CA1212327A - Antimycotic agent with a high release of active compound, in the form of a cream - Google Patents
Antimycotic agent with a high release of active compound, in the form of a creamInfo
- Publication number
- CA1212327A CA1212327A CA000450707A CA450707A CA1212327A CA 1212327 A CA1212327 A CA 1212327A CA 000450707 A CA000450707 A CA 000450707A CA 450707 A CA450707 A CA 450707A CA 1212327 A CA1212327 A CA 1212327A
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- CA
- Canada
- Prior art keywords
- bifonazole
- antimycotic agent
- agent according
- antimycotic
- isopropyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- 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
-
- 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
- A61K31/415—1,2-Diazoles
-
- 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
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
Antimycotic agent with a high release of active compound, in the form of a cream ABSTRACT OF THE DISCLOSURE
.
The invention relates to the provision of improved antimycotic, cream compositions containing bifonazole as an antimycotic composition and including 5-25% by weight of a spreading agent.
.
The invention relates to the provision of improved antimycotic, cream compositions containing bifonazole as an antimycotic composition and including 5-25% by weight of a spreading agent.
Description
The present invention relates to a novel formula-tion of the known antimycotic compound bifonazole of the formula ~3~ O ~3 which has a relatively h;gh release of the active compound and thereby permits short-term therapy Formulations of antimycotic derivatives have al-ready been disclosed for the treatment of mycdses in humans, above all mycose~ of the skin and cutaneous appendages. A therapy time of 14 to 21 days has been requ;red for complete cure w;th these formulations.
In order Jo shorten the duration of therapy, for example in the case of vaginal or buccal mycoses or dermatomycoses~ higher release of the active compounds in an aqueous medium is necessary in particular to eliminate the germs and to achieve a mycologically reliable cure.
The known formulations are of only limited su;tabil;ty for th;s, because only a smalL amount of the active compound available dissolves in the volume of liquid at the infec-t;on s;te. Thus if a shorten;ng ;n the durat;on of therapy, for example to a few days with a single daily adm;n;str2t;0n, is Jo be achieved, with or ~ithou~ a fur-ther increase in the concentration of act;ve compound, opt;mum bioava;lab;lity of the active compound must be ensured.
It has now been found that formulat;ons of bifona-zole which conta;n 5 - 25X of a spread;ng agent, in add;-t;on to the conventional formulation substances and Le A 22 266 _, solvents, release a greater amount of the active compound and thereby permit a shortening of the duration of therapy to a few days. This effect of higher release of active compound can achieve an increase up to a power of ten.
Accordingly, the present invention provides an antimycotic agent in the form of a cream composition which has a high release of active compound and which contains bifonazole, or a pharmaceuti-cally acceptable salt thereof, a solvent, one or more formulation auxiliaries and 5 to 25% by weight of a spreading agent.
The antimycotic agent can be prepared by aamixing bifonazole or a pharmaceu'cically acceptable salt thereof with a solvent, one or more Eormulation auxiliaries and 5 to 25% by weight of a spreading agent.
The bifonazole or pharmaceutically acceptable salt can be prepared by (a) reacting the carbinol of the formula CH ~3 OH
is reacted with thionyl-bis-imidazole, if appropriate in the presence of a diluent, or (b) reacting the halogeno-methane of the formula Hal with (1) imidazole, if appropriate in the presence of an g acid-binding agent and if appropriate in the presence of a diluent, or
In order Jo shorten the duration of therapy, for example in the case of vaginal or buccal mycoses or dermatomycoses~ higher release of the active compounds in an aqueous medium is necessary in particular to eliminate the germs and to achieve a mycologically reliable cure.
The known formulations are of only limited su;tabil;ty for th;s, because only a smalL amount of the active compound available dissolves in the volume of liquid at the infec-t;on s;te. Thus if a shorten;ng ;n the durat;on of therapy, for example to a few days with a single daily adm;n;str2t;0n, is Jo be achieved, with or ~ithou~ a fur-ther increase in the concentration of act;ve compound, opt;mum bioava;lab;lity of the active compound must be ensured.
