ANTIFUNGAL AEROSOL SOLUTION

Abstract: Aerosol solutions of certain relatively insoluble imidazole derivatives, particularly miconazole and miconazole nitrate, are prepared in a solvent system based on a mixture of a lower alcohol and a solubilizing agent with a hydrocarbon propellant. The solution provides at least 1.0 percent, and preferably from 1.5 to 2.5 percent by weight active agent on the basis of non-volatile residue. The solutions are phar­ macologically acceptable for topical application in the treat­ ment of fungal skin infections.

Description: ANTIFUNGAL AEROSOL SOLUTION Field of Invention This invention relates to antifungal solutions for dermatological use and more particularly to aerosol solutions of certain imidazole derivatives which are effective in treating fungal skin infections. Background Imidazole derivatives of the class l-(ss-aryl)ethyl- imidazole ethers useful for their antifungal properties are disclosed in USP 3,717,655, incorporated herein by reference for its teaching of the preparation and use of such compounds. As described in this patent imidazole derivatives of the defined class have the formula: EMI1.1 and the therapeutically active acid addition salts thereof, wherein: R, R1 and R2 are each a member selected from the group consisting of hydrogen and lower alkyl; n is the integer 1 or 2; Ar is a member selected from the group consisting of phenyl, mono-, di- and tri-halophenyl, lower alkylphenyl, lower alkoxyphenyl, -thienyl and halothienyl; Ar' is a member selected frown the group consisting of phenyl, nono-, di- and tri-halophenyl, mono- and di-(lower alkyl) phenyl, lower alkoxyphenyl ane cyanophenyl; R' is a member selected froin the group consisting of hydrogen, methyl and ethyl; and R" is a member selected from the group consisting of hydrogen and methyl. The '655 patent further discloses that compositions comprising such imidazole derivatives as the active ingredient in a solvent or a solid, semi-solid or liquid diluent or carrier provide an effective method of combatting fungus growth. According to the patent, "The subject compounds can be used in suitable solvents or diluents, in the form of emulsions, suspensions, dispersions or oint Anent, on suitable solid or seni-solidd carrier substances, in ordinary or synthetic soaps, detergents or dispersion media, if desired, together with other compounds having arachnicidal, insecticidal, ovicidal, fungicidal and/or bactericidal effects, or together with inactive additives." "Inert solvents used for the production of liquid preparations should preferably not be readily inflammable and should be as far as possible odorless and as far as possible non-toxic to warm-blooded animals or plants in the relevant surroundings. Solvents suitable for this purpose are high-boiling oils, for example, of vegetable origin, and lover-boiling solvents with a flash point of at least 30'C, such as, for example, isopropanol dimethysulfoxide, hydrogenated naphtbalenes and alkylated napthalenes. It is, of course, also possible to use mixtures of solvents. Solutions can be prepared in the usual way, if necessary, with assistance of solution promoters. Other liquid forms which can be used consist of emulsions or suspensions of the active compound in water or suitable inert solvents, or also concentrates for preparing such emulsions, which can be directly adjusted to the required concentration. For this purpose, the active ingredient is, for example, mixed with a dispersing or emulsifying agent. The active component can also be dissolved or dispersed in a suitable inert solvent and mixed simultaneously or subsequently with a dispersing or emulsifying agent." "Furthermore, it is possible for the active component to be used in the form of aerosols. For this purpose, the active component is dissolved or dispersed, if necessary, with the aid of suitable inert solvents as carrier liquids, such as difluorodichloromethane, which at atmospheric pressure boils at a temperature lower than room temperature, or in other volatile solvents. In this way, solutions under pressure are obtained which, when sprayed, yield aerosols which are particularly suitable for controlling or combatting fungi and bacteria, e.g., in closed chambers and storage rooms, and for application to vegetation for eradicating or for preventing infections by fungi or bacteria." "The subject compounds and conpositions thereof can be applied by conventional methods. For example a fungus or bacterial growth or a material to be treated or to be protected against attack by fungus or bacterium can be treated with the subject co,.lpounds and the compositions thereof by dusting, sprinkling, spraying, brushing, dipping, smearing, impregnating or other suitable means." 