LU85271A1 - ANTIMYCOTIC AGENT WITH HIGH ACTIVE SUBSTANCE RELEASE IN THE FORM OF CREAM - Google Patents
ANTIMYCOTIC AGENT WITH HIGH ACTIVE SUBSTANCE RELEASE IN THE FORM OF CREAM Download PDFInfo
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- LU85271A1 LU85271A1 LU85271A LU85271A LU85271A1 LU 85271 A1 LU85271 A1 LU 85271A1 LU 85271 A LU85271 A LU 85271A LU 85271 A LU85271 A LU 85271A LU 85271 A1 LU85271 A1 LU 85271A1
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- bifonazole
- optionally
- diluent
- imidazole
- cream
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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
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- 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)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
_ 1 - /* '_ 1 - /* '
Antimykotisches Mittel mit hoher Wirkstoff-Freisetzung in Form von CremeAntifungal agent with high active ingredient release in the form of cream
Die vorliegende Erfindung betrifft eine neuartige Formulierung des bekannten antimykotischen Bifonazols der FormelThe present invention relates to a novel formulation of the known antifungal bifonazole of the formula
NN
u.u.
5 die eine höhere Freisetzung des Wirkstoffes aufweist und dadurch eine Kurzzeittherapie ermöglicht.5 which has a higher release of the active ingredient and thus enables short-term therapy.
Für die Behandlung von Mykosen beim Menschen, vor allem * die Mykosen der Haut und der Hautanhangsgebilde, sind be reits Zubereitungen von antimykotischen Derivaten be-' 10 kannt geworden. Mit diesen Zubereitungen wurden für eine vollständige Sanierung 14 bis 21 Tage Therapiezeit benötigt.Preparations of antifungal derivatives have already been known for the treatment of mycoses in humans, especially * the mycoses of the skin and the appendages of the skin. With these preparations, 14 to 21 days of therapy were required for complete refurbishment.
Um z.B. bei Vaginal- oder Buccal-Mykosen oder Dermatomykosen zu einer Verkürzung der Therapiedauer zu kommen,To e.g. to reduce the duration of therapy for vaginal or buccal mycoses or dermatomycoses,
Le A 22 266-Ausland t - 2 - t - - benötigt man, besonders zur Eliminierung der Keime, bzw. um eine mykologisch gesicherte Sanierung zu erzielen, eine höhere Freisetzung der Wirkstoffe im wäßrigen Milieu. Dafür sind die bekannten Formulierungen 5 nur begrenzt geeignet, weil sich von dem vorhandenen Wirkstoffangebot nur ein kleiner Anteil im Flüssigkeitsvolumen am Ort der Infektion löst. Wenn man nun durch oder ohne weitere Erhöhung der Wirkstoffkonzentration eine Verkürzung der Therapiedauer, z.B. auf einige Tage 10 bei täglicher einmaliger Applikation, erreichen will, muß man für eine optimale Bioverfügbarkeit des Wirkstoffes Sorge tragen.Le A 22 266 abroad t - 2 - t - - one needs, especially to eliminate the germs or to achieve a mycologically safe remediation, a higher release of the active substances in the aqueous environment. The known formulations 5 are only suitable for this to a limited extent, because only a small proportion of the liquid volume at the site of the infection dissolves from the available active substance. If one now shortens the duration of therapy by or without further increasing the active substance concentration, e.g. to reach 10 for a few days with a single daily application, care must be taken to ensure optimal bioavailability of the active ingredient.
Es wurde nun'gefunden, daß solche Formulierungen des Bifonazols, die neben üblichen Formulierungsstoffen 1 5 und Lösungsmitteln 5 - 25 % Spreitmittel enthalten, den Wirkstoff in höherem Maße freisetzen und dadurch eine Verkürzung der Therapiedauer auf einige Tage ermöglichen. Dieser Effekt der höheren Wirkstoff-Frei-setzung kann bis zu einer Zehnerpotenz erreichen.It has now been found that such formulations of bifonazole, which in addition to conventional formulations 15 and solvents contain 5-25% spreading agent, release the active ingredient to a greater extent and thereby enable the duration of therapy to be shortened to a few days. This effect of the higher release of active ingredient can reach up to a power of ten.
