5:1 (w/w). More preferably the weight ratio of ethanol and propylene glycol is 2,95:1, 3,0:1 or 3,05:1 (w/w).
  • the present invention also relates to a specific topical pharmaceutical spray composition
  • a specific topical pharmaceutical spray composition comprises a.0,01 to 1,00 % by weight of difluocortolone valerate, b.0,10 to 5,00 % by weight of isoconazole nitrate, c.75,00 % by weight of ethanol, preferably ethanol %95, d.25,00 % by weight of propylene glycol, wherein the weight ratio of ethanol and propylene glycol is between 3,0:1 (w/w).
  • the invention also relates to a process for preparing a topical pharmaceutical spray compositions as described above, comprising the steps of: a) Adding: propylene glycole, difluocortolone valerate and isoconazole nitrate b) Mixing c) Made up volume with ethanol d) Mixing e) Filling f) Packaging.
  • the present invention provides pharmaceutical composition comprising combination of said active ingredients characterized by a) Stability is enhanced for these substances adversely affected by oxygen and or moisture, b) Simple and also competitive manufacturing process, c) Enhanced patient compliance and convenience, d) It is advantageous when a rapid onset of action is needed, e) The product is administered easily and quickly, f) A dose can be removed with out contamination of materials, g) When sterility is an important factor, it can be maintained while a dose is being dispensed, h) Rapid onset of action, avoidance of degradation of the drug in the GIT and first pass effect, i) Lower dose of drug can be used and hence minimize adverse and side effects, j) Medication can be delivered directly to the affected area in a desired form, k) Irritation produced by the mechanical application of topical medication is reduced or eliminated, l) Application of medication in thin layer.
  • spray composition comprising active ingredients such as isoconazole nitrate and difluocortolone valerate are below.
  • composition comprising difluocortolone valerate and isoconazole nitrate, wherein the weight ratio of ethanohpropylene glycol is 3,0:1 (w/w) according to Table 1.
  • Phase III Study A multicenter, single-arm, phase III, efficacy and safety study of the spray form (mantazol spray) of the isokonazole-diflucortolone combination investigated in the initial or intermediate treatment of deep surface fungal infections with severe inflammation or eczema)
  • Phase III Study design 34 subjects, multi-center, open-label, single-arm, prospective clinical trial.
  • ethanol and propylene glycol is used in a specific weight ratio is between 4,0:1 to 2,0:1 (w/w), preferable between 3,5:1 to 2,5:1.

Abstract

The present invention relates to a topical pharmaceutical spray compositions comprising difluocortolone valerate, isoconazole nitrate, ethanol and propylene glycol, the process for preparing the compositions and uses thereof. The weight ratio of ethanol:propylene glycol is between 4,0:1 to 2,0:1 (w/w). More specifically, present invention relates to a topical pharmaceutical spray composition comprising 0,01 to 1,00 % by weight of difluocortolone valerate, 0,10 to 5,00 % by weight of isoconazole nitrate, 60,00 to 90,00 % by weight of ethanol 95 %, 8,00 to 40,00 % by weight of propylene glycol.

Description

TOPICAL PHARMACEUTICAL COMPOSITIONS CONTAINING DIFLUOCORTOLONE AND ISOCONAZOLE
Field of invention
The present invention relates to the preparation of pharmaceutical compositions comprising difluocortolone and isoconazole; and also relevant excipients, useful for the treatment of dermatological disorder such as fungal infections.
Background of the invention
There are millions of different species of fungi on Earth, but only a few of them is known to make people sick. Most fungi are not dangerous, but some types can be harmful to health.
Many types of fungal germs (fungi) live outdoors in soil and on plants as well as on many indoor surfaces and on human skin. Fungal infections are often caused by microscopic fungi that are common in the environment.
