GB2137091A - Antimycotic Agent With a High Release of Active Compounds, in the Form of a Cream - Google Patents

Antimycotic Agent With a High Release of Active Compounds, in the Form of a Cream Download PDF

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Publication number
GB2137091A
GB2137091A GB08408067A GB8408067A GB2137091A GB 2137091 A GB2137091 A GB 2137091A GB 08408067 A GB08408067 A GB 08408067A GB 8408067 A GB8408067 A GB 8408067A GB 2137091 A GB2137091 A GB 2137091A
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Prior art keywords
appropriate
reacted
bifonazole
diluent
antimycotic
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Granted
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GB08408067A
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GB2137091B (en
GB8408067D0 (en
Inventor
Karlheinz Adams
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Bayer AG
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Bayer AG
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    • 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

The invention relates to antimycotic cream compositions containing bifonazole as an antimycotic compound and including 5-25% by weight of a spreading agent, which is preferably selected from silicone oils, fatty acids, fatty acid esters, fatty alcohols and triglycerides.

Description

SPECIFICATION Antimycotic Agent with a High Release of Active Compounds, in the Form of a Cream The present invention relates to a novel formulation of the known antimycotic compound bifonazole of the formula
which has a relatively high release of the active compound and thereby permits short-term therapy.
Formulations of antimycotic derivatives have already been disclosed for the treatment of mycoses in humans, above all mycoses of the skin and cutaneous appendages. A therapy time of 1 4 to 21 days has been required for complete cure with these formulations.
In order to shorten the duration of therapy, for example in the case of vaginal or bucall 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 suitability for this, because only a small amount of the active compound available dissolves in the volume of liquid at the infection site. Thus, if a shortening in the duration of therapy, for example to a few days with a single daily administration, it is to be achieved, with or without a further increase in the concentration of active compound, optimum bioavailability of the active compound must be ensured.
It has now been found that formulations of bifonazole which contain 525% of a spreading agent, in addition to the conventional formulation substances and 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 ap increase up to a power of ten.
The formulations according to the invention are prepared by a process in which, in a manner which is known per se, either (a) the carbinol of the formula
is reacted with thionyl-bis-imidazole, if appropriate in the presence of a diluent, or (b) the halogeno-methane of the formula
is either 1) reacted with imidazole, if appropriate in the presence of an acid-binding agent and if appropriate in the presence of a diluent, or 2) reacted with the silver salt or alkali metal salts of the imidazole, if appropriate in the presence of a diluent, or 3) reacted with trimethylsilylimidazole of the formula
if appropriate in the presence of a diluent, and, if appropriate, the azol-1-yl-methane thereby obtained is reacted with physiologically acceptable acids, and the product thereby obtained is mixed with 525% of a spreading agent, conventional formulation auxiliaries and a solvent.
The agents according to the invention contain bifonazole in amounts of 0.05%-i .5%, preferably of 0.1 --1 and very particularly preferably 1%.
Spreading agents are understood as meaning oily liquids which distribute themselves particularly readily on the skin [R. Keymer, Pharm. Ind. 32 [1970], 577-581]. The following compounds 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-fatty alcohols, isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated fatty alcohols of C,2C8 chain lengths, iso-propyl 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, triglyceride 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 suitable; isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated fatty alcohols of C,2C,8 chain lengths, waxy fatty acid esters, such as synthetic duck uropygial gland fat, silicone oils and a mixture of isopropyl myristate/isopropyl stearate/isopropyl palmitate.
The following auxiliairies and/or formulation base auxiliaries can be used in the preparation of the agents according to the invention.
"Glyceryl stearates", a mixture Oil-in-water cream base, of monoglycerides and diglycerides not self-emulsifying of palmitic acid and stearic acid Colloidally disperse mixture of Oil-in-water emulsion cetyl-stearyl alcohol and sodium base, self-emulsifying cetyl-stearyl sulphate Esters of a branched fatty acid Oil component with a with saturated C,6C,8-fatty marked hydrophobic effect alcohols for skin protection products Cetyl palmitate Synthetic spermaceti, consistency for creams, ointments, emulsions Polyethylene stearate Nonionic hydrophylic emulsifier Cetyl-stearyl alcohol oxy- Nonionic oil-in-water emulsifier ethylated with about 1 2 moles of ethylene oxide Cetyl-stearyl alcohol oxy- Nonionic oil-in-water emulsifier ethylated with about 30 moles of ethylene oxide Sorbitan and glycerol fatty Nonionic emulsifier acid esters Suitable formulation auxiliaries are: a. substances which, for example, can stabilise a suspension, for example colloidal silicic acid, montmorillonites and the like.