20 Die erfindungsgemäßen Zubereitungen werden hergestellt, indem man in an sich bekannter Weise entweder (a) das Carbinol der FormelThe preparations according to the invention are prepared by either (a) the carbinol of the formula in a manner known per se
OHOH
mit Thionyl-bis-imidazol gegebenenfalls in Gegen-25 wart eines Verdünnungsmittels, umsetzt, oderwith thionyl-bis-imidazole, optionally in the presence of a diluent, or
Le A 22 266 ft - 3 - i f (b) das Halogen-methan der FormelLe A 22 266 ft - 3 - i f (b) the halomethane of the formula
Hal entweder 1) mit Imidazol gegebenenfalls in Gegenwart eines 5 Säurebindemittels und gegebenenfalls in Gegenwart eines Verdünnungsmittels umsetzt, oder 2) mit Silber- oder Alkalisalzen des Imidazols, gegebenenfalls in Gegenwart eines Verdünnungsmittels, umsetzt, oder 10 j) mit Trimethylsilylimidazol der FormelHal either 1) with imidazole, optionally in the presence of an acid binder and optionally in the presence of a diluent, or 2) with silver or alkali metal salts of imidazole, optionally in the presence of a diluent, or 10 j) with trimethylsilylimidazole of the formula
Si(CH3) 3 NSi (CH3) 3 N
/ \ 11 ü-n gegebenenfalls in Gegenwart eines Verdünnungsmittels, umsetzt, und das dabei erhaltene Azolyl-(1)-methan gegebenenfalls mit physiologisch verträglichen Säuren 15 umsetzt, und das dabei erhaltene Produkt mit 5 - 25 %/ \ 11 ü-n optionally in the presence of a diluent, and the azolyl- (1) -methane obtained is optionally reacted with physiologically acceptable acids 15, and the product obtained is 5 - 25%
Spreitmittel, üblichen Formulierungshilfsstoffen und Lösungsmittel vermischt.Spreading agents, customary formulation auxiliaries and solvents are mixed.
Le A 22 266 - 4 - ft ft i j iLe A 22 266 - 4 - ft ft i j i
Bifonazol ist in den erfindungsgemäßen Mitteln in Mengen von 0,05 % - 1,5 %, vorzugsweise von 0,1 - 1 %, ganz besonders bevorzugt 1 %, vorhanden.Bifonazole is present in the agents according to the invention in amounts of 0.05% - 1.5%, preferably 0.1 - 1%, very particularly preferably 1%.
Unter Spreitmitteln werden ölige Flüssigkeiten ver-5 standen, die sich auf der Haut besonders gut verteilen /R. Keymer, Pharm. Ind. 32 /1970?/ 577-583.7· Für die erfindungsgemäßen Mittel eignen sich als Spreitmittel insbesondere folgende Verbindungen:Spreading agents are understood to be oily liquids that are particularly well distributed on the skin / R. Keymer, Pharm. Ind. 32/1970? / 577-583.7 · The following compounds are particularly suitable as spreading agents for the agents according to the invention:
Silikonöle verschiedener Viskosität.Silicone oils of different viscosities.