4"When the subject compounds are deployed in combination with suitable carrier , e.g., in solution, suspension, dust, powder, ointment, emulsion, and the like forms, a high activity over a very high range of dilution is observed. For example, concentrations of the active ingredient ranging from 0.1-10 percent by weight, based on the weight of composition employed, have been found effective in combatting fungi or bacteria. Of course, higher concentrations may also be employed as warranted by the particular situation." An example of an imidazole solution is given in Example LX of the '655 patent where five parts of 1-tp-chloro-B-(2,6- dichlorobenzyloxyaphenethyl3 inidazole are dissolved in 95 parts of alkylated naphthalene and used as a spray for the treatment of fungus infected subjects or on walls, floors or other objects to prevent infection by fungi. Such solutions-of the imidazole derivatives, while effective antifungal ooQpo5itions, are obviously not suitable for dermatological use due to the presence of the strong organic solvent which has a-. irritating and defatting effect on tissue. Moreover, such solutions would suffer from the same defects if formulated with a propellant for aerosol application and would not be acceptable for dermatological use. A preferred imidazole derivative for use in the present invention is l-t2,4-dichloro-ss-(2,4-dichlorobenzyloxy)- phenethyl) imidazole nitrate which has the common nane miconazole nitrate. The solubility of miconazole nitrate in inmost pharmaceutically acceptable solvents is too low to provide the desired concentration of at least one percent pharmaceutical active agent for use as a dermatological product. In many solvent systems, the incorporation of the propellant causes phase separation of an otherwise hemogeneous solution, making the formulation unsuitable for use as an aerosol spray. It is accordingly an object of the present invention to provide a nek aerosol system for compounds of the class l-(-aryl)ethyl-imidazole ethers. It is a further object to provide a new solvent and propellant system: in which such imidazole ethers are present to the extent of at least one percent on a non-volatile residue basis excluding the propellant and volatile solvents. It is a yet further object of this invention to provide a dermatological antifungal aerosol composition comprising a aryl)ethyl-imidazole ether derivative in a pharmaceutically acceptable, single phase aerosol system. A still further object of this invention is to provide a dermatological antifungal cotaposition comprising a therapeutically effective concentration of miconazole or miconazole nitrate in an aerosol solvent system. These and other objects of this invention will be apparent from the ensuing description and claims. Summary The dermatological antifungal compositions of the present invention comprise a therapeutically effective amount of at least about 1.0 percent by weight exclusive of propellant and other volatiles of an imidazole derivative of the type l-(B-aryl)ethyl-imidazole in an aerosol system consisting essentially of: (i) 3 to 20t of a lower alkanol as a volatile solvent. (ii) 5 to 25% of a non-volatile solubilizing agent comprising a fatty acid salt or an ester or amide of a fatty acid; (iii) O to 5% of a polyhydric alcohol as a non-volatile cosolvent; (iv) O to 0.05% of an antioxidant, and (v) 60 to 85% of a nornally gaseous hydrocarbon propellant. In a preferred formulation, the imidazole derivative is miconazole or miconazole nitrate. Formulations containing from about 1.0 to 2.5 percent by weight of miconazole/ miconazole nitrate on a nonvolatile residue basis are effective antifungal colapositions useful in treating skin infections, are pharmacologically acceptable for topical use and dry rapidly for the convenience of the user. Description of Preferred Embodiments The 1-(ss-aryl)ethylimidazole ethers utilized as the active antifungal agent in the compositions of the present invention are knoWn compounds, the preparation of which is disclosed in USP 3,717,655. Such compounds have the formula: EMI6.1 wherein R, R1 and R2 are each a member selected from the group consisting of hydrogen and lower alkyl; n is the integer 1 or 2; Yr is a meiber selected from the group consisting of phenyl, mono-, di- and tri-halophenyl, lower alkylphenyl, loser alkoxyphenyl, thienyl and halothienyl; Ar' is a meter selected fron the group consisting of phenyl, mono-, di- and tri-halophenyl, mono- and di-(lo*er alkyl) phenyl, lower alkoxyphenyl and cyanophenyl; R' is a member selected from the group consisting of hydrogen, methyl and ethyl; and R" is a member selected from the group consisting of hydrogen and methyl. As used herein, "lower alkyl" and "lower alkoxy" may be straight or branch chained saturated hydrocarbons having from 1 to about 6 carbons, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like alkyls, and, respectively, the corresponding alkoxys such as methoxy, ethoxy, propoxy, isopropoxy, etc. The preferred lower alkyl and lower alkoxy are Inethyl and methoxy, respectively. The tern "halo" refers to halogens of atomic weight less than 127, i.e., fluoro, iodo, broino, and chloro. A particularly preferred imidazole ether representative of the above compounds is miconazole, 1-C2,4-dichloro-B-(2,4- dichlorobenzyloxy)phenethyl) imidazole as the base or