CA1180661A - Antimycotic agents which have a good release of active compound - Google Patents
Antimycotic agents which have a good release of active compoundInfo
- Publication number
- CA1180661A CA1180661A CA000391479A CA391479A CA1180661A CA 1180661 A CA1180661 A CA 1180661A CA 000391479 A CA000391479 A CA 000391479A CA 391479 A CA391479 A CA 391479A CA 1180661 A CA1180661 A CA 1180661A
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- Prior art keywords
- formulation according
- active compound
- isopropyl
- antimycotic
- acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
-
- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- Oil, Petroleum & Natural Gas (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
'Antimycotic agents which have a good release of active compound"
ABSTRACT OF THE DISCLOSURE
The invention relates to formulations of antimycotic active compounds, said formulations containing benzyl alcohol and a spreading agent to provide high bioavailability of the active compounds and make short-term therapy possible.
ABSTRACT OF THE DISCLOSURE
The invention relates to formulations of antimycotic active compounds, said formulations containing benzyl alcohol and a spreading agent to provide high bioavailability of the active compounds and make short-term therapy possible.
Description
The present invention relates to certain novel antimycotic formula-tions of antimycotic active compounds ~hich may in tllemselves be Xnown WhiCll have a relatively good release of the active compoullds ancl tllereby m:l~e short-term therapy possible.
Formulations of alltilllycotic ~Ic~rlv;l-tives for the treat:lllellt of mycos-es in hummls above all mycoses of thc~ s1~in and of cllcallcous ap l-elld;lges, llave already beell disclosed. llsillg those k`orlll~lla~iolls a ehcrnl)y period ot` 1-~ to 2l days hlls been re(lll:ired for a complete cllre.
ln order to shorten the perlo(l of theral~y ~or e~ ple in the case of vaginal or buccal mycoses or dermatolllycoses a relatively good release of the active compounds in an aqueous medium is required in particular to eli-minate the germs and in order to achieve a mycologically certain cure~ The known formulations are suitable for this only to a limited e~tent because only a small proportion of the available active compound is released in the liquid volume at the site of infection. If a shortening of the period of therapy for e~cample to one day and a single application is to be achieved ith or ~ithout a further increase in the concelltration of active compoulld~
optimum bioavailabill-ty of tlle active compoulld must be ensllred.
Accordillg to tlle present inve;ltio~ e provide an ;ntimycotic formu-lation ~hich coDlprises an antilllycotically effective amollllt of a compoulld ~ to 5% of benzyl alcollol anl ~5 to ~O!li of a spren(ling agent~ Tlle formulation may also contaill furtller formulatioll au~ili;lries~
The formulatiolls of the presel~t in~Selltioll rele;lst tlle active com-pound -to a higher degree and thereby ma~e it possille to shorten the periocl of tllerapy to 1 day. This et`fect of better rele.lse of tile active compo~md can be as much as ten-fold.
Active ccmpounds which can be farmulated in this manner are any oF the compounds having an antimycotic action, in particular imidazole derivatives and triazole derivatives. They are generally present in the agents according to the invention in am~unts oF 0.05O to l~, 0.1 to 'IO~ by w~ight.
The active compounds wlth the following Formulae may be mentioned as preFcrrecl ~amples:
~3 (I) ~G_Ç3 clotri}~ .ol-, ~Cl ~ C~
(II) ~rifon~Ol~ and ~ C ~ lolilbarrol~.
CIII ) ¦ Cl ~I-Le A ~0 573 D6~
Numerous other azole derivatives having an anti-mycotic action are known from DE-OS (German Published Specification) 2,430,039. They can li~ewise be used as active compounds in the agents according to the inven-tion.
By spreading-agent~ there are understood oily liquids wl-ich are particularly readily distributed on the s~in [R. I(eymer, Pharm. Ind. 32 [1970~, 577-58l]. The compounds which follow are partlcularly suitable as sprendin~ agents t`or the agents according to the~ invention:
Sllicone olls of various viscosities;
-Fatty acid esters, such as ethyl stearate, di-n-butyl . .
adipate3 lauric acid he~yl ester, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated C16-C18-fatty alcohols, iso-propyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated fatty alcohols of C12-C18 chain length, isopropyl stearate, oleic acid oleyl esterS oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters, such as synthesised duck uropygial gland fat, dibutyl phthalate, adipic acid diisopropyl ester and ester mixtures related to the latter;
rides, such as caprylic/capric acid triglyceride, triglyceride mi~tures with vegetable fatty acids of C8-C12 chain length or other specially selected naturally occur-ring fatty acids, partial glyceride mi~tures of saturated or unsaturated fatty acids which optionally also contain hydro~yl groups and monoglycerides of C8/C10- fatty acids;
Fatty alcohols, such as isotridecyl alcohol, 2-octyl-dodecanol, cetyl stearyl alcnhol and oleyl alcohnl; andFatty acids, such as oleic acid.
The compounds which follow are particularly suitable spreading-oils: isopropyl myristate, isopropyl palmitate, caprylic/capric acid ester~ of saturated fatty alcnhols of C12-Cl~ chain length 3 wa~y fatty acid esters ~such as Le_A 20 573 6~
synthesised duck uropygial gland fat), silicone oils and an isopropyl myristate/isopropyl stearate/isopropyl palmitate mixture.
The Following other auxiliaries and/or formulation base auxiliaries can be used in the preparation of the agents according to th~ invention.
"Glyceryl stearates"t a mixture oil-:in-water cream of mono- and di-glycerides of base~ not self-palmitic acid and stearic acid ~mulc3i~ying 10 Colloidally clisperse mi~ture oil~in-watcr emulsion oF cetyl stearyl alcohol and base, self`-sodium cctyl-stearyl sulphate emulslfying Esters of a branched fatty acid oil component with a 15 wi-th saturated C16-C18~fatty pronounced hydro-alcohols phooic effect for sl<in-protection products 20 Cetyl palmitate artificial spermaceti, consistency for creams, ointments, emulsions Polyethylene stearate non-ionic hydrophilic emulsifier Cetyl stearyl alcohol o~y- non-ionic oil-in-water ethylated with about 1'~ mol emulsifier of ethylene n~ide 30 Cetyl stearyl ~lcohol ~y- non-ionic oil-in-wate~
ethylated with about 30 mol emulsifier of ethylene o~ide e A 20 573 sorbitane and glycerol fatty non ionic emulsifier acid ester Slightly crosslinked poly- sweller, thic~ener and acrylic acid of stabiliser extremely high molecular weight Furthermore, the following formulat.ion au~iliarias can also be used: glyccrol, viscous paraffin, highly liguid parafFin, triethanolanline, co.llagen, allantoil-, novant.isolic acicl and perfumc oils.