It has now been found that formulat;ons of bifona-zole which conta;n 5 - 25X of a spread;ng agent, in add;-t;on to the conventional formulation substances and Le A 22 266 _, solvents, release a greater amount of the active compound and thereby permit a shortening of the duration of therapy to a few days. This effect of higher release of active compound can achieve an increase up to a power of ten.
Accordingly, the present invention provides an antimycotic agent in the form of a cream composition which has a high release of active compound and which contains bifonazole, or a pharmaceuti-cally acceptable salt thereof, a solvent, one or more formulation auxiliaries and 5 to 25% by weight of a spreading agent.
The antimycotic agent can be prepared by aamixing bifonazole or a pharmaceu'cically acceptable salt thereof with a solvent, one or more Eormulation auxiliaries and 5 to 25% by weight of a spreading agent.
The bifonazole or pharmaceutically acceptable salt can be prepared by (a) reacting the carbinol of the formula CH ~3 OH
is reacted with thionyl-bis-imidazole, if appropriate in the presence of a diluent, or (b) reacting the halogeno-methane of the formula Hal with (1) imidazole, if appropriate in the presence of an g acid-binding agent and if appropriate in the presence of a diluent, or
(2) a silver salt of alkali metal salt of imidazole, if appropriate in the presence of a diluent, or
(3) a trimethylsilylimidazole of the formula ~i(CH3)3 if appropriate in the presence of a diluent, and, if appropriate, the azol-l-yl-methane thereby obtained is reacted with a physio-logically acceptable acid, to form a pharmaceutically acceptable salt.
The agents according to the invention contain bifonazole in amounts of 0.05% to 1.5~, preferably of 0.1 to 1% and very particularly preferably lo.
Spreading agents are understood as meaning oily liquids which distribute themselves particularly readily on the skin [R. Keymer, Pharm. Ind. 32 [1970], 557-581]. The following com-pounds are particularly suitable spreading agents for the agents according to the invention:
Silicone oils of various viscosities.
Fatty acid esters, such as ethyl stearate, di-n-butyl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain lengths with saturated C16-C18-fat-ty alcohols, isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated fatty alcohols of C12-C18 chain lengths, isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate, waxy fatty acid esters, such as synthetic duck .,~
uropygial gland fat, dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter and the like.
Triglycerides, such as caprylic/capric acid triglyceride, tri-glyceride mixtures with vegetable fatty acids of C8-C12 chain lengths or other specially selected naturally occurring fatty acids, partial glyceride mixtures of saturated or unsaturated fatty acids, optionally containing hydroxyl groups, monoglycerides of the C8/C10-fatty acids and the like.
Fatty alcohols, such as isotridecyl alcohol, 2-octyl-dodecanol, cetylstearyl alcohol and oleyl alcohol.
Fatty acids, such as, for example, oleic acid.
The following spreading oils are particularly - 3a -,. .
3Z~
The agents according to the invention contain bifonazole in amounts of 0.05% to 1.5~, preferably of 0.1 to 1% and very particularly preferably lo.
Spreading agents are understood as meaning oily liquids which distribute themselves particularly readily on the skin [R. Keymer, Pharm. Ind. 32 [1970], 557-581]. The following com-pounds are particularly suitable spreading agents for the agents according to the invention:
Silicone oils of various viscosities.
Fatty acid esters, such as ethyl stearate, di-n-butyl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain lengths with saturated C16-C18-fat-ty alcohols, isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated fatty alcohols of C12-C18 chain lengths, isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate, waxy fatty acid esters, such as synthetic duck .,~
uropygial gland fat, dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter and the like.
Triglycerides, such as caprylic/capric acid triglyceride, tri-glyceride mixtures with vegetable fatty acids of C8-C12 chain lengths or other specially selected naturally occurring fatty acids, partial glyceride mixtures of saturated or unsaturated fatty acids, optionally containing hydroxyl groups, monoglycerides of the C8/C10-fatty acids and the like.