Diflucortolone is classed as a potent topical corticosteroid. Topical corticosteroids are also referred to as topical steroids. Difluocortolone is used as a topical treatment of the symptoms of inflammatory skin disorders like eczema, seborrheic eczema, lichen planus and psoriasis. All these disorders present as a common characteristic the occurrence of symptoms as itching, swelling, redness and scaling. Diflucortolone relieves the symptoms of a flare-up by reducing inflammation, itching and redness.
Diflucortolone valerate is a potent corticosteroid esterified with valeric acid. It is insoluble in water, freely soluble in dichloromethane, 1,4-dioxane, slightly soluble in methanol, and sparingly soluble in ether.
Difluocortolone valerate, has a chemical name as (6a, 1 1 b, 16a)-6,9-Di fluoro- 1 1 -hydroxy- 16- methyl-3,20-dioxopregna-l,4-dien-21-yl valerate and its chemical structure is shown in the Figure I.
Figure imgf000003_0001
Figure 1 : Difluocortolone valerate Isoconazole is structurally related to miconazole and econazole and was synthesized by Janssen Pharmaceutica. Isoconazole is an azole antifungal agent for the treatment of infections. It can be used an antifungal agent and also antibacterial drug. Isoconazole has broad-spectrum activity in vitro against dermatophytes, pathogenic yeasts, pathogenic filamentous fungi, gram-positive bacteria, and trichomonads.
Isoconazole nitrate has a chemical name as l-{2-[(2,6-Dichlorobenzyl)oxy]-2-(2,4- dichlorophenyl)ethyl}-lH-imidazole nitrate (1:1) and its chemical structure is shown in the Figure 2.
Figure imgf000004_0001
Figure 2: Isoconazole nitrate
Existing drugs comprising isoconazole nitrate in the form of topical sprays are Travogen, leaden, leaden VSFF marketed by Bayer AG. There is no drugs comprising difluocortolone valerate in the form of topical sprays.
Difluocortolone valerate / Isoconazole nitrate is marketed under the trademark “Travocort 0.1 + 1% w/w Cream” by Bayer. It is used to treat fungal infections of the skin where inflammation (redness, swelling, soreness) is also a problem. Isoconazole nitrate treats fungal diseases of the skin and diflucortolone valerate suppresses inflammation of the skin and soothes complaints such as itching, burning and pain. Travocort contains two active substances, isoconazole nitrate and diflucortolone valerate. Travocort includes white soft paraffin, liquid paraffin, cetostearyl alcohol, polysorbate 60, sorbitan stearate, disodium edetate dihydrate and purified water.
It is compared the mycological and clinical efficacy and tolerability of isoconazole nitrate alone vs isoconazole nitrate and diflucortolone valerate in multicenter study using patients with tinea inguinalis disease. According to results, this combination therapy is an effective and well- tolerated regimen in adult patients with tinea inguinalis. This study was performed according to (Veraldi S, Persico MC and Schianchi R., Isoconazole nitrate vs isoconazole nitrate and diflucortolone valerate in the treatment of tinea inguinalis, Journal of Drugs in Dermatology. November 2012;ll(ll):e70-3) Summary of the invention
Present invention relates to a topical pharmaceutical spray composition comprising; a) difluocortolone valerate and b) isoconazole nitrate, c) ethanol, preferably ethanol %95, and d) propylene glycol. wherein the weight ratio of ethanokpropylene glycol is between 4,0:1 to 2,0:1 (w/w), preferably 3,5:1 to 2,5:1 (w/w). More preferably the weight ratio of ethanokpropylene glycol is 2,95:1, 3,0:1 or 3,05:1 (w/w).
The present invention also relates to a process for preparing a topical pharmaceutical spray composition and uses of the composition.