Further compounds which are suitable au~iliaries are:
(a) Substances which, for e~ample, can stabilise a sus-pension, for e~ample colloidal silicic acid or montmorillo-nites;
(b) Surface-active agents (including emulsifiers and wetting agents), for example .1. anionic surface-active agents, such as Na lauryl sulphate, fatty alcohol ether-sulphates and the mono-ethanolamine salts of mono-/di-alkyl polyglycol ether-orthophosphates;
Formulations of alltilllycotic ~Ic~rlv;l-tives for the treat:lllellt of mycos-es in hummls above all mycoses of thc~ s1~in and of cllcallcous ap l-elld;lges, llave already beell disclosed. llsillg those k`orlll~lla~iolls a ehcrnl)y period ot` 1-~ to 2l days hlls been re(lll:ired for a complete cllre.
ln order to shorten the perlo(l of theral~y ~or e~ ple in the case of vaginal or buccal mycoses or dermatolllycoses a relatively good release of the active compounds in an aqueous medium is required in particular to eli-minate the germs and in order to achieve a mycologically certain cure~ The known formulations are suitable for this only to a limited e~tent because only a small proportion of the available active compound is released in the liquid volume at the site of infection. If a shortening of the period of therapy for e~cample to one day and a single application is to be achieved ith or ~ithout a further increase in the concelltration of active compoulld~
optimum bioavailabill-ty of tlle active compoulld must be ensllred.
Accordillg to tlle present inve;ltio~ e provide an ;ntimycotic formu-lation ~hich coDlprises an antilllycotically effective amollllt of a compoulld ~ to 5% of benzyl alcollol anl ~5 to ~O!li of a spren(ling agent~ Tlle formulation may also contaill furtller formulatioll au~ili;lries~
The formulatiolls of the presel~t in~Selltioll rele;lst tlle active com-pound -to a higher degree and thereby ma~e it possille to shorten the periocl of tllerapy to 1 day. This et`fect of better rele.lse of tile active compo~md can be as much as ten-fold.
Active ccmpounds which can be farmulated in this manner are any oF the compounds having an antimycotic action, in particular imidazole derivatives and triazole derivatives. They are generally present in the agents according to the invention in am~unts oF 0.05O to l~, 0.1 to 'IO~ by w~ight.
The active compounds wlth the following Formulae may be mentioned as preFcrrecl ~amples:
~3 (I) ~G_Ç3 clotri}~ .ol-, ~Cl ~ C~
(II) ~rifon~Ol~ and ~ C ~ lolilbarrol~.
CIII ) ¦ Cl ~I-Le A ~0 573 D6~
Numerous other azole derivatives having an anti-mycotic action are known from DE-OS (German Published Specification) 2,430,039. They can li~ewise be used as active compounds in the agents according to the inven-tion.
By spreading-agent~ there are understood oily liquids wl-ich are particularly readily distributed on the s~in [R. I(eymer, Pharm. Ind. 32 [1970~, 577-58l]. The compounds which follow are partlcularly suitable as sprendin~ agents t`or the agents according to the~ invention:
Sllicone olls of various viscosities;
-Fatty acid esters, such as ethyl stearate, di-n-butyl . .
adipate3 lauric acid he~yl ester, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated C16-C18-fatty alcohols, iso-propyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated fatty alcohols of C12-C18 chain length, isopropyl stearate, oleic acid oleyl esterS oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters, such as synthesised duck uropygial gland fat, dibutyl phthalate, adipic acid diisopropyl ester and ester mixtures related to the latter;
rides, such as caprylic/capric acid triglyceride, triglyceride mi~tures with vegetable fatty acids of C8-C12 chain length or other specially selected naturally occur-ring fatty acids, partial glyceride mi~tures of saturated or unsaturated fatty acids which optionally also contain hydro~yl groups and monoglycerides of C8/C10- fatty acids;
Fatty alcohols, such as isotridecyl alcohol, 2-octyl-dodecanol, cetyl stearyl alcnhol and oleyl alcohnl; andFatty acids, such as oleic acid.
The compounds which follow are particularly suitable spreading-oils: isopropyl myristate, isopropyl palmitate, caprylic/capric acid ester~ of saturated fatty alcnhols of C12-Cl~ chain length 3 wa~y fatty acid esters ~such as Le_A 20 573 6~
synthesised duck uropygial gland fat), silicone oils and an isopropyl myristate/isopropyl stearate/isopropyl palmitate mixture.
The Following other auxiliaries and/or formulation base auxiliaries can be used in the preparation of the agents according to th~ invention.
"Glyceryl stearates"t a mixture oil-:in-water cream of mono- and di-glycerides of base~ not self-palmitic acid and stearic acid ~mulc3i~ying 10 Colloidally clisperse mi~ture oil~in-watcr emulsion oF cetyl stearyl alcohol and base, self`-sodium cctyl-stearyl sulphate emulslfying Esters of a branched fatty acid oil component with a 15 wi-th saturated C16-C18~fatty pronounced hydro-alcohols phooic effect for sl<in-protection products 20 Cetyl palmitate artificial spermaceti, consistency for creams, ointments, emulsions Polyethylene stearate non-ionic hydrophilic emulsifier Cetyl stearyl alcohol o~y- non-ionic oil-in-water ethylated with about 1'~ mol emulsifier of ethylene n~ide 30 Cetyl stearyl ~lcohol ~y- non-ionic oil-in-wate~
ethylated with about 30 mol emulsifier of ethylene o~ide e A 20 573 sorbitane and glycerol fatty non ionic emulsifier acid ester Slightly crosslinked poly- sweller, thic~ener and acrylic acid of stabiliser extremely high molecular weight Furthermore, the following formulat.ion au~iliarias can also be used: glyccrol, viscous paraffin, highly liguid parafFin, triethanolanline, co.llagen, allantoil-, novant.isolic acicl and perfumc oils.