Fatty alcohols, such as isotridecyl alcohol, 2-octyl-dodecanol, cetylstearyl alcohol and oleyl alcohol.
Fatty acids, such as, for example, oleic acid.
The following spreading oils are particularly - 3a -,. .
3Z~
- 4 -su;table: ;sopropyl myr;state, ;sopropyl palm;tate, capryl;c/capric acid esters of saturated fatty alcohols of C12-C1g cha;n lengths, waxy fatty ac;d esters, such as synthetic duck uropygial gland fat, silicone oiLs and a mixture of isopropyl myristate/isopropyl stearate/iso-propyl paLm;tate.
The following auxiliaries and/sr formulation base auxiliaries can be used in the preparation of the agents according to the invention.
"Glyceryl stearates", a mixture Oil-in-~ater cream base, of monoglycerides and diglycer- not self-emulsifying ides of palmitic acid and stear;c acid Colloidally disperse mixture of Oil-in-water emulsion cetyl-stearyl alcohol and sod- base, self-emulsifying ium cetyl stearyl sulphate Esters of a branched fatty ac;d O;l component with a with saturated C16-C18-fatty marked hydrophobic effect alcohols for skin protection products Cetyl palmitate Synthetic spermaceti, consistency for creams, ; ointments, emulsions Polyethylene stearate Nonionic hydrophylic emulsif;er Cetyl-stearyl alcohol oxy- Nonionic oil-in-~ater ethylated with about ~2 moles emulsifier of ethylene ox;de , .
-` ~l2~z~
The following auxiliaries and/sr formulation base auxiliaries can be used in the preparation of the agents according to the invention.
"Glyceryl stearates", a mixture Oil-in-~ater cream base, of monoglycerides and diglycer- not self-emulsifying ides of palmitic acid and stear;c acid Colloidally disperse mixture of Oil-in-water emulsion cetyl-stearyl alcohol and sod- base, self-emulsifying ium cetyl stearyl sulphate Esters of a branched fatty ac;d O;l component with a with saturated C16-C18-fatty marked hydrophobic effect alcohols for skin protection products Cetyl palmitate Synthetic spermaceti, consistency for creams, ; ointments, emulsions Polyethylene stearate Nonionic hydrophylic emulsif;er Cetyl-stearyl alcohol oxy- Nonionic oil-in-~ater ethylated with about ~2 moles emulsifier of ethylene ox;de , .
-` ~l2~z~
- 5 -Cetyl-stearyl aLcohol oxy- Nonionic oil-in-~ater ethylated with about 30 moles emuls;f;er of ethylene oxide Sorb;tan and glyceroL fatty Nonionic enuls;fier 5 acid esters Su;table formulation aux;l;ar;es are:
a. substances ~h;cho for example, can stabilise a suspen-sion, for example collo;dal s;lic;c ac;d, montmor;llonites and the like.
b. Surfactants (;ncludes emulsifiers and wetting agents), for example 1. anionic, such as Na lauryl-sulphate, fatty alcohol ether-sulphates and monoethanolamine salts of mono/dialkyl polyglycol ether orthophosphates; 2. cat-;on;c, such as cetyltrimethylammon;um chlor;de; 3. ampho-lytic, such as di-Na-N-lauryl- ~ininodipropionate or lecithin and 4~ nonionic, for example polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorb;-tan monostearate, cetyl alcohol, glycerol monostearate, polyoxyethylene stearate and alkyLphenol polyglycol ethers c. Stabilisers for preventing the chemical degradation which occurs to some active compounds such as ant;ox;-dants, for example tocopherols or butylhydroxyan;sole.
d. Softeners, for example propylene glycol, glycerol di-and tri~propylene glycol, tr;ethanolamine, waxes and thelike.
Suitable solvents are water and all water-miscible solvents. Examples of solvents which can be used are alkanols, such as ethanol and isopropyl alcohol, propylene glycol~ Methylcellosolve, Cellosolve, esters, morpholines, d;oxane, dimethylsulphoxide, dimethylformamide, tetra-hydrofuran and cyclohexanoneO
One or more solvents can be used in the prepara-tion of the formulations accord;ng to the invention.