as the nitrate salt having the formula: EMI7.1 The imidazole ethers in general and the miconazoles in particular have very low solubilities in most solvents suitable for use in topical pharmaceutical cor.lpositions such as in the treatment of fungal skin infections. The solubility of laiconazole nitrate, for example, in several cannon solvents has heen determined to be as follows: Solvent G/100 ml. Water 0.03 NaOH Insoluble HCl 0.1 N 0.05 40E PG/water 0.13 Propylene Glycol 0.15 PE 300 0.13 Methanol 1.5 Ethanol 0.76 2-Propanol 0.13 Acetone 0.34 Hexane 0.03 Chloroform 0.31 Ethyl Acetate 0.07 Benzene 0.05 Methyl Isobutylketone 0.04 Tetrahydrofuran 0.2 In the treatment of fungal skin infections, it is desirable that the antifungal agent be easily applied with a nininum of discomfort and inconvenience to the user. Miconazole nitrate has already found wide application as an over-the-counter antifungal preparation in the form of ointlzent, creams and dry powders. Attempts to formulate miconazole nitrate as an aerosol solution which could be dispensed with conventional hydrocarbon propellants was frustrated by the extremely low solubility of miconazole nitrate -in pharlaaceutically acceptable solvents compatible with hydrocarbon propellants. The present invention overcolles this problem by providing a solvent system capable of dissolving fran 1.0 to about 2.5 percent by weight miconazole nitrate exclusive of propellant and other volatiles to provide a single phase. quick drying and effective aerosol antifungal composition. The solvent/propellant system according to this invention consists essentially of: (i) 3 to 20% of a lower alkanol as a volatile solvent; (ii) 5 to 25% of a non-volatile solubilizing agent comprising a fatty acid salt or an ester or anide of a fatty acid; (iii) O to 5% of a polyhydric alcohol as a non-volatile cosolvent; (iv) O to 0.058 of an antioxidant; and (v) 60 to 85% of a normally gaseous hydrocarbon propellant. The volatile solvent (i) is preferably ethanol or a mixture of ethanol and benzyl alcohol. The solubilizing agent (ii) is preferably selected from the group consisting of sorbitan sesquioleate, polysorbate 20, polysorbate 60, sodium laurate, sodium oleate, cocamide diethanolamide (Cocamide DEA), sodium lauryl sulfate, lauramide diethanolamide (Lauramide DEA), dioctyl sodium sulfosuccinate and mixtures thereof. The polyhydric alcohol (iii) is preferably selected from the group consisting of polyethylene glycol 200 or 400, glycerin, propylene glycol, dipropylene glycol and mixtures thereof. The antioxidant (iv) is preferably selected from the group consisting of butylated hydroxytoluene, butylated hydroxy anisole, tocopherols and mixtures thereof. The hydrocarbon propellant (v) is preferably selected from the group consisting of n-butane, iso-butane, propane, and mixtures thereof. Specific aerosol formulations may be selected frown the various suitable and preferred conponents as identified above or their equivalents according to the particular needs and desires of the formulator. Representative exan.ples of some formulations providing acceptable single pbase aerosol solutions for miconazole and miconazole nitrate are as follows: : 96 w/w basis % w/w non-volatiles a) Miconazole Nitrate 0.188 2.14 Tocopherols 0.003 Benzyl Alcohol 1.981 Cocamide DEA 2.368 Sorbitan Sesquioleate 4.239 Ethyl Alcohol 16.831 Hydrocarbon Propellant A-46 qs 100.000 b) Miconazole Nitrate 0.289 1.38 Btylatedhydroxytoluene 0.003 Cocamide DEA 9.378 Sorbitan Sesquioleate 10.806 Polyethylene Glycol 400 0.375 Ethyl Alcohol 4.761 Hydrocarbon Propellant qs to 100.000 c) Miconazole Nitrate 0.342 2.0 Sorbitan Sesquioleate 15.880 Dipropylene Glycol 0.854 Ethyl Alcohol 8.540 Hydrocarbon Propellants qs to 100.000 t w/w basis % w/w non-volatiles d) Miconazole Nitrate 0.269 2.1 Butylatedhydroxyanisole 0.003 Cocamide DEA 3.839 Sorbitan Sesquioleate 7.486 Polyethylene Glycol 200 1.216 Ethyl Alcohol 12.795 Hydrocarbon Propellants qs to 100.000 e) Miconazole Nitrate 0.342 2.0 Lauramide DEA 16.734 Ethyl Alcohol 8.540 Hydrocarbon Propellants qs to 100.000 f) iTiconazole Nitrate 0.294 2.0 Cocanide DEA 4.704 Sorbitan Sesquioleate 9.261 Cococaprylate 0.441 Ethyl Alcohol 10.900 Hydrocarbon Propellants qs to 100.000 ltne above formulations are readily prepared by first mixing together the solvents and solubilizing agent to obtain a uniform clear solution. The miconazole (base or nitrate) is next dissolved in the solution with vigorous agitation. When the solution again clears, the antioxidant is added to complete the formulation of the aerosol concentrate which is then transferred to a suitable container and pressurized with the hydrocarbon propellant. Aerosol solutions prepared in accordance with the present invention contain frola about 1.0 to 2.5 percent active imidazole by weight on the basis of non-volatile residue. Such solutions of miconazole are effective antifungal dernatological compositions which are pharmacologically acceptable for topical application in the treatment of fungal skin infections.