Further compounds which are suitable au~iliaries are:
(a) Substances which, for e~ample, can stabilise a sus-pension, for e~ample colloidal silicic acid or montmorillo-nites;
(b) Surface-active agents (including emulsifiers and wetting agents), for example .1. anionic surface-active agents, such as Na lauryl sulphate, fatty alcohol ether-sulphates and the mono-ethanolamine salts of mono-/di-alkyl polyglycol ether-orthophosphates;
2. cationic surface-active agents, such as cetyl tri-methylammonium chloride;
3. ampholytic surface-active agents, such as di-Na-N-lauryl-~-iminodipropionate or lecithin; and
4. non~anionic surface-active agents, for example polyo~yethylated-castor oil, polyo~yathylated sorbitanr mono-oleate, sorbitane monost~srate, cetyl alcohol/
glycerol monostearate, polyoxyethylene stearate and alkyl-phenol polyglycol ethers;
(c) Stabilisers for preventing the chemical degradation which occurs in the case of so,ne aCti~f~ cor..~ounds, such as antio.~idants, for e~ample tocopherols and butyl-hydroxyanisole; and (d) Pl~sticisers, for e~ample propylene glycol, glycerol, Le A 20 573 dipropylene and tripropylene glycol, triethanolamine, and waxes.
Possible gel-forming agents which may be used as auxiliaries are macromolecular compounds which can be dissolved or partially swollen both in water and in organic solvents and Form a type of film after drying.
If the macrornolecular auxlliaries are classified C~<eipert et al., Die Pharma~ie 2~, 145-lR3 (l973~, ionic macromolecules in salt ~`orm are used above a;ll. rhes~
are, inter alia, sodlum carbo~ymcthylcellulose, poly-acrylic acid, polymethacrylic acid and salts thereof, sodium amylopectin semiglycolate, alginic acid and propyl-ene glycol alginate as the sodium salt, gum arabic, ~anthan gum and guar gum~
Amphoteric macromolecules, such as protein deriva-tives, for example gelatin, are just as suitable as non-ionic polymers, for example methylcellulose, hydroxy-propylcellulose and soluble starches, which fulfil the above requirements.
Suitable solvents which may be present in the formula-tions of the present invention are water and any of the water-mixcible solvents. Possible solvents are, for e~ample, alkanols (such as ethanol and isopropyl alcohol), propylene glycol, methylcellosolve, cellosolve, esters, morpholines, dioxane~ dimethylsulpho~ide, dimethylformamide, tetrahydrofuran and cyclohe~anone.
One or more solvents can be employed in the pre-paration of the formulations accordiny to the present invention.
The following E~amples I to IS illustrate formulations according to the present :invention.
Example ~ Emulsion, oil-in-water.
Phase I
"Glyceryl stearates" (mi~ture of mono- and di-clycerides of palmitic and stearic acid) 8 .00 9 Le A 20 573 2-Octyldodecanol 10.00 g Cetyl stearyl a].cohol oxyethylated with about 12 mol. of ethylene o~cide1.50 g Cetyl stearyl alcohol o~ye-thylatecl Witil about 30 mol. of etllylellc o~;;ide l~5n ~
I~araffin, viscous 6.()n g .1,2~ ropylclle glyco:l 5.0() g Capry:lic/cal)ric ac:icl t~ glYcc~ :i.cle ~.0() g Tllc mi~t-lre is stlrrccl, and meltcd at 70C.
Pllase II
Water, demilleralisecl 5S.OO g Phase III
Clotrimazole, 1.00 g dissolved in benzyl alcohol .00 g Phase I, which had been warmed to 70C, was aclded "~ith stirring, to Phase II, ~Yhich had been warmcd ~o 75C. The mi~ture ~as allow2d to cool slowly to 40C, phase III was added and the mi~ture was c.ooled to room temp-erature, ~Yith stirring. The crude emulsion ~Yas holllogenisecl at 20 to '5C in a high-pressure homogeniser~
~0 Examples 2 to 6 an(l 12 to 15 are pr-cessed :in all alr.llogolls maoller.
Emulsioll, oil-in-~Yater ~icrollisecl ~rifolln~ole I ~ on "Glyceryl steara~es", m.i~ture o:~ mollo-allcl .I.i-g~lycericles of palmitic alld stearic ncid '1.OO g etyl stearyl alcollol o~yethyl;ltecl~Yitll abollt l' mol.
o~ ethylelle o~ide 3 00 g 2-Octyldodecanol 10.00 g Viscous paraffin
glycerol monostearate, polyoxyethylene stearate and alkyl-phenol polyglycol ethers;
(c) Stabilisers for preventing the chemical degradation which occurs in the case of so,ne aCti~f~ cor..~ounds, such as antio.~idants, for e~ample tocopherols and butyl-hydroxyanisole; and (d) Pl~sticisers, for e~ample propylene glycol, glycerol, Le A 20 573 dipropylene and tripropylene glycol, triethanolamine, and waxes.
Possible gel-forming agents which may be used as auxiliaries are macromolecular compounds which can be dissolved or partially swollen both in water and in organic solvents and Form a type of film after drying.
If the macrornolecular auxlliaries are classified C~<eipert et al., Die Pharma~ie 2~, 145-lR3 (l973~, ionic macromolecules in salt ~`orm are used above a;ll. rhes~
are, inter alia, sodlum carbo~ymcthylcellulose, poly-acrylic acid, polymethacrylic acid and salts thereof, sodium amylopectin semiglycolate, alginic acid and propyl-ene glycol alginate as the sodium salt, gum arabic, ~anthan gum and guar gum~
Amphoteric macromolecules, such as protein deriva-tives, for example gelatin, are just as suitable as non-ionic polymers, for example methylcellulose, hydroxy-propylcellulose and soluble starches, which fulfil the above requirements.