,, ' .
~Z~3Z7
a. substances ~h;cho for example, can stabilise a suspen-sion, for example collo;dal s;lic;c ac;d, montmor;llonites and the like.
b. Surfactants (;ncludes emulsifiers and wetting agents), for example 1. anionic, such as Na lauryl-sulphate, fatty alcohol ether-sulphates and monoethanolamine salts of mono/dialkyl polyglycol ether orthophosphates; 2. cat-;on;c, such as cetyltrimethylammon;um chlor;de; 3. ampho-lytic, such as di-Na-N-lauryl- ~ininodipropionate or lecithin and 4~ nonionic, for example polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorb;-tan monostearate, cetyl alcohol, glycerol monostearate, polyoxyethylene stearate and alkyLphenol polyglycol ethers c. Stabilisers for preventing the chemical degradation which occurs to some active compounds such as ant;ox;-dants, for example tocopherols or butylhydroxyan;sole.
d. Softeners, for example propylene glycol, glycerol di-and tri~propylene glycol, tr;ethanolamine, waxes and thelike.
Suitable solvents are water and all water-miscible solvents. Examples of solvents which can be used are alkanols, such as ethanol and isopropyl alcohol, propylene glycol~ Methylcellosolve, Cellosolve, esters, morpholines, d;oxane, dimethylsulphoxide, dimethylformamide, tetra-hydrofuran and cyclohexanoneO
One or more solvents can be used in the prepara-tion of the formulations accord;ng to the invention.
,, ' .
~Z~3Z7
- 6 -Preparation ox the active compound bifonazole -CH-N
Process Yar;ant Sa) 13.6 y (O.Z mole)of imidazoLe are dissolved in 150 ml of acetonitrile, and 3.5 ml of thionyl chloride are added at ~0C. 13 g ~0.05 mole)of diphenyL-phenyl-car-b;nol are added to the soLution of thionyl bis-imidazole thus obtained. After the mixture has been left to stand at room temperature f4r 15 hours, the solvent is removed by distillation in vacuo. The residue is taken up in chloroform and the mixture is washed with water. The organic phase is separated off, dr;ed over sod;um sulphate and filtered and the solvent ;s d;stilled off in vacuo.
The 07 ly residue is dissolved in ethyl acetate and the solution is freed from insoluble, resinous constituents by filtration The solvent is distilled off again in vacuo and the residue ;s purified by recrystallisati4n from acetonitrile. 8.7 9 (56% of theory) of diphenyl-;m;da-zole-1-phenyl-methane (bifonazole) of Melting point 142C
are obtained.
Starting substance -CH-OH
38.8 9 (0.15 mole of 4-phenyl-benzophenone are dissolved in 200 ml of ethanolO and 3 9 ~0.075 mole) of sod;um borohydr;de are added. After the mixture has been heated under reflux for 15 hours, the cooled reaction 3Z~
Process Yar;ant Sa) 13.6 y (O.Z mole)of imidazoLe are dissolved in 150 ml of acetonitrile, and 3.5 ml of thionyl chloride are added at ~0C. 13 g ~0.05 mole)of diphenyL-phenyl-car-b;nol are added to the soLution of thionyl bis-imidazole thus obtained. After the mixture has been left to stand at room temperature f4r 15 hours, the solvent is removed by distillation in vacuo. The residue is taken up in chloroform and the mixture is washed with water. The organic phase is separated off, dr;ed over sod;um sulphate and filtered and the solvent ;s d;stilled off in vacuo.
The 07 ly residue is dissolved in ethyl acetate and the solution is freed from insoluble, resinous constituents by filtration The solvent is distilled off again in vacuo and the residue ;s purified by recrystallisati4n from acetonitrile. 8.7 9 (56% of theory) of diphenyl-;m;da-zole-1-phenyl-methane (bifonazole) of Melting point 142C
are obtained.