b. Surfactants (includes 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. cationic, such as cetyltrimethylammonium chloride; 3. ampholytic, such as di-Na-N-lauryl-P-iminodipropionate or lecithin; and 4. nonionic, for example polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan 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 antioxidants, for example tocopherols or butylhydroxyanisole.
d. Softeners, for example propylene glycol, glycerol, di- and tri-propylene glycol, triethanoiamine, waxes and the like.
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, dioxane, dimethylsulphoxide, dimethylformamide, tetrahydrofuran and cyclohexanone.
One or more solvents can be used in the preparation of the formulations according to tlie invention.
Preparation of the Active Compound Bifonazole
Process Variant (a) 13.6 g (0.2 mole) of imidazole are dissolved in 1 50 ml of acetonitrile, and 3.5 ml of thionyl chloride are added at 100C. 13 g (0.05 mole) of diphenyl-phenyl-carbinol are added to the solution of thionyl-bis-imidazole thus obtained. After the mixture has been left to stand at room temperature for 1 5 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, dried over sodium sulphate and filtered and the solvent is distilled off in vacuo. The oily 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 is purified by recrystallisation from acetonitrile. 8.7 g (56% of theory) of diphenyl-imidazole-1-phenyl-methane (bifonazole) of melting point 1 420 C are obtained.
Starting Substance
38.8 g (0.1 5 mole) of 4-phenyl-benzophenone are dissolved in 200 ml of ethanol, and 3 g (0.075 mole) of sodium borohydride are added. After the mixture has been heated under reflux for 1 5 hours, the cooled reaction mixture is hydrolysed with water containing a small amount of hydrochloric acid.
The solid thereby formed is purified by recrystallisation from ethanol. 36 g (89% of theory) of diphenylphenyl-carbinol of melting point 72-730C are obtained.
Process Variant (b/3.) 1 67 g (0.6 mole) of diphenyl-phenyl-chloromethane and 92 g (0.66 mole) of trimethylsilylimidazole, dissolved in 500 ml of acetonitrile, are heated under reflux for 1 5 hours. After the solvent has been distilled off, the crystalline residue is purified by recrystallisation from ethyl acetate.
97 g (52% of theory) of diphenyl-imidazol-1-yl-phenyl-methane (bifonazole) of melting point 1420C are obtained.
EXAMPLE 1 Cream, Oil-in-Water Phase I Sorbitan monostearate 2.0 g Polyoxyethylene (20)-sorbitan monostearate 1.5 g Synthetic spermaceti 3.Q g Cetyl-stearyl alcohol 10.0 g 2-Octyidodecanol 13.5 g Warm to 750 C, stir, mix.
Phase Il Bifonazole 1.0 g Add to phase I, stir, dissolve.
Phase Ill Benzyl alcohol 1.09 Water, demineralised 68.0 g Warm to 750C and add to phase ll. Mix intensively, cool slowly to room temperature, with further stirring. Homogenise.
EXAMPLE 2 Cream, Oil-in-Water Phase I Sorbitan monostearate 1-3 g Polyoxyethylene (20)-sorbitan monostearate 0.5-2.5 g Synthetic spermaceti 2-4 g Cetyl-stearyl alcohol 5-1 5 g 2-Octyidodecanol 5-25 g Warm to 750C, stir, mix.
Phase II Bifonazole 0.5-1.5g Add to phase I, stir, dissolve.
Phase Ill Benzyl alcohol 0.5-1.5g Water demineralised quant. sat.
Warm to 750C and add to phase II, mix intensively, cool slowly to room temperature, with further stirring. Homogenise.
Testing of the Activity of the Agents According to the Invention on Guinea Pigs Infected with Trichophyton Trichophyton-infected Pirbright white guinea pigs weighing on average 600 g were used as the test model for comparative testing of the activity of the formulations according to the invention. The backs of the animals were shaved with electric clippers such that stubble about 1/10 mm long remained.
The animals were infected with Trichophyton mentagrophytes by gently rubbing a spore suspension, which had been germinated in Sabouraud nutrient solution for 24 hours, of the pathogen on an approximately 2x2 cm area of their shaved backs. 0.5 ml of germ suspension containing 13 x105 infectious fungal particles, was applied per animal.
With this mode of infection, the first symptoms of dermatophytosis manifest themselves as reddening and scaling of the skin 2-3 days after infection. In the case of untreated animals, the dermatophytosis is of maximum severity about 14 days after infection: areas of hair loss and bloody integumentary defects within a scaly edge zone changed by inflammation.
The formulations to be tested were applied locally to the reddened infection site of the animals once, on the 2nd day after infection, and were gently rubbed in with a horn spatula. In each case 0.5 mi of the formulations=5 mg of active compound (1% 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 exhibit a very good action in this test.
If formulation which, besides bifonazole, contain no spreading agent are used for comparison, an effect corresponding to that of the formulations according to the invention is achieved only after three applications.
It will of course be understood that the present invention has been described above purely by way of example, and modifications of detail can be made within the scope and spirit of the invention.