Suitable solvents which may be present in the formula-tions of the present invention are water and any of the water-mixcible solvents. Possible solvents are, for e~ample, alkanols (such as ethanol and isopropyl alcohol), propylene glycol, methylcellosolve, cellosolve, esters, morpholines, dioxane~ dimethylsulpho~ide, dimethylformamide, tetrahydrofuran and cyclohe~anone.
One or more solvents can be employed in the pre-paration of the formulations accordiny to the present invention.
The following E~amples I to IS illustrate formulations according to the present :invention.
Example ~ Emulsion, oil-in-water.
Phase I
"Glyceryl stearates" (mi~ture of mono- and di-clycerides of palmitic and stearic acid) 8 .00 9 Le A 20 573 2-Octyldodecanol 10.00 g Cetyl stearyl a].cohol oxyethylated with about 12 mol. of ethylene o~cide1.50 g Cetyl stearyl alcohol o~ye-thylatecl Witil about 30 mol. of etllylellc o~;;ide l~5n ~
I~araffin, viscous 6.()n g .1,2~ ropylclle glyco:l 5.0() g Capry:lic/cal)ric ac:icl t~ glYcc~ :i.cle ~.0() g Tllc mi~t-lre is stlrrccl, and meltcd at 70C.
Pllase II
Water, demilleralisecl 5S.OO g Phase III
Clotrimazole, 1.00 g dissolved in benzyl alcohol .00 g Phase I, which had been warmed to 70C, was aclded "~ith stirring, to Phase II, ~Yhich had been warmcd ~o 75C. The mi~ture ~as allow2d to cool slowly to 40C, phase III was added and the mi~ture was c.ooled to room temp-erature, ~Yith stirring. The crude emulsion ~Yas holllogenisecl at 20 to '5C in a high-pressure homogeniser~
~0 Examples 2 to 6 an(l 12 to 15 are pr-cessed :in all alr.llogolls maoller.
Emulsioll, oil-in-~Yater ~icrollisecl ~rifolln~ole I ~ on "Glyceryl steara~es", m.i~ture o:~ mollo-allcl .I.i-g~lycericles of palmitic alld stearic ncid '1.OO g etyl stearyl alcollol o~yethyl;ltecl~Yitll abollt l' mol.
o~ ethylelle o~ide 3 00 g 2-Octyldodecanol 10.00 g Viscous paraffin
5.00 Benzyl alcohol Demineralised wa~er to 100 ml -7a_ Example 3 Emulsion, oil-in-water Micronised trifonazole l.OO g "Glyceryl stearates", mixture of mono- and di-glycerides of palmitic and stear.ic acid 9.00 9 Cetyl stearyl alcohol o~yethylated with about 12 mol. o~ ethylene oxide3.00 g 2-Octyldodecanol IO.OO g Benzyl alcohol 5.00 9 Isopropyl myr.;state 5 00 9 .lO Demineralised ~vater to lOO ml Exan~ ~4 Cream, soft consistency, oil-in-water Micronised clotrimazole I.OO g "Glyceryl stearates", mixture of mono- and dl-glycerides of palmitic and stearic acid 4.00 9 15 Cetyl palmitate 4.00 9 Cetyl stearyl alcohol oxyethylated with about 12 mol. of ethylene.oxide1~00 g Cetyl stearyl alcohol oxyethylated with about 30 mol of ethylene oxide1~00 g 20 Isopropyl myristate/isopropyl palmitate, isopropyl stearate mixture 5.00 9 Slightly crosslinked polyacrylic acid of extremely high M.W. o 50 g 45O strength sodium hydroxide 0.11 g 25 Glycerol 3.00 9 Ben~yl alcohol 3.00 g Demineralised water to lOO ml ~ Cream, soft consistency, oil-in-wster ~licronised clotrima~sIe l.OO g l'Glyceryl stearates", mi~ture of mono- and di-glycerides of palmitic and stearic acid 4.00 g Cetyl palmitate 4.00 g 35 Cetyl stearyl alcohol o~yethylated with Le A 20 573 .
about 12 mol. of ethylene oxide 1.00 9 Cetyl stearyl alcohol oxyethylated with about 30 mol. of ethylene oxide l.00 9 Isopropyl myristate/isopropyl palmitate/
isopropyl stearate mi~ture 5.00 9 Slightly crosslinl<ed polyacrylic acid of extremely high molecular weight 0.50 9 45O strength sodium hydro~ide 0.11 9 Glycerol 3.00 9 Ben~y:l alcohol ~.00 9 Demineralised water to 100 ml Exall!ple 6 Cresm, soft consistency, oil-in-water Micronised trifonazole 1.00 g "Glyceryl stearates", mixture of mono- and 15 di-glycerides of palmitic and stearic acid '~.00 9 Cetyl palmitate 4.00 9 Cetyl stearyl alcohol oxyethylated with about 12 mol. of ethylene o~ide 1.00 9 Cetyl stearyl alcohol oxyethylated with about 30 mol~ of ethylene oxide 1.00 g Isopropyl myristate/isopropyl palmitate/' isopropyl stearate mixture 5.00 9 Slightly crosslinked polyacrylic acid of extremely high molecular weight 0.50 g 45~0 strength sodium hydroxide 0.11 9 Glycerol 3.00 9 Benzyl alcohol 3.00 9 Demineralised water to 100 ml Example 7 Emulsion, non-greasy, oil-in-water Phase I
ûleic acid decyl Pster ~.5n 9 Isopropyl myristate ~.50 9 Paraffin, highly liqwid 4.00 9 Polyethylene stearate 0.90 9 35 Sorbitane and glycerol fatty acid esters 0.60 9 Le A 20 573 The mixture is stirred and melted, at 70C for 10 minutes.
Phase II
Water, demineralised 50.00 9 Allantoin 0.10 9 Carbopol mucus Alcohol, denat~red 10~00 o Carbopol 934 (slighly crosslinked polyacrylic acicl) 0.70 ~
~o Water, demineralised 2_.945 9 A disperslon was obtained with a "Turra~" and the dispersion was allowed to swell for 2 hours and then neutralised with 0.155 9 of 45~ strength sodium nydro~ide solution.