Starting substance -CH-OH
38.8 9 (0.15 mole of 4-phenyl-benzophenone are dissolved in 200 ml of ethanolO and 3 9 ~0.075 mole) of sod;um borohydr;de are added. After the mixture has been heated under reflux for 15 hours, the cooled reaction 3Z~
- 7 -m;xture is hydrolysed with water conta;ning a small amount of hydrochloric acid. The solid thereby formed ;s purif;ed by recrystallisation from ethanol. 36 g ~89X of theory) of diphenyl-phenyl-carbinol of melting point 7Z-73C are obtained.
Prscess Yariant (b/3.) 167 9 ~0.6 mole of diphenyl-phenyl-chloro-methane and 92 9 IS0.66 mole) of trimethyls;lyl;m;dazole, dissolved ;n 500 ml of acetonitrile, are heated under reflux for 15 hours. After the solvent has been dis-willed off, the crystalline residue is purified by recrystall;sat;on from ethyl acetate. 97 9 t52% of theory) of diphenyl-imidazol-1-yl-phenyl-methane ~bi-fonazole) of melting point 142C are obtained.
15 Example 1 Cream, oil-in-water Phase I
Sorbitan monostearate 2.0 9 Polyoxyethylene ~20)-sorb;tan monostearate 1.5 g 20 Synthetic spermacet; 3.0 9 Cetyl-stearyl alcohol 10.0 9 2-Octyldodecanol 13.5 9 Warm to 75C, stir, mix.
Phase II
25 Bifonazole 1.0 9 Add to phase I, stir, dissolve.
Phase III
~enzyl alcohol 1.0 9 Water, demineralised 68.0 9 Warm to 75C and add to phase II. Mix intensively, cool slowly to room temperature, with further stirring Homogen;se.
Example 2 Cream, oil-in-water Phase I
35 Sorbitan monostearate 1 - 3 9 Polyoxyethylene t20)-sorbitan ~2~;~327
Prscess Yariant (b/3.) 167 9 ~0.6 mole of diphenyl-phenyl-chloro-methane and 92 9 IS0.66 mole) of trimethyls;lyl;m;dazole, dissolved ;n 500 ml of acetonitrile, are heated under reflux for 15 hours. After the solvent has been dis-willed off, the crystalline residue is purified by recrystall;sat;on from ethyl acetate. 97 9 t52% of theory) of diphenyl-imidazol-1-yl-phenyl-methane ~bi-fonazole) of melting point 142C are obtained.
15 Example 1 Cream, oil-in-water Phase I
Sorbitan monostearate 2.0 9 Polyoxyethylene ~20)-sorb;tan monostearate 1.5 g 20 Synthetic spermacet; 3.0 9 Cetyl-stearyl alcohol 10.0 9 2-Octyldodecanol 13.5 9 Warm to 75C, stir, mix.
Phase II
25 Bifonazole 1.0 9 Add to phase I, stir, dissolve.
Phase III
~enzyl alcohol 1.0 9 Water, demineralised 68.0 9 Warm to 75C and add to phase II. Mix intensively, cool slowly to room temperature, with further stirring Homogen;se.
Example 2 Cream, oil-in-water Phase I
35 Sorbitan monostearate 1 - 3 9 Polyoxyethylene t20)-sorbitan ~2~;~327
- 8 -monostearate 0.5 Z.5 9 Synthetic spermacet; 2 - 4 9 Cetyl-stearyl alcohol 5 15 9 2-Octyldodecanol 5 - 25 9 warm to 75C, stir, m;x.
Phase II
Bifonazole 0.5 - 1.5 9 Add to phase I, stir, dissolve.
Phase III
Benzyl alcohol 0.5 - 1.5 9 water demineraLised quant. sat.
Warm to 75C and add to phase II, m;x ;ntens;vely, cool slowly to room temperature, with further st;rring.