10 Fettsäureester, wie Ethylstearat, Di-n-butyl-adipat,10 fatty acid esters, such as ethyl stearate, di-n-butyl adipate,
Laurinsäurehexylester, Dipropylen-glykolpelargonat, Ester einer verzweigten Fettsäure mittlerer Kettenlänge mit gesättigten Fettalkoholen C16"C18' Isopropylmyristat, Iso-propylpalmitat, Capryl/Caprinsäureester von gesättigten 15 Fettalkoholen der Kettenlänge ci2-ci8' Isopropylstearat, ölsäureoleylester, ölsäuredecylester, Ethyloleat, Milchsäureethylester, wachsartige Fettsäureester wie künstliches Entenbürzeldrüsenfett, Dibutylphthalat, Adipin-säurediisopropylester, letzterem verwandte Estergemische 20 u.a.Hexyl laurate, dipropylene glycol pelargonate, ester of a branched fatty acid of medium chain length with saturated fatty alcohols C16 "C18 'isopropyl myristate, isopropyl palmitate, caprylic / capric acid ester of saturated 15 fatty alcohols of chain length ci2-ci8' isopropyl stearate, oleic acid ethyl ester, oleic acid ethyl ester, oleic acid ethyl ester, oleic acid ethyl ester, oleic acid ethyl estersilate, oleic acid ethyl ester ethyl acetate such as artificial duckling gland fat, dibutyl phthalate, adipic acid diisopropyl ester, ester mixtures related to the latter 20 and others
Triglyceride, wie Capryl/Caprinsäuretriglycerid, Triglyceridgemische mit Pflanzenfettsäuren der Kettenlänge C8*"^12 0c^er anderen speziell ausgewählten natürlichen Fettsäuren, Partialglyceridgemische gesättigter oder 25 ungesättigter evtl, auch hydroxylgruppenhaltige Fettsäuren, Monoglyceride der Cg/C^-Fettsäuren u.a.Triglycerides, such as caprylic / capric triglyceride, triglyceride mixtures with vegetable fatty acids of chain length C8 * "^ 12 0c ^ er other specially selected natural fatty acids, partial glyceride mixtures of saturated or 25 unsaturated, possibly also fatty acids containing hydroxyl groups, monoglycerides of Cg / C ^ fatty acids and others.
'Le A 22 266 . . ‘ .'Le A 22 266. . ’.
« - 5 - *«- 5 - *
Fettalkoholey wie Isotridecylalkohol, 2-0ctyldodecanol, Cetylstearyl-Alkohol, Oleylalkohol.Fatty alcohols such as isotridecyl alcohol, 2-0ctyldodecanol, cetylstearyl alcohol, oleyl alcohol.
Fettsäuren/ wie z.B. ölsäure.Fatty acids / such as oleic acid.
Besonders gut geeignete spreitende öle sind die folgen-5 den: Isopropylmyristat, Isopropylpalmitat, Capryl/Caprin-säureester von gesättigten Fettalkoholen der Kettenlänge c-|2“c18' wac^sart^9e Fettsäureester wie künstliches Entenbürzeldrüsenfett, Silikonöle, Isopropylmyristat/ Isopropy1stearat/Isopropylpalmitat-Gemisch.Particularly suitable spreading oils are the follow-5 to: isopropyl palmitate, caprylic / capric säureester c- of saturated fatty alcohols of chain length | 2 'c18' wac ^ sart ^ 9e fatty acid ester such as artificial duck preen gland oil, silicone oils, isopropyl / Isopropy1stearat / isopropyl -Mixture.
10 Folgende Hilfs- und/oder Formulierungs-Grundhilfsstoffe können bei der Herstellung der erfindungsgemäßen Mittel verwendet werden.The following auxiliaries and / or formulation auxiliaries can be used in the preparation of the agents according to the invention.