Claims: CLAIMS 1. A dernatological antifungal aerosol composition comprising: (a) a solvent and propellant system consisting essentially of 3 to 20% of a lower alkanol as a volatile solvent; 5 to 25% of a non-volatile solubilizing agent comprising a fatty acid salt or an ester or amide of a fatty acid; 0 to 5% of a polyhydric alcohol as a nonvolatile cosolvent; 0 to 0.05% of an antioxidant; and 60 to 85% of a normally gaseous hydrocarbon as a propellant; and (b) a therapeutically effective amount equal to at least 1.0% by weight of the aerosol colXlposition exclusive of propellant and other volatiles of a l-(ss-aryl)ethyl- inidazole derivative having the formula: EMI13.1 and the therapeutically active acid addition salts thereof, wherein: : R, R1 and R2 are each a member selected from the group consisting of hydrogen and lower alkyl; n is the integer 1 or 2; kr is a member selected from the group consisting of phenyl, mono-, di- and tri-halophenyl, lower alkylphenyl, lower alkoxyphenyl, thienyl and halothienyl; Ar' is a member selected from the group consisting of phenyl, mono-, di- and tri-halophenyl, mono- and di(lower alkyl) phenyl, lower alkoxyphenyl and cyanophenyl; R' is a member selected from the group consisting of hydrogen, methyl and ethyl; and R'l is a member selected fron the group consisting of hydrogen and methyl. 2. A solution of Claim 1 wherein said lower alkanol is ethyl alcohol. 3. A solution of claim 1 or claim 2 wherein said solubilizing agent is selected frorn the group consisting of sorbitan sesquioleate, polysorbate 20, polysorbate 60, sodium lalrate, sodium oleate, cocanaide diethanolanide, sodium lauryl sulfate, lauramide diethanolamide, dioctyl sodiura sulfosuccinate and mixtures thereof. 4. A solution of any one of clasp 1 to 3 wherein said antioxidant is selected frcm the group consisting of butylated hydroxytoluene, butylated hydroxy anisole, tocopherols and mixtures thereof. 5, A solution of any one of claims 1 to 4 wherein said hydrocarbon propellant is selected from the group consisting of nbutane, iso-butane, propane and mixtures thereof. 6. A solution of any one of claims 1 to 5 wherein said imidazole derivative is 1-C2,4-dichloro--(2,4-aichlorobenzyloxy phenethyl]-imidazole or 1-2,4-dichloro-B-(2,4-aichloro- benzyloxy)phenethyl3-imidazole nitrate. 7. A solution of Claim 6 wherein said solvent and propellant system consists essentially of from about 15 to 205 by weight of said system of a solvent comprising 15 to 20% ethyl alcohol and 0 to 3% benzyl alcohol; from about 5 to 10% by weight of said system of solubilizing agent selected from the group consisting of cocamide diethanolamide, sorbitan sesquioleate, and mixtures thereof; from about 0.001 to 0.005% by weight of said system of an antioxidant; and from about 70 to 805e by weight of said system of a hydrocarbon propellant. 8. 9 solution of Claim 7 wherein said antioxidant is tocopherols. 9. A method of producing an aerosol composition according to any one of claims 1 to 8 comprising mixing together to form a homogeneous solution from 3 to 20% of a lower alkanol as a volatile solvent; 5 to 25% of a non-volatile solubilizing agent comprising a fatty acid salt or an ester or amide of a fatty acid; 0 to 5% of a polyhydric alcohol as a non-volatile cosolvent; 0 to 0.05% of an antioxidant; and a therapeutically effective amount equal to at least 1% by weight of the composition exclusive of volatiles of a l-(B-aryl) ethylimidazole as defined in claim 1 and pressurising the homogeneous solution with 60 to 85% of a normal gaseous hydrocarbon as a propellant.

Inventors: DAS, SUDEB, MARTIN ST. FLACKS
Applicants: ORTHO PHARMACEUTICAL CORPORATION
Application year: 1985
Main classification: A61K31
IPC codes: A61K31, A61K9