Homogenise~
Test;ng of the act;v;ty of the agents according to the ;nvent;on on guinea p;gs infected with Trichophyton Trichophyton-;nfected P;rbri0th white guinea pigs weighing on average 600 g were used as the test model for comparative testing of the act;v;ty of the formulations accord;ng to the invent;on. The backs of the an;mals were shaved with electr;c cl;ppers such that stubble about 1/10 mm long rema;ned.
The an;mals were ;nfected w;th Tr;chophyton mentagrophyte by gently rubbing a spore suspens;on, wh;ch had been germ1nated in Sabouraud nutrient solution for 24 hours of the pathogen on an approximately 2 x 2 cm area of their shaved backs. 0.5 ml of germ suspens;on containing 1 - 3 x 105 infectious fungal particles, has appl;ed per an;mal.
With th;s mode of ;nfection, the f;rst symptoms of dermatophytosis man;fest themselves as redden;ng and scal;ng of the skin 2 - 3 days after ;nfect;on. In the case of untreated animals, the dermatophytosis ;s of max;mum severity about 14 days after ;nfectionr areas of ha;r loss and bloody integumentary defects within a scaly edge zone changed by inflammation.
Phase II
Bifonazole 0.5 - 1.5 9 Add to phase I, stir, dissolve.
Phase III
Benzyl alcohol 0.5 - 1.5 9 water demineraLised quant. sat.
Warm to 75C and add to phase II, m;x ;ntens;vely, cool slowly to room temperature, with further st;rring.
Homogenise~
Test;ng of the act;v;ty of the agents according to the ;nvent;on on guinea p;gs infected with Trichophyton Trichophyton-;nfected P;rbri0th white guinea pigs weighing on average 600 g were used as the test model for comparative testing of the act;v;ty of the formulations accord;ng to the invent;on. The backs of the an;mals were shaved with electr;c cl;ppers such that stubble about 1/10 mm long rema;ned.
The an;mals were ;nfected w;th Tr;chophyton mentagrophyte by gently rubbing a spore suspens;on, wh;ch had been germ1nated in Sabouraud nutrient solution for 24 hours of the pathogen on an approximately 2 x 2 cm area of their shaved backs. 0.5 ml of germ suspens;on containing 1 - 3 x 105 infectious fungal particles, has appl;ed per an;mal.
With th;s mode of ;nfection, the f;rst symptoms of dermatophytosis man;fest themselves as redden;ng and scal;ng of the skin 2 - 3 days after ;nfect;on. In the case of untreated animals, the dermatophytosis ;s of max;mum severity about 14 days after ;nfectionr areas of ha;r loss and bloody integumentary defects within a scaly edge zone changed by inflammation.
9 _ The formulations to be tested were applied locally to the reddened infection size of the animals once, on the 2nd day after infection, and were gently rubbed in with a horn spatula. In each case O.S ml of the formulations = S mg of active compound ~1X strength formulation was applied. The progress of the infection was evaluated daily up to the 20th day after infection.
The formulations according to the invention exhi-bit a very good action ;n this test.
If formulations which, besides bifonazole, con-tain no spreading agent are used for comparison, an effect corresponding tr, that of the formulations accord-ing to the invention is achieved only after three applicat~sns.
, ., ,
The formulations according to the invention exhi-bit a very good action ;n this test.
If formulations which, besides bifonazole, con-tain no spreading agent are used for comparison, an effect corresponding tr, that of the formulations accord-ing to the invention is achieved only after three applicat~sns.
, ., ,
Claims (9)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. An antimycotic agent in the form of a cream composition which has a high release of active compound and which contains bifonazole, or a pharmaceutically acceptable salt thereof, a sol-vent, one or more formulation auxiliaries and 5 to 25% by weight of a spreading agent.
2. An antimycotic agent according to claim 1, which contains 0.05 to 1.5% of bifonazole.
3. An antimycotic agent according to claim 1, which contains 0.1 to 1% of bifonazole.
4. An antimycotic agent according to claim 1, which contains 1.0% of bifonazole.
5. An antimycotic agent according to claim 1, 2 or 3 wherein the spreading agent is a silicone oil, a fatty acid ester, a triglyceride, a fatty alcohol or a fatty acid.