"Glycerylstearate", Gemisch von Mono- 0/W Creme-Grund- und Diglyceriden der Palmitin- und läge nicht selbst 15 Stearinsäure emulgierend"Glyceryl stearate", a mixture of mono 0 / W cream base and diglycerides of palmitin and would not itself emulsify 15 stearic acid
Kolloiddisperses Gemisch aus Cetyl- 0/W Emulsions-Colloid-disperse mixture of cetyl 0 / W emulsion
Stearylalkohol und Natrium-Cetyl- Grundlage selbstStearyl alcohol and sodium cetyl base itself
Stearylsulfat emulgierendStearyl sulfate emulsifying
Ester einer verzweigten Fettsäure Ölkomponente mit 20 mit gesättigten Fettalkoholen ausgeprägt hydro- C16_C18 phoben Effekt fürEster of a branched fatty acid oil component with 20 with saturated fatty alcohols pronounced hydro- C16_C18 phobic effect for
Hautschutzpräpa rateSkin protection preparations
Le A 22 266 t ft -6-Le A 22 266 t ft -6-
Cetylpalraitat synthetischerCetyl palraitat synthetic
Walrat, Konsistenz für Cremes, Salben,Whale, consistency for creams, ointments,
CC.
EmulsionenEmulsions
Polyethylenstearat nichtionogener hydrophiler EmulgatorPolyethylene stearate non-ionic hydrophilic emulsifier
Cetylstearylalkohol mit ca. 12 Mol nichtionogener 10 Ethylenoxid 0/W EmulgatorCetylstearyl alcohol with approx. 12 mol non-ionic 10 ethylene oxide 0 / W emulsifier
Cetylstearylalkohol mit ca. 30 Mol nichtionogenerCetylstearyl alcohol with about 30 moles of nonionic
Ethylenoxid O/W EmulgatorEthylene oxide O / W emulsifier
Sorbitan und Glycerinfettsäureester nichtionogenerSorbitan and glycerin fatty acid esters non-ionogenic
Emulgator 15 Als Formulierungshilfsstoffe kommen in Frage: a. Substanzen, die z.B. eine Suspension stabilisieren können, z.B. kolloidale Kieselsäure, Montmorillonite u. a.Emulsifier 15 Possible formulation auxiliaries are: a. Substances e.g. can stabilize a suspension, e.g. colloidal silica, montmorillonite and the like a.
Le A 22 266 % t % - 7 - b. Tenside (beinhaltet Emulgatoren und Netzmittel), z.B.Le A 22 266% t% - 7 - b. Surfactants (contains emulsifiers and wetting agents), e.g.
1. anionaktive, wie Na-Laurylsulfat, Fettalkohol“ ethersulfate, Mono/Dialkylpolyglykolether-orthophosphorsäureester-Monoethanolaminsalz; 5 2. kationaktive/ wie Cetyltrimethylammoniumchlorid; 3. ampholytische, wie Di-Na-N-lauryl-ß-ininodi-propionat oder Lecithin; 4. nicht ionogene, z.B. polyoxyethyliertes Rizinusöl, polyoxyethyliertes Sorbitan-Monooleat, Sor- 10 bitan-Monostearat, Cetylalkohol. Glycerinmono- stearat, Polyoxyethylenstearat, Alkylphenolpolyglykolether .1. anionic, such as Na lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt; 5 2. cationic / like cetyltrimethylammonium chloride; 3. ampholytic, such as di-Na-N-lauryl-β-ininodipropionate or lecithin; 4. non-ionic, e.g. polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sor 10 bitan monostearate, cetyl alcohol. Glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ether.
c. Stabilisatoren zur Verhinderung des bei einigen Wirkstoffen eintretenden chemischen Abbaues, wie 15 Antioxydantien, z.B. Tocopherole, Butylhydroxyanisol.c. Stabilizers to prevent chemical degradation from some active ingredients, such as 15 antioxidants, e.g. Tocopherols, butylated hydroxyanisole.
d. Weichmacher, z.B. Propylenglykol, Glycerin, Di- und Tripropylenglykol, Triaethanolamin, Wachse etc.d. Plasticizers, e.g. Propylene glycol, glycerin, di- and tripropylene glycol, triaethanolamine, waxes etc.