Phase I, which had been warmed to 70C, was added, with stirring, to phase II, which had been heated to 75C, and the mixture was cooled to 45C. The carbopol mucus was stirred in at 45C and cooled further to 40C.
l.00 9 of collagen was added at 40C and cooled to 25C.
Then l~0 9 of lomba~ole was dissolved in 3.0 9 of ben7yl alcohol and the solution was added to phase I and II.
0.600 9 of perfume was then added and the crude emulsion was homogenised, with stirring, in a high-pressure homogeniser at 20C to 25GC.
Examples 8, 9, 10 and 11 were processed in an analogous manner.
Example 3 Emulsion, non-greasy, oil-ln-water ~licronised lamba7ole 0.10 9 Oleic acid decyl ester 2.50 9 30 Isopropyl myristate 2.50 9 Highly liquid paraffin 4.00 9 Polyethylene stearate 0.90 9 Sorbitane and glycerol fatty acid esters 0.60 9 35 Allantoin û.10 9 Le A 20 573 45O strength sodiuln hydroxide 0.155 9 Slightly crosslinked polyacrylic acid of extremely high molecular weight0.70 9 Collagen l.G0 9 Benzyl alcohol 3.ûO g Ethanol lO.00 9 Perfume oil 0.63 g Demi.nerallsed water to lno ml E~ample 9 Emulslon, non-greasy~ oll-.in-water 10 ~llcronised lombazole O.û5 g Oleic acld decyl ester 7. sn 9 Isopropyl myristflte 2.50 9 Highly liquld paraffin 4.00 9 Polyethylene stearate 0.90 9 15 Sorbitane and glycerol fatty acid esters 0.60 9 Allantoin 0.10 9 Slightly crosslinked polyacrylic acid of extremely high molecular weight 0.70 9 45O strength sodium hydroxiden. 155 9 20 Collagen 1.00 9 Benzyl alcohol 3.00 9 Ethanol 10.00 9 Perfume oil 0.60 9 Demlneralised water to lO0 ml Example 10 Emulsion, non~greasy, oil-in-water Micronised trifonazole 0.10 9 Oleic acid decyl ester 2.50 9 Isopropyl myristate 7.50 9 Highly liquid paraffin 4.00 9 30 Polyethylene stearate 0,90 9 Sorbitane and glycerol fatty acld esters 0.60 9 Allantoin 0.10 9 45O strength sodium hydroxide0.155 9 Slightly crosslinked polyacrylic acid 35 of extremely high molecular weight 0.70 g Le A 20 573 Collagen 1.00 9 Benzyl alcohol 3.00 9 Ethanol 10.00 g Perfume oil 3.60 9 Deminerali~ed water to lO0 ml Example l1 Emulsion, non-greasy, oil-in-water Micronised triFonazole 0 05 9 Oleic acicl decyl estcr 2.50 y Isopropyl myrlstatc 2.50 ~
10 Highly liquid paraffln !1,00 9 Polyethylene stearate 0 90 9 Sorbitane and glycerol fatty acid esters 0.60 9 Allantoin 0.10 9 45O strength sodium hydroxide0.155 g 15 Slightly crosslinked polyacrylic acid of extremely high molecular weight0.70 9 Collagen 1.00 9 Benzyl alcohol 3.00 9 Ethanol 10.00 9 20 Perfume oil 0.60 9 Demineralised water to 100 ml Example 12 Cream, soft consistency, oil-in-water Micronised trifonazole 0.10 9 "Glyceryl stearates", mixture of mono- and 25 di-glycerides of palmitic and staaric acid 4.00 9 Cetyl palmitate 4.00 9 Cetyl stearyl alcohol, oxyethylated with about 12 mol. oF ethylene oxide1.00 9 Cetyl stearyl alcohol, oxyethylated with about 30 mol.~ of ethylene oxide1 00 9 Isopropyl myristate/isop~pyl palmitàte~
isopropyl stea~ate mixture 5.00 9 Slightly crosslinked polyacrylic acid of extremely high molecular weight 0.50 9 45~0 strength sodium hydroxide0.11 9 Le A 20 573 Glycerol 3 oo g Benzyl alcohol 3.00 g Demineralised water to 100 ml Example 13 Cream, soft consistency, oil-in-water ..... _ .. .
5 Micronised trifonazole 0.05 g "Glyceryl stearates", mi.~ture of mono- and di-glycerides of palmitic and stearic acid ll 00 ;
Cetyl palmitate 4~0 --s Cety:L stearyl alcohol o~yethyllted with 10 about 12 mol O.t' ethylene o~ide l.PO g Cetyl stearyl alcohol o~yethylated with about 30 mol of ethylene oxide 1.00 g Isopropyl myristate/isopropyl palmitate, isopropyl stearate mi~ture ~00 g 15 Slightly crosslinked polyacrylic acid of extremely high molecular weight 0 50 g 45% strength sodium hydroxide 0.11 g Glycerol 3.00 g Benzyl alcohol 3.00 g 20 Demineralised water to 100 ml Example 14 Cream, soft eonsistency, oil-in-water Lombazole 1.00 g "Glyceryl stearates", mixture of mono-and di-glycerides of palmitic and stearic acid 4 00 g 25 Na stearate 16~0Q g Cetyl stearyl alcohol o~yethylar~d with about 12 mol of ethylene o~ide 3 00 g Benzyl alcohol 3.50 ~
2-Octyldodeeanol 2~50 g 30 Coeonut oil acid isopropyl e~ter (Isc~rcpyl n~-rist~e/ 2 5~ g isopropyl pa~nitate/iso~r~pyl ste~atell~iYt~
paraffin, highly llquld` 3.00 g ~ater~ demineralised to 100.00 ml Exam~le- 15 (transparent cream in gel form) Le A 20 573 Clotrimazole 1.00 9 Cetyl stearyl alcohol oxye-thylated with about 30 mols of ethylene oxide14.00 ~
Coconut oil acid isopropyl ester20.00 y 2-Octyldodecanol 5.00 y Benzyl alcohol 3.00 y Water, demineraliseclto lO0.00 ml The following E~ampLe illustratas the activlty of certaln formu.Lations accorclin~ to the prascr1t lnvcl-tion.