Claims (7)

1. Antimycotic agents with a higher release of the active compounds and containing bifonazole, a solvent and conventional formulation auxiliaries, characterised in that they contain 525% by weight of a spreading agent.
2. Antimycotic agents according to Claim 1, characterised in that they contain 0.051.5%, preferably 0.11%, of bifonazole.
3. Antimycotic agents according to Claim 1, characterised in that they contain 1.0% of bifonazole.
4. Process for the preparation of formulations of bifonazole, characterised in that, in a manner which is known per se, either (a) the carbinol of the formula
is reacted with thionyl-bis-imidazole, if appropriate in the presence of a diluent, or (b) the halogeno-methane of the formula
is either 1) reacted with imidazole, if appropriate in the presence of an acid-binding agent and if appropriate in the presence of a diluent, or 2) reacted with the silver salt or alkali metal salts of the imidazole, if appropriate in the presence of a diluent, or 3) reacted with trimethylsilylimidazole of the formula
if appropriate in the presence of a diluent, and, if appropriate, the azol-1-yl-methanes thereby obtained is reacted with physiologically acceptable acids, and the product thereby obtained is mixed with 525% of a spreading agent, conventional formulation auxiliaries and a solvent.
5. Antimycotic agent according to Claim 1, substantially as described in Example 1 or Example 2.
6. Process according to Claim 4, substantially as hereinbefore described under "Process variant (a)" or "Process variant (b/3)".
7. Composition as defined in Claim 1 for use in combating mycoses.
GB08408067A 1983-03-30 1984-03-29 Antimycotic agent with a high release of active compounds, in the form of a cream Expired GB2137091B (en)

Applications Claiming Priority (1)

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

Publications (3)

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GB8408067D0 GB8408067D0 (en) 1984-05-10
GB2137091A true GB2137091A (en) 1984-10-03
GB2137091B GB2137091B (en) 1986-10-01

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ID=6195162

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GB08408067A Expired GB2137091B (en) 1983-03-30 1984-03-29 Antimycotic agent with a high release of active compounds, in the form of a cream

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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) ES530846A0 (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)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0457333A2 (en) * 1990-05-17 1991-11-21 Bristol-Myers Squibb Company Topical composition
WO1993025238A1 (en) * 1992-06-08 1993-12-23 Schering-Plough Healthcare Products, Inc. Stable imidazole anti-fungal powder compositions

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0054205A1 (en) * 1980-12-05 1982-06-23 Bayer Ag Anti-fungal composition in emulsion form with a higher release rate of the drug
EP0058887A1 (en) * 1981-02-23 1982-09-01 Bayer Ag Antifungal compositions with a higher rate of the drug release as a stick

Family Cites Families (3)

* Cited by examiner, † Cited by third party
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
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
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0054205A1 (en) * 1980-12-05 1982-06-23 Bayer Ag Anti-fungal composition in emulsion form with a higher release rate of the drug
EP0058887A1 (en) * 1981-02-23 1982-09-01 Bayer Ag Antifungal compositions with a higher rate of the drug release as a stick

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0457333A2 (en) * 1990-05-17 1991-11-21 Bristol-Myers Squibb Company Topical composition
EP0457333A3 (en) * 1990-05-17 1992-12-02 Bristol-Myers Squibb Company Topical composition
WO1993025238A1 (en) * 1992-06-08 1993-12-23 Schering-Plough Healthcare Products, Inc. Stable imidazole anti-fungal powder compositions
US5711954A (en) * 1992-06-08 1998-01-27 Schering-Plough Healthcare Products, Inc. Stable imidazole anti-fungal powder compositions

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Publication number Publication date
ES539289A0 (en) 1985-11-16
SE8401748D0 (en) 1984-03-29
GB2137091B (en) 1986-10-01
PH20420A (en) 1987-01-05
CY1358A (en) 1987-08-07
GR81485B (en) 1984-12-11
ES8601692A1 (en) 1985-11-16
CA1212327A (en) 1986-10-07
BE899278A (en) 1984-10-01
IT8420303A0 (en) 1984-03-29
SE8401748L (en) 1984-10-01
FR2543435A1 (en) 1984-10-05
ES8601693A1 (en) 1985-11-16
DE3311701A1 (en) 1984-10-04
ES8503947A1 (en) 1985-04-16
LU85271A1 (en) 1984-11-14
IT1173761B (en) 1987-06-24
JPS59184106A (en) 1984-10-19
PT78313A (en) 1984-04-01
KE3704A (en) 1987-03-27
ES530846A0 (en) 1985-04-16
FR2543435B1 (en) 1988-06-17
ZA842337B (en) 1984-11-28
PT78313B (en) 1986-06-02
AU2623684A (en) 1984-10-04
AU564956B2 (en) 1987-09-03
ES539290A0 (en) 1985-11-16
KR840008284A (en) 1984-12-14
GB8408067D0 (en) 1984-05-10
CH660126A5 (en) 1987-03-31

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