Als Lösungsmittel sind Wasser und auch alle mit Wasser mischbaren Lösungsmittel geeignet. In Betracht kommen 20 z.B. Alkanole, wie Ethanol und Isopropylalkohol, Propylenglykol, Methylcellosolve, Cellosolve, Ester, Morpholine, Dioxan, Dimethylsulfoxid, Dimethylformamid, Tetrahydrofuran, Cyclohexanon.Water and all water-miscible solvents are suitable as solvents. Consider 20 e.g. Alkanols, such as ethanol and isopropyl alcohol, propylene glycol, methyl cellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, cyclohexanone.
Bei der Herstellung der erfindungsgemäßen Formu-25 lierungen können ein oder mehrere Lösungsmittel eingesetzt werden.One or more solvents can be used in the preparation of the formulations according to the invention.
Le A 22 266 * ♦ « - 8 -Le A 22 266 * ♦ «- 8 -
Herstellung des Wirkstoffs Bifonazol /1 /1% ~Production of the active ingredient bifonazole / 1/1% ~
! II! II
-N-N
Verfahrensvariante (a) 13,6 g (0,2 Mol) Imidazol werden in 150 ml Acetonitril ge-5 löst und bei 10°C mit 3,5 ml Thionylchlorid versetzt. Zu der so erhaltenen Lösung von Thionyl-bis-imidazol gibt man 13 g (0,05 Mol) Diphenyl-phenyl-carbinol. Nach 15-stündigem Stehen bei Raumtemperatur wird das Lösungsmittel durch Abdestillieren im Vakuum entfernt. Der Rückstand wird in 10 Chloroform aufgenommen und mit Wasser gewaschen. Die organische Phase wird abgetrennt, über Natriumsulfat getrocknet, filtriert und das Lösungsmittel im Vakuum abdestilliert. Der ölige Rückstand wird in Essigester gelöst und durch Filtration von unlöslichen, harzigen Be-15 standteilen befreit. Das Lösungsmittel wird erneut im Vakuum abdestilliert und der Rückstand durch Umkristallisation aus Acetonitril gereinigt. Man erhält 8,7 g (56 % der Theorie) Diphenyl-imidazolyl-(1 )-phenyl-methan (Bifonazol) vom Schmelzpunkt 142°C.Process variant (a) 13.6 g (0.2 mol) of imidazole are dissolved in 150 ml of acetonitrile and 3.5 ml of thionyl chloride are added at 10 ° C. 13 g (0.05 mol) of diphenyl-phenyl-carbinol are added to the solution of thionyl-bis-imidazole thus obtained. After standing at room temperature for 15 hours, the solvent is removed by distillation in vacuo. The residue is taken up in 10 chloroform and washed with water. The organic phase is separated off, dried over sodium sulfate, filtered and the solvent is distilled off in vacuo. The oily residue is dissolved in ethyl acetate and the insoluble, resinous constituents are removed by filtration. The solvent is distilled off again in vacuo and the residue is purified by recrystallization from acetonitrile. 8.7 g (56% of theory) of diphenyl-imidazolyl- (1) -phenyl-methane (bifonazole) of melting point 142 ° C. are obtained.
Le A 22 266 b - 9 - t 4.Le A 22 266 b - 9 - t 4.
AusgangsproduktStarting product
OHOH
38,8 g (0,15 Mol) 4-Phenyl-benzophenon werden in 200 ml Ethanol gelöst und mit 3 g (0,075 Mol) Natriumborhydrid 5 versetzt. Nach 15-stündigem Erhitzen unter Rückfluß wird das erkaltete Reaktionsgemisch mit schwach salzsaurem Wasser hydrolysiert. Der dabei entstehende Feststoff wird durch Umkristallisieren aus Ethanol gereinigt. Man erhält 36 g (89 % der Theorie) Diphenyl-phenyl-carbinol vom 10 Schmelzpunkt 72-73°C.38.8 g (0.15 mol) of 4-phenylbenzophenone are dissolved in 200 ml of ethanol and 3 g (0.075 mol) of sodium borohydride 5 are added. After heating under reflux for 15 hours, the cooled reaction mixture is hydrolyzed with weakly hydrochloric acid water. The resulting solid is purified by recrystallization from ethanol. 36 g (89% of theory) of diphenyl-phenyl-carbinol having a melting point of 72-73 ° C. are obtained.