I0 lestin~ t_e s___vitv oF the formulations acc_rd ng to tha invention on Trichophyton-infacted yuineaeigs.
_______~______~__.___ _____________ _____ _ _, Trichophyton-inFected Pirbright white guineapiys with an average weight oF 600 9 were used as a test model for a comparative examination of the activity of the formulations according to the invention. The backs of the animals ~ere shaved with electric hair-clippers such that hair stubble about 1/lO mm long remained.
Infection of Trichophyton mentagrophytes was effected by lightly rubbing in a spore suSpenSiQn of the pathogen, which had been initially germinated for 24 hours in Sabouraud nutrient solution, over an approximately 2 x 2 cm area of the shaved back of the animals. 0.5 ml of germ suspension, which contained 1 - 3 ~ 105 infectious fungus particles, were applied per animal.
In the case of this mode of infection, the first symptoms of dermatophytosis showed as reddening and scaling of the sl<in ~-3 days after infection. In the case of un-treated animals, the dermatophytosis wss most pronounced about 14 days ar`ter infection: los~ of hair in patches and bloody integumentary defocts within a phloyistically changed, scaly edge ~one.
The formulation~ to be tested were applied locally once, on the 2nd day after infection, to the reddened infection.sitPs on the animals and were rubbed lightly with a horn spatula. In each case 0.5 ml of the formulations Le ~ 20 573 ~= 5 mg of active compound as 1% strength formu1ation) was appliecd. The course of the infectioil was evaluated da:ily up to the 30th day after infec-ti.on.
The test rcsults can be seell from the -t~ble belo~.
~ent of ex~ Act:ion on Tr:icl~Qphyton-in~ected U~ ig~;
4**1~
2 ****
3 ****
'I
****
about 12 mol. of ethylene oxide 1.00 9 Cetyl stearyl alcohol oxyethylated with about 30 mol. of ethylene oxide l.00 9 Isopropyl myristate/isopropyl palmitate/
isopropyl stearate mi~ture 5.00 9 Slightly crosslinl<ed polyacrylic acid of extremely high molecular weight 0.50 9 45O strength sodium hydro~ide 0.11 9 Glycerol 3.00 9 Ben~y:l alcohol ~.00 9 Demineralised water to 100 ml Exall!ple 6 Cresm, soft consistency, oil-in-water Micronised trifonazole 1.00 g "Glyceryl stearates", mixture of mono- and 15 di-glycerides of palmitic and stearic acid '~.00 9 Cetyl palmitate 4.00 9 Cetyl stearyl alcohol oxyethylated with about 12 mol. of ethylene o~ide 1.00 9 Cetyl stearyl alcohol oxyethylated with about 30 mol~ of ethylene oxide 1.00 g Isopropyl myristate/isopropyl palmitate/' isopropyl stearate mixture 5.00 9 Slightly crosslinked polyacrylic acid of extremely high molecular weight 0.50 g 45~0 strength sodium hydroxide 0.11 9 Glycerol 3.00 9 Benzyl alcohol 3.00 9 Demineralised water to 100 ml Example 7 Emulsion, non-greasy, oil-in-water Phase I
ûleic acid decyl Pster ~.5n 9 Isopropyl myristate ~.50 9 Paraffin, highly liqwid 4.00 9 Polyethylene stearate 0.90 9 35 Sorbitane and glycerol fatty acid esters 0.60 9 Le A 20 573 The mixture is stirred and melted, at 70C for 10 minutes.
Phase II
Water, demineralised 50.00 9 Allantoin 0.10 9 Carbopol mucus Alcohol, denat~red 10~00 o Carbopol 934 (slighly crosslinked polyacrylic acicl) 0.70 ~
~o Water, demineralised 2_.945 9 A disperslon was obtained with a "Turra~" and the dispersion was allowed to swell for 2 hours and then neutralised with 0.155 9 of 45~ strength sodium nydro~ide solution.
Phase I, which had been warmed to 70C, was added, with stirring, to phase II, which had been heated to 75C, and the mixture was cooled to 45C. The carbopol mucus was stirred in at 45C and cooled further to 40C.
l.00 9 of collagen was added at 40C and cooled to 25C.
Then l~0 9 of lomba~ole was dissolved in 3.0 9 of ben7yl alcohol and the solution was added to phase I and II.
0.600 9 of perfume was then added and the crude emulsion was homogenised, with stirring, in a high-pressure homogeniser at 20C to 25GC.
Examples 8, 9, 10 and 11 were processed in an analogous manner.