6. An antimycotic agent according to claim 1, 2 or 3 wherein the solvent is water or water-miscible solvent.
7. An antimycotic agent according to claim 1, 2 or 3 wherein the spreading agent is isopropyl myristate, isopropyl palmitate, isopropyl stearate, a capric or caprylic acid ester of a saturated fatty alcohol of 12 to 18 carbon atoms, a waxy fatty acid ester, a silicone oil or a mixture of isopropyl myristate, isopropyl stearate and isopropyl palmitate, and wherein the solvent is water, ethanol, isopropyl alcohol propylene glycol, 2-methoxyethanol, 2-ethoxyethanol, an ester, morpholine, dioxane, dimethylsulphoxide, dimethyl-formamide, tetrahydrofuran or cyclohexanone.
8. A process for preparing an antimycotic agent according to Claim 1 which comprises admixing bifonazole or a pharmaceutically acceptable salt thereof with a solvent, one or more formulation auxiliaries and 5-25% by weight of a spreading agent.
9. A process according to Claim 8 wherein the bifonazole or pharmaceuti-cally acceptable salt thereof is prepared by (a) reacting the carbinol of formula with thionyl-bis-imidazole, or (b) reacting the halogenomethane of the formula with (1) imidazole, (2) a silver or alkali metal salt of imidazole, or (3) a trimethylsilylimidazole of the formula and, if required, converting the obtained bifonazole to a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19833311701 DE3311701A1 (en) | 1983-03-30 | 1983-03-30 | ANTIMYCOTIC AGENTS WITH HIGH ACTIVE SUBSTANCE RELEASE IN THE FORM OF CREAM |
| DEP3311701.2 | 1983-03-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1212327A true CA1212327A (en) | 1986-10-07 |
Family
ID=6195162
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000450707A Expired CA1212327A (en) | 1983-03-30 | 1984-03-28 | Antimycotic agent with a high release of active compound, in the form of a cream |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS59184106A (en) |
| KR (1) | KR840008284A (en) |
| AU (1) | AU564956B2 (en) |
| BE (1) | BE899278A (en) |
| CA (1) | CA1212327A (en) |
| CH (1) | CH660126A5 (en) |
| CY (1) | CY1358A (en) |
| DE (1) | DE3311701A1 (en) |
| ES (3) | ES8503947A1 (en) |
| FR (1) | FR2543435B1 (en) |
| GB (1) | GB2137091B (en) |
| GR (1) | GR81485B (en) |
| IT (1) | IT1173761B (en) |
| KE (1) | KE3704A (en) |
| LU (1) | LU85271A1 (en) |
| PH (1) | PH20420A (en) |
| PT (1) | PT78313B (en) |
| SE (1) | SE8401748L (en) |
| ZA (1) | ZA842337B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5087620A (en) * | 1990-05-17 | 1992-02-11 | Bristol-Myers Squibb Co. | Controlled dermal penetration enhancement using imidazoles |
| ZA934007B (en) * | 1992-06-08 | 1994-03-09 | Schering Plough Healthcare | Stable imidazole anti-fungal powder compositions |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2461406C2 (en) * | 1974-12-24 | 1984-06-14 | Bayer Ag, 5090 Leverkusen | Azolyl- (1) -methanes and their salts, processes for their preparation and medicaments containing them |