Verfahrenvariante (b/3.) 167 g (0,6 Mol) Diphenyl-phenyl-chlor-methan und 92 g (0,66 Mol) Trimethylsilylimidazol, gelöst in 500 ml Acetonitril, werden 15 Stunden unter Rückfluß erhitzt.Process variant (b / 3.) 167 g (0.6 mol) of diphenylphenylchloromethane and 92 g (0.66 mol) of trimethylsilylimidazole, dissolved in 500 ml of acetonitrile, are heated under reflux for 15 hours.
15 Nach Abdestillieren des Lösungsmittels wird der kristalline Rückstand durch Umkristallisation aus Essigester gereinigt. Man erhält 97 g (52 % der Theorie) Diphenyl-imidazolyl-(1)-phenyl-methan (Bifonazol) vom Schmelzpunkt 142°C.15 After the solvent has been distilled off, the crystalline residue is purified by recrystallization from ethyl acetate. 97 g (52% of theory) of diphenyl-imidazolyl- (1) -phenyl-methane (bifonazole) with a melting point of 142 ° C. are obtained.
Le A 22 266 « - 10 - * *Le A 22 266 «- 10 - * *
VV
Beispiel 1 Creme,O/W Phase IExample 1 Cream, O / W Phase I
Sorbitanmonostearat 2,0 g * Polyoxyethylen (20)- 5 sorbitanmonostearat 1,5 gSorbitan monostearate 2.0 g * Polyoxyethylene (20) - 5 sorbitan monostearate 1.5 g
Walrat künstlich 3,0 gArtificial walnut 3.0 g
Cetylstearylalkohol 10,0 g 2-Octyldodecanol 13,5 gCetylstearyl alcohol 10.0 g 2-octyldodecanol 13.5 g
Auf 75°C erwärmen, rühren, mischen.Warm to 75 ° C, stir, mix.
10 Phase II10 Phase II
Bifonazol 1,0 g zur Phase I geben, rühren, lösen.Add 1.0 g bifonazole to phase I, stir, dissolve.
Phase IIIPhase III
Benzylalkohol 1,0 g 15 Wasser, entmineralisiert 68,0 g auf 75°C erwärmen und zur Phase II geben. Intensiv mischen, langsam unter weiterem Rühren auf Raumtemperatur abkühlen. Homogenisieren.Benzyl alcohol 1.0 g 15 water, demineralized, heat 68.0 g to 75 ° C and add to phase II. Mix vigorously, slowly cool to room temperature with continued stirring. Homogenize.
- Le A 22 266 «- Le A 22 266 «
JJ
- 11 - » *- 11 - »*
Beispiel 2 Creme, 0/W Phase IExample 2 Cream, 0 / W Phase I
Sorbitanmonostearat 1 - 3 gSorbitan monostearate 1 - 3 g
Polyoxyethylen (20)- 5 sorbitanmonostearat 0,5 - 2,5 gPolyoxyethylene (20) - 5 sorbitan monostearate 0.5 - 2.5 g
Walrat künstlich 2 - 4 gArtificial walnut 2 - 4 g
Cetylstearylalkohol 5 - 15 g 2-Octyldodecanol 5 - 25 gCetylstearyl alcohol 5-15 g 2-octyldodecanol 5-25 g
Auf 75°C erwärmen, rühren, mischen.Warm to 75 ° C, stir, mix.
10 Phase II10 Phase II
Bifonazol 0,5 - 1,5 g zur Phase I geben, rühren, lösen.Add 0.5 - 1.5 g of bifonazole to phase I, stir, dissolve.
Phase IIIPhase III
Benzylalkohol 0,5 - 1,5 g 15 Wasser entmineralisiert quant.sat.Benzyl alcohol 0.5 - 1.5 g 15 water demineralized quant.sat.