The term "topical" as used herein is meant to encompass any condition, disease or disorder manifested on body surfaces such as the skin or mucosal membranes; such as the vagina, anus, throat, eyes and ears, including any tissue covering a body of a mammalian subject consisting of the outer, thinner epidermis (epithelial tissue) and the inner, thicker dermis (connective tissue), that is anchored to the subcutaneous layer. It should be noted that a composition or kit of the invention is intended for dermatological use on any type of skin area, being an exterior exposed area (such as for example areas of the skin, scalp, hair, and nails), an interior skin area such as a mucosal membrane (such as for example mucosal membrane around and on the nostrils, the lips, the ears, the genital area, and the anus) or any vicinal areas in close proximity with the treated skin or mucosal membrane areas wherein said composition and agents comprised in said composition may reach via any kind of diffusion mechanisms to a skin area or mucosal membrane.
Detailed description of the invention
Difluocortolone valerate and isoconazole nitrate combination product may be used more effectively, comparing with single activity of difluocortolone valerate due to possible fungal infection, so as to provide a pharmaceutical form for the desired therapeutic effect.
The success of a dermotological drug depends on the ability of the drug to penetrate through skin in sufficient quantities to achieve the desired therapeutic effect. The present invention provides to increase the rate of percutaneous penetration, thereby shortening the time period in which the active agents can show their effect.
In one aspect, the components of the pharmaceutical composition according to the present invention are brought together into a spray for topical administration according to standard practice and procedures well known to one of ordinary skill in the art using conventional composition and manufacturing techniques.
Another object is to provide improved manufacturing processes which is simple, cost-effective and time saving for preparing the topical spray compositions of difluocortolone valerate and isoconazole nitrate.
The present invention may be used for the treatment of inflammatory or eczematous skin conditions which are accompanied by fungal infections.
The present invention shows well physical properties depends on its solubility characteristics in appropriate excipients for topical compositions. It shows good properties to provide basic physical stability.
The topical spray compositions of difluocortolone valerate and isoconazole nitrate comprise one or more pharmaceutically acceptable excipient(s). Pharmaceutically acceptable excipients comprise, but are not limited to, polymers, emollients, solvents, pH adjusting agents, preservatives, fragrances, stabilizers, penetration enhancers, moisturizers, and mixtures thereof.
Emollients can be selected from the group, but are not limited to, liquid vaseline, paraffinum liquidum, petrolatum, propylene glycol, fatty acid esters, mineral oil including dimethicone, waxes including white wax, spermacetic wax, squalene, cetearyl alcohol, cetostearyl alcohol, stearyl alcohol, 2-Octyldodecanol, mineral oil USP, light mineral oil NF, liquid paraffin BP, light liquid paraffin BP, candellilla wax, sweet almond oil, apricot oil, emu oil, argan oil, glycerin, coconut oil, grape seed oil, honey, lanolin and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred emollient is propylene glycol.
Solvents/cosolvents can be selected from the group, but not limited to, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, purified water and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred solvent is ethanol.
It is found that when difluocortolone valerate and isoconazole nitrate topical spray composition, is prepared with difluocortolone valerate and isoconazole nitrate in a specific weight ratio of ethanol and propylene glycol is between 4,0:1 to 2,0:1 (w/w). Safety/Efficiency clinical study results were satisfy by using in composition the weight ratio of ethanol and propylene glycol is between 4,0:1 to 2,0:1 (w/w). (Table 1-5)
The present inventions provide pharmaceutical compositions comprising difluocortolone valerate and isoconazole nitrate and relevant excipients, characterized by i) to control / program the release of the active ingredient according to desired therapeutical needs, and ii) a simple and competitive manufacturing process. Present invention relates to a topical pharmaceutical spray composition comprising; a) difluocortolone valerate and b) isoconazole nitrate, c) ethanol, preferably ethanol %95, and d) propylene glycol. wherein the weight ratio of ethanohpropylene glycol is between 4,0:1 to 2,0:1 (w/w).
Preferably the weight ratio of ethanol and propylene glycol is between 3,5:1 to 2,5:1 (w/w). More preferably the weight ratio of ethanol and propylene glycol is 2,95:1, 3,0:1 or 3,05:1 (w/w).