Example 3 Emulsion, non-greasy, oil-ln-water ~licronised lamba7ole 0.10 9 Oleic acid decyl ester 2.50 9 30 Isopropyl myristate 2.50 9 Highly liquid paraffin 4.00 9 Polyethylene stearate 0.90 9 Sorbitane and glycerol fatty acid esters 0.60 9 35 Allantoin û.10 9 Le A 20 573 45O strength sodiuln hydroxide 0.155 9 Slightly crosslinked polyacrylic acid of extremely high molecular weight0.70 9 Collagen l.G0 9 Benzyl alcohol 3.ûO g Ethanol lO.00 9 Perfume oil 0.63 g Demi.nerallsed water to lno ml E~ample 9 Emulslon, non-greasy~ oll-.in-water 10 ~llcronised lombazole O.û5 g Oleic acld decyl ester 7. sn 9 Isopropyl myristflte 2.50 9 Highly liquld paraffin 4.00 9 Polyethylene stearate 0.90 9 15 Sorbitane and glycerol fatty acid esters 0.60 9 Allantoin 0.10 9 Slightly crosslinked polyacrylic acid of extremely high molecular weight 0.70 9 45O strength sodium hydroxiden. 155 9 20 Collagen 1.00 9 Benzyl alcohol 3.00 9 Ethanol 10.00 9 Perfume oil 0.60 9 Demlneralised water to lO0 ml Example 10 Emulsion, non~greasy, oil-in-water Micronised trifonazole 0.10 9 Oleic acid decyl ester 2.50 9 Isopropyl myristate 7.50 9 Highly liquid paraffin 4.00 9 30 Polyethylene stearate 0,90 9 Sorbitane and glycerol fatty acld esters 0.60 9 Allantoin 0.10 9 45O strength sodium hydroxide0.155 9 Slightly crosslinked polyacrylic acid 35 of extremely high molecular weight 0.70 g Le A 20 573 Collagen 1.00 9 Benzyl alcohol 3.00 9 Ethanol 10.00 g Perfume oil 3.60 9 Deminerali~ed water to lO0 ml Example l1 Emulsion, non-greasy, oil-in-water Micronised triFonazole 0 05 9 Oleic acicl decyl estcr 2.50 y Isopropyl myrlstatc 2.50 ~
10 Highly liquid paraffln !1,00 9 Polyethylene stearate 0 90 9 Sorbitane and glycerol fatty acid esters 0.60 9 Allantoin 0.10 9 45O strength sodium hydroxide0.155 g 15 Slightly crosslinked polyacrylic acid of extremely high molecular weight0.70 9 Collagen 1.00 9 Benzyl alcohol 3.00 9 Ethanol 10.00 9 20 Perfume oil 0.60 9 Demineralised water to 100 ml Example 12 Cream, soft consistency, oil-in-water Micronised trifonazole 0.10 9 "Glyceryl stearates", mixture of mono- and 25 di-glycerides of palmitic and staaric acid 4.00 9 Cetyl palmitate 4.00 9 Cetyl stearyl alcohol, oxyethylated with about 12 mol. oF ethylene oxide1.00 9 Cetyl stearyl alcohol, oxyethylated with about 30 mol.~ of ethylene oxide1 00 9 Isopropyl myristate/isop~pyl palmitàte~
isopropyl stea~ate mixture 5.00 9 Slightly crosslinked polyacrylic acid of extremely high molecular weight 0.50 9 45~0 strength sodium hydroxide0.11 9 Le A 20 573 Glycerol 3 oo g Benzyl alcohol 3.00 g Demineralised water to 100 ml Example 13 Cream, soft consistency, oil-in-water ..... _ .. .
5 Micronised trifonazole 0.05 g "Glyceryl stearates", mi.~ture of mono- and di-glycerides of palmitic and stearic acid ll 00 ;
Cetyl palmitate 4~0 --s Cety:L stearyl alcohol o~yethyllted with 10 about 12 mol O.t' ethylene o~ide l.PO g Cetyl stearyl alcohol o~yethylated with about 30 mol of ethylene oxide 1.00 g Isopropyl myristate/isopropyl palmitate, isopropyl stearate mi~ture ~00 g 15 Slightly crosslinked polyacrylic acid of extremely high molecular weight 0 50 g 45% strength sodium hydroxide 0.11 g Glycerol 3.00 g Benzyl alcohol 3.00 g 20 Demineralised water to 100 ml Example 14 Cream, soft eonsistency, oil-in-water Lombazole 1.00 g "Glyceryl stearates", mixture of mono-and di-glycerides of palmitic and stearic acid 4 00 g 25 Na stearate 16~0Q g Cetyl stearyl alcohol o~yethylar~d with about 12 mol of ethylene o~ide 3 00 g Benzyl alcohol 3.50 ~
2-Octyldodeeanol 2~50 g 30 Coeonut oil acid isopropyl e~ter (Isc~rcpyl n~-rist~e/ 2 5~ g isopropyl pa~nitate/iso~r~pyl ste~atell~iYt~
paraffin, highly llquld` 3.00 g ~ater~ demineralised to 100.00 ml Exam~le- 15 (transparent cream in gel form) Le A 20 573 Clotrimazole 1.00 9 Cetyl stearyl alcohol oxye-thylated with about 30 mols of ethylene oxide14.00 ~
Coconut oil acid isopropyl ester20.00 y 2-Octyldodecanol 5.00 y Benzyl alcohol 3.00 y Water, demineraliseclto lO0.00 ml The following E~ampLe illustratas the activlty of certaln formu.Lations accorclin~ to the prascr1t lnvcl-tion.
I0 lestin~ t_e s___vitv oF the formulations acc_rd ng to tha invention on Trichophyton-infacted yuineaeigs.
_______~______~__.___ _____________ _____ _ _, Trichophyton-inFected Pirbright white guineapiys with an average weight oF 600 9 were used as a test model for a comparative examination of the activity of the formulations according to the invention. The backs of the animals ~ere shaved with electric hair-clippers such that hair stubble about 1/lO mm long remained.
Infection of Trichophyton mentagrophytes was effected by lightly rubbing in a spore suSpenSiQn of the pathogen, which had been initially germinated for 24 hours in Sabouraud nutrient solution, over an approximately 2 x 2 cm area of the shaved back of the animals. 0.5 ml of germ suspension, which contained 1 - 3 ~ 105 infectious fungus particles, were applied per animal.
In the case of this mode of infection, the first symptoms of dermatophytosis showed as reddening and scaling of the sl<in ~-3 days after infection. In the case of un-treated animals, the dermatophytosis wss most pronounced about 14 days ar`ter infection: los~ of hair in patches and bloody integumentary defocts within a phloyistically changed, scaly edge ~one.
The formulation~ to be tested were applied locally once, on the 2nd day after infection, to the reddened infection.sitPs on the animals and were rubbed lightly with a horn spatula. In each case 0.5 ml of the formulations Le ~ 20 573 ~= 5 mg of active compound as 1% strength formu1ation) was appliecd. The course of the infectioil was evaluated da:ily up to the 30th day after infec-ti.on.
The test rcsults can be seell from the -t~ble belo~.
~ent of ex~ Act:ion on Tr:icl~Qphyton-in~ected U~ ig~;
4**1~
2 ****
3 ****
'I
****
6 ****
7 ****
****
9 ****
12 ***
2n l~ ****
****
****: very goocl actlo *** : goo~l ~ctio ** : actioll * : Sligllt ~ICtiOIl O : 110 actioll l~llell insteacl of the formulatloll~ according to the invelltioll, form-l-lations which contained no benzyl alcohol and no spreading agent ~ere used, an effect which corresponded to that of tile formulations according to the invention was achieved only after three appllcations.