» auf 75°C erwärmen und zur Phase II geben, intensiv mischen, langsam unter weiterem Rühren auf Raumtemperatur abkühlen. Homogenisieren.»Warm up to 75 ° C and add to phase II, mix intensively, slowly cool to room temperature with continued stirring. Homogenize.
Le A 22 266 » - 12 - (t 1 4 vLe A 22 266 »- 12 - (t 1 4 v
Wirksamkeitstestung der erfindungsgemäßen Mittel am Trichophyton-infizierten Meerschweinchen.Effectiveness test of the agents according to the invention on Trichophyton-infected guinea pigs.
Als Testmodell zur vergleichenden Wirksamkeitsprüfung der erfindungsgemäßen Formulierungen verwendeten wir 5 Trichophyton-infizierte Pirbright-white-Meerschwein- chen mit einem durchschnittlichen Gewicht von 600 g. Die Tiere wurden auf dem Rücken mit einer elektrischen Haarschneidemaschine so geschoren, daß ca. 1/10 mm lange Haarstümpfe stehen blieben.We used 5 trichophyton-infected Pirbright white guinea pigs with an average weight of 600 g as a test model for comparative effectiveness testing of the formulations according to the invention. The animals were shaved on their backs with an electric hair clipper so that hair stumps about 1/10 mm long remained.
1° Die Infektion mit Trichophyton mentagrophytes erfolgte durch leichtes Verreiben einer 24 Stunden in Sabouraud-Nährlösung angekeimten Sporensuspension des Erregers auf einer ca. 2 x 2 cm großen Fläche des geschorenen Rückens der Tiere. Aufgetragen wurden pro Tier 0,5 ml 4 C 5 13 Keimsuspension, die 1 - 3 x 10 infektiöse Pilzpartikel enthielten.1 ° Trichophyton mentagrophytes was infected by gently rubbing in a spore suspension of the pathogen germinated in Sabouraud nutrient solution for 24 hours on an approx. 2 x 2 cm area of the sheared back of the animals. 0.5 ml of 4 C 5 13 germ suspension, which contained 1-3 x 10 infectious fungal particles, was applied to each animal.
Bei diesem Infektionsmodus zeigen sich 2-3 Tage post infectionem die ersten Symptome der Dermatopnytose als Rötung und Schuppung der Haut. Bei unbehandelten Tieren 2^ ist ca. 14 Tage p.i. die Dermatophytose maximal ausgeprägt: Flächiger Haarausfall und blutige Integument-Defekte innerhalb einer entzündlich veränderten, schuppigen Randzone.With this mode of infection, the first symptoms of dermatopnytosis appear as reddening and scaling of the skin 2-3 days after infection. In untreated animals 2 ^ is approx. 14 days p.i. the dermatophytosis is maximal: extensive hair loss and bloody integument defects within an inflammatory, scaly peripheral area.
Die zu prüfenden Formulierungen wurden 1-mal, am 2. Tag 25 post infectionem, lokal auf die gerötete Infektionsstelle der Tiere appliziert und mit einem Hornspatel leichtThe formulations to be tested were applied once, on the second day 25 post infection, locally to the reddened infection site of the animals and lightly with a horn spatula
Le A 22 266 - 13 - * i ύ % l !w verrieben. Es wurden jeweils 0,5 ml der Formulierungen = 5 mg Wirkstoff (1 %-ige Formulierung) aufgetragen. Die Bewertung des Infektionsablaufs erfolgte täglich bis zum 20. Tag p.i.Le A 22 266 - 13 - * i ύ% l! W triturated. 0.5 ml of the formulations = 5 mg of active ingredient (1% formulation) were applied in each case. The course of the infection was evaluated daily until the 20th day p.i.
^ In diesem Test zeigen die erfindungsgemäßen Formulierungen eine sehr gute Wirkung.^ In this test, the formulations according to the invention show a very good effect.