The invention also relates to the use of a topical pharmaceutical spray composition as described above for the treatment of inflammatory skin conditions such as eczema and dermatitis, and also relieving the symptoms of a flare-up, itching and redness.
The present invention also relates to a specific topical pharmaceutical spray composition comprises a.0,01 to 1,00 % by weight of difluocortolone valerate, b.0,10 to 5,00 % by weight of isoconazole nitrate, c.60,00 to 90,00 % by weight of ethanol, preferably ethanol %95, d.8,00 to 40,00 % by weight of propylene glycol, wherein the weight ratio of ethanol and propylene glycol is between 4,0: 1 to 2,0: 1 (w/w), preferably 3,5:1 to 2,5:1 (w/w). More preferably the weight ratio of ethanol and propylene glycol is 2,95:1, 3,0:1 or 3,05:1 (w/w).
The present invention also relates to a specific topical pharmaceutical spray composition comprises a.0,01 to 1,00 % by weight of difluocortolone valerate, b.0,10 to 5,00 % by weight of isoconazole nitrate, c.70,00 to 80,00 % by weight of ethanol, preferably ethanol %95, d.20,00 to 35,00 % by weight of propylene glycol, wherein the weight ratio of ethanol and propylene glycol is between 4,0: 1 to 2,0: 1 (w/w), preferably 3,5:1 to 2,5:1 (w/w). More preferably the weight ratio of ethanol and propylene glycol is 2,95:1, 3,0:1 or 3,05:1 (w/w).
The present invention also relates to a specific topical pharmaceutical spray composition comprises a.0,01 to 1,00 % by weight of difluocortolone valerate, b.0,10 to 5,00 % by weight of isoconazole nitrate, c.75,00 % by weight of ethanol, preferably ethanol %95, d.25,00 % by weight of propylene glycol, wherein the weight ratio of ethanol and propylene glycol is between 3,0:1 (w/w). The invention also relates to a process for preparing a topical pharmaceutical spray compositions as described above, comprising the steps of: a) Adding: propylene glycole, difluocortolone valerate and isoconazole nitrate b) Mixing c) Made up volume with ethanol d) Mixing e) Filling f) Packaging.
Advantages
The present invention provides pharmaceutical composition comprising combination of said active ingredients characterized by a) Stability is enhanced for these substances adversely affected by oxygen and or moisture, b) Simple and also competitive manufacturing process, c) Enhanced patient compliance and convenience, d) It is advantageous when a rapid onset of action is needed, e) The product is administered easily and quickly, f) A dose can be removed with out contamination of materials, g) When sterility is an important factor, it can be maintained while a dose is being dispensed, h) Rapid onset of action, avoidance of degradation of the drug in the GIT and first pass effect, i) Lower dose of drug can be used and hence minimize adverse and side effects, j) Medication can be delivered directly to the affected area in a desired form, k) Irritation produced by the mechanical application of topical medication is reduced or eliminated, l) Application of medication in thin layer.
Examples for spray composition comprising active ingredients such as isoconazole nitrate and difluocortolone valerate are below.
Examples
Figure imgf000008_0001
Phase III: Safety/efficiency clinical study
It is used pharmaceutical composition comprising difluocortolone valerate and isoconazole nitrate, wherein the weight ratio of ethanohpropylene glycol is 3,0:1 (w/w) according to Table 1.
Table 1: Pharmaceutical spray composition of Safety/efficiency clinical study:
Figure imgf000009_0002
Safety/efficiency clinical study results were satisfy by using in composition the weight ratio of ethanohpropylene glycol is 3,0:1 (w/w). Information about the study is as follows:
Phase III Study: A multicenter, single-arm, phase III, efficacy and safety study of the spray form (mantazol spray) of the isokonazole-diflucortolone combination investigated in the initial or intermediate treatment of deep surface fungal infections with severe inflammation or eczema)
Phase III Study design: 34 subjects, multi-center, open-label, single-arm, prospective clinical trial.