| DE3045915A1 (en) * | 1980-12-05 | 1982-07-08 | Bayer Ag, 5090 Leverkusen | ANTIMYCOTIC AGENTS WITH HIGH ACTIVE SUBSTANCE RELEASE IN THE FORM OF ELASTIC LIQUID PLASTERS |
| DE3045914A1 (en) * | 1980-12-05 | 1982-07-22 | Bayer Ag, 5090 Leverkusen | ANTIMYCOTIC AGENTS WITH HIGH ACTIVE SUBSTANCE RELEASE IN THE FORM OF ELASTIC LIQUID PLASTERS |
| DE3045913A1 (en) * | 1980-12-05 | 1982-07-08 | Bayer Ag, 5090 Leverkusen | ANTIMYCOTIC AGENTS WITH HIGH ACTIVE SUBSTANCE RELEASE |
| DE3106635A1 (en) * | 1981-02-23 | 1982-09-09 | Bayer Ag | ANTIMYCOTIC AGENT WITH HIGH ACTIVE SUBSTANCE RELEASE IN THE FORM OF PEN |
-
1983
- 1983-03-30 DE DE19833311701 patent/DE3311701A1/en not_active Withdrawn
-
1984
- 1984-03-22 ES ES530846A patent/ES8503947A1/en not_active Expired
- 1984-03-26 JP JP59056374A patent/JPS59184106A/en active Pending
- 1984-03-26 PT PT78313A patent/PT78313B/en unknown
- 1984-03-27 PH PH30446A patent/PH20420A/en unknown
- 1984-03-28 CA CA000450707A patent/CA1212327A/en not_active Expired
- 1984-03-28 GR GR74236A patent/GR81485B/el unknown
- 1984-03-28 LU LU85271A patent/LU85271A1/en unknown
- 1984-03-29 SE SE8401748A patent/SE8401748L/en unknown
- 1984-03-29 GB GB08408067A patent/GB2137091B/en not_active Expired
- 1984-03-29 FR FR8404906A patent/FR2543435B1/en not_active Expired
- 1984-03-29 CH CH1598/84A patent/CH660126A5/en not_active IP Right Cessation
- 1984-03-29 AU AU26236/84A patent/AU564956B2/en not_active Expired
- 1984-03-29 CY CY135884A patent/CY1358A/en unknown
- 1984-03-29 BE BE0/212659A patent/BE899278A/en not_active IP Right Cessation
- 1984-03-29 ZA ZA842337A patent/ZA842337B/en unknown
- 1984-03-29 IT IT20303/84A patent/IT1173761B/en active
- 1984-03-30 KR KR1019840001659A patent/KR840008284A/en not_active Application Discontinuation
- 1984-12-31 ES ES539289A patent/ES539289A0/en active Granted
- 1984-12-31 ES ES539290A patent/ES8601693A1/en not_active Expired
-
1987
- 1987-03-09 KE KE3704A patent/KE3704A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ES539290A0 (en) | 1985-11-16 |
| GB2137091A (en) | 1984-10-03 |
| ES8601693A1 (en) | 1985-11-16 |
| CH660126A5 (en) | 1987-03-31 |
| DE3311701A1 (en) | 1984-10-04 |
| AU2623684A (en) | 1984-10-04 |
| IT8420303A0 (en) | 1984-03-29 |
| SE8401748D0 (en) | 1984-03-29 |
| FR2543435A1 (en) | 1984-10-05 |
| ES8601692A1 (en) | 1985-11-16 |
| ZA842337B (en) | 1984-11-28 |
| PT78313B (en) | 1986-06-02 |
| FR2543435B1 (en) | 1988-06-17 |
| SE8401748L (en) | 1984-10-01 |
| ES539289A0 (en) | 1985-11-16 |
| PH20420A (en) | 1987-01-05 |
| KE3704A (en) | 1987-03-27 |
| GB2137091B (en) | 1986-10-01 |
| CY1358A (en) | 1987-08-07 |
| ES530846A0 (en) | 1985-04-16 |
| LU85271A1 (en) | 1984-11-14 |
| AU564956B2 (en) | 1987-09-03 |
| BE899278A (en) | 1984-10-01 |
| PT78313A (en) | 1984-04-01 |
| GB8408067D0 (en) | 1984-05-10 |
| GR81485B (en) | 1984-12-11 |
| IT1173761B (en) | 1987-06-24 |
| JPS59184106A (en) | 1984-10-19 |
| ES8503947A1 (en) | 1985-04-16 |
| KR840008284A (en) | 1984-12-14 |
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