Verwendet man zum Vergleich Formulierungen, die neben Bifonazol kein Spreitmittel enthalten, so wird ein Effekt, der dem der erfindungsgemäßen Formulierungen 10 entspricht, erst nach dreimaliger Applikation erreicht.If, for comparison, formulations are used which contain no spreading agent in addition to bifonazole, an effect which corresponds to that of the formulations 10 according to the invention is only achieved after three applications.
Le A 22 266Le A 22 266
Claims (5)
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 |
| DE3311701 | 1983-03-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| LU85271A1 true LU85271A1 (en) | 1984-11-14 |
Family
ID=6195162
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LU85271A LU85271A1 (en) | 1983-03-30 | 1984-03-28 | ANTIMYCOTIC AGENT WITH HIGH ACTIVE SUBSTANCE RELEASE IN THE FORM OF 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 |
| WO1993025238A1 (en) * | 1992-06-08 | 1993-12-23 | Schering-Plough Healthcare Products, Inc. | 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 |
| DE3045913A1 (en) * | 1980-12-05 | 1982-07-08 | Bayer Ag, 5090 Leverkusen | ANTIMYCOTIC AGENTS WITH HIGH ACTIVE SUBSTANCE RELEASE |
| 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 |
| 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 LU LU85271A patent/LU85271A1/en unknown
- 1984-03-28 GR GR74236A patent/GR81485B/el unknown
- 1984-03-29 CH CH1598/84A patent/CH660126A5/en not_active IP Right Cessation
- 1984-03-29 IT IT20303/84A patent/IT1173761B/en active
- 1984-03-29 AU AU26236/84A patent/AU564956B2/en not_active Expired
- 1984-03-29 BE BE0/212659A patent/BE899278A/en not_active IP Right Cessation
- 1984-03-29 FR FR8404906A patent/FR2543435B1/en not_active Expired
- 1984-03-29 ZA ZA842337A patent/ZA842337B/en unknown
- 1984-03-29 CY CY135884A patent/CY1358A/en unknown
- 1984-03-29 SE SE8401748A patent/SE8401748L/en unknown
- 1984-03-29 GB GB08408067A patent/GB2137091B/en not_active Expired
- 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/ES539290A0/en active Granted
-
1987
- 1987-03-09 KE KE3704A patent/KE3704A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ES8601693A1 (en) | 1985-11-16 |
| ES530846A0 (en) | 1985-04-16 |
| ES8503947A1 (en) | 1985-04-16 |
| PT78313A (en) | 1984-04-01 |
| SE8401748L (en) | 1984-10-01 |
| AU564956B2 (en) | 1987-09-03 |
| GB2137091B (en) | 1986-10-01 |
| CY1358A (en) | 1987-08-07 |
| KR840008284A (en) | 1984-12-14 |
| CH660126A5 (en) | 1987-03-31 |
| IT8420303A0 (en) | 1984-03-29 |
| ES8601692A1 (en) | 1985-11-16 |
| JPS59184106A (en) | 1984-10-19 |
| ES539290A0 (en) | 1985-11-16 |
| PH20420A (en) | 1987-01-05 |
| FR2543435B1 (en) | 1988-06-17 |
| CA1212327A (en) | 1986-10-07 |
| DE3311701A1 (en) | 1984-10-04 |
| ES539289A0 (en) | 1985-11-16 |
| KE3704A (en) | 1987-03-27 |
| BE899278A (en) | 1984-10-01 |
| ZA842337B (en) | 1984-11-28 |
| PT78313B (en) | 1986-06-02 |
| AU2623684A (en) | 1984-10-04 |
| IT1173761B (en) | 1987-06-24 |
| GB8408067D0 (en) | 1984-05-10 |
| GB2137091A (en) | 1984-10-03 |
| FR2543435A1 (en) | 1984-10-05 |
| SE8401748D0 (en) | 1984-03-29 |
| GR81485B (en) | 1984-12-11 |
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