We have found that “while all culture results were positive before treatment, 31 (91.18%) culture results were found to be negative after treatment.”
Before treatment, all culture results were positive. But after treatment, culture results were negative for 31 out of 34 subjects. It was successful in 91.18% of the subjects. (Table 2)
Table 2: Comparison of lesion number, lesion size and VAS scores before and after treatment
Before Treatment After Treatment p value
Lesion Number 2.5 (1-15) 1 (0-6) <0.001 Lesion Size (cm2) 2 (0.03-24) 0.275 (0-5) <0.001 VAS Erythema 4 (1-9) 1 (0-7) <0.001 VAS Squama 6.15*2.13 2.03*1.75 <0.001 VAS Itching 7.74*1.71
Figure imgf000009_0001
Descriptive statistics: Median (Minimum-Maximum), Averageistandard deviation VAS score: Visual Analogue Scale
A synergistic effect is observed over safety efficiency clinical study of difluocortolone valerate and isoconazole nitrate throughout other pharmaceutical excipients. Therefore, ethanol and propylene glycol is used in a specific weight ratio is between 4,0:1 to 2,0:1 (w/w), preferable between 3,5:1 to 2,5:1.

Claims

1. A topical pharmaceutical spray composition comprising; a) difluocortolone valerate, b) isoconazole nitrate, c) ethanol, preferably ethanol %95 and d) propylene glycol wherein the weight ratio of ethanol :propylene glycol in composition is between 4,0:1 to 2,0:1 (w/w).
2. A topical pharmaceutical spray composition according to claim 1, the weight ratio of ethanokpropylene glycol is between 3,5:1 to 2,5:1 (w/w).
3. A topical pharmaceutical spray composition according to any preceding claims; wherein composition comprises a. 0,01 to 1,00 % by weight of difluocortolone valerate, b. 0,10 to 5,00 % by weight of isoconazole nitrate, c. 60,00 to 90,00 % by weight of ethanol 95 %, d. 8,00 to 40,00 % by weight of propylene glycol.
4 A process for preparing a topical pharmaceutical spray composition according to any preceding claims, comprising the steps of; a) Adding: propylene glycole, difluocortolone valerate and isoconazole nitrate b) Mixing c) Made up volume with ethanol d) Mixing e) Filling f) Packaging.
5. A topical pharmaceutical spray composition according to any of preceding claims, for use in the treatment of inflammatory skin conditions such as eczema and dermatitis, and also relieving the symptoms of a flare-up, itching and redness, which are accompanied by fungal infection.
PCT/TR2019/050896 2019-10-24 2019-10-24 Topical pharmaceutical compositions containing difluocortolone and isoconazole WO2021080527A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150258119A1 (en) * 2014-03-11 2015-09-17 Promius Pharma, LLC Topical corticosteroid compositions
WO2017091168A1 (en) * 2015-11-28 2017-06-01 Pharmacti̇ve İlaç San. Ve Ti̇c. A.Ş. A topical spray comprising isoconazole nitrate and difluocortolone valerate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150258119A1 (en) * 2014-03-11 2015-09-17 Promius Pharma, LLC Topical corticosteroid compositions
WO2017091168A1 (en) * 2015-11-28 2017-06-01 Pharmacti̇ve İlaç San. Ve Ti̇c. A.Ş. A topical spray comprising isoconazole nitrate and difluocortolone valerate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
VERALDI STEFANO: "Isoconazole nitrate: a unique broad-spectrum antimicrobial azole effective in the treatment of dermatomycoses, both as monotherapy and in combination with corticosteroids", MYCOSES, vol. 56, no. Suppl. 1, May 2013 (2013-05-01), pages 3 - 15, XP002755043, DOI: 10.1111/myc.12054 *

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