****
9 ****
12 ***
2n l~ ****
****
****: very goocl actlo *** : goo~l ~ctio ** : actioll * : Sligllt ~ICtiOIl O : 110 actioll l~llell insteacl of the formulatloll~ according to the invelltioll, form-l-lations which contained no benzyl alcohol and no spreading agent ~ere used, an effect which corresponded to that of tile formulations according to the invention was achieved only after three appllcations.
Claims (11)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. An antimycotic formulation which comprises an antimycotically effective amount of anantimycotic compound, 3 to 5% of benzyl alcohol and 2.5 to 20% of a spreading agent.
2. A formulation according to claim 1, in which the antimycotic active compound is an imidazole derivative or a triazole derivative.
3. A formulation according to claim 2, in which the antimycotic active compound is clotrimazole of the formula
4. A formulation according to claim 2, in which the antimycotic active derivative is trifonazole of the formula
5. A formulation according to claim 2, in which the antimycotic active compound is lombazole of the formula
6. A formulation according to claim 1, 2 or 3, in which the antimy-cotic active compound is present in an amount of 0.05 to 1%, by weight.
7. A formulation according to claim 4 or 5, in which the antimycotic active compound is present in an amount of 0.05 to 1%, by weight.
8. A formulation according to claim 1, 2, or 3, in which the antimy-cotic active compound is present in an amount of 0.01 to 1%, by weight.
9. A formulation according to claim 4 or 5, in which the antimycotic active compound is present in an amount of 0.1 to 1%, by weight.
10. A formulation according to claim 1, 2 or 3, in which the speading agent is selected from isopropyl myristate, isoproply palmitato, capriylic/
capric acid esters of saturated fatty alcohols of C12-C18 chain length, waxy faty acid esters, silicone oils and an isopropyl myristate/isoproply stear-ate/isopropyl palmitate mixture.
capric acid esters of saturated fatty alcohols of C12-C18 chain length, waxy faty acid esters, silicone oils and an isopropyl myristate/isoproply stear-ate/isopropyl palmitate mixture.
11. A formulation according to claim 4 or 5, in which the spreading agent is selected from isoproply myristato, isopropyl palmitate, caprylic/
fatty acid esters, silicone oils and an isopropyl myristate/isopropyl stear-ate/isopropyl palmitate mixture.
fatty acid esters, silicone oils and an isopropyl myristate/isopropyl stear-ate/isopropyl palmitate mixture.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3045913.3 | 1980-12-05 | ||
| DE19803045913 DE3045913A1 (en) | 1980-12-05 | 1980-12-05 | ANTIMYCOTIC AGENTS WITH HIGH ACTIVE SUBSTANCE RELEASE |
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| Publication Number | Publication Date |
|---|---|
| CA1180661A true CA1180661A (en) | 1985-01-08 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000391479A Expired CA1180661A (en) | 1980-12-05 | 1981-12-04 | Antimycotic agents which have a good release of active compound |
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| Country | Link |
|---|---|
| EP (1) | EP0054205B1 (en) |
| JP (1) | JPS57120516A (en) |
| KR (1) | KR880000724B1 (en) |
| AT (1) | ATE11219T1 (en) |
| AU (1) | AU546451B2 (en) |
| CA (1) | CA1180661A (en) |
| DE (2) | DE3045913A1 (en) |
| DK (1) | DK538481A (en) |
| ES (1) | ES507726A0 (en) |
| FI (1) | FI813883L (en) |
| IL (1) | IL64434A0 (en) |
| NO (1) | NO158922C (en) |
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|---|---|---|---|---|
| US4721724A (en) * | 1985-06-05 | 1988-01-26 | Bayer Aktiengesellschaft | Formulations containing azole derivatives, and their use for atraumatic nail removal |
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| CH655656B (en) * | 1982-10-07 | 1986-05-15 | ||
| DE3244027A1 (en) * | 1982-11-27 | 1984-05-30 | Bayer Ag, 5090 Leverkusen | ANTIMYCOTIC AGENTS WITH HIGH ACTIVE SUBSTANCE RELEASE IN THE FORM OF GEL SYSTEMS |
| DE3311700A1 (en) * | 1983-03-30 | 1984-10-04 | Bayer Ag | ANTIMYCOTIC AGENTS WITH HIGH ACTIVE SUBSTANCE RELEASE IN THE FORM OF SOLUTION AND SPRAY |
| DE3311701A1 (en) * | 1983-03-30 | 1984-10-04 | Bayer Ag | ANTIMYCOTIC AGENTS WITH HIGH ACTIVE SUBSTANCE RELEASE IN THE FORM OF CREAM |
| DE3323833A1 (en) * | 1983-07-01 | 1985-01-03 | Troponwerke Gmbh & Co Kg | OVEN AMATE PREPARATION |
| US4731384A (en) * | 1983-07-01 | 1988-03-15 | Troponwerke Gmbh & Co, Kg | Etofenamate formulation |
| DE3323832A1 (en) * | 1983-07-01 | 1985-01-03 | Troponwerke Gmbh & Co Kg | OVEN AMATE PREPARATION |
| JPS6058914A (en) * | 1983-09-12 | 1985-04-05 | Shionogi & Co Ltd | Antimycotic gel preparation for external use containing imidazoles |
| CS253719B2 (en) * | 1984-03-07 | 1987-12-17 | Janssen Pharmaceutica Nv | Emulsible concentrate with fungicide activity and process for preparing thereof |
| JPS6261915A (en) * | 1985-09-10 | 1987-03-18 | Taisho Pharmaceut Co Ltd | Antimycotic agent for external use |
| DE3600947A1 (en) * | 1986-01-15 | 1987-07-16 | Kali Chemie Pharma Gmbh | ANTIMYCOTIC EMULSIONS |
| HU200914B (en) * | 1987-03-09 | 1990-09-28 | Horvath Gyoengyi Lengyelne | Process for producing new medical dosage unit suitable for local treatment of fungus infection of nails |
| JPH01246219A (en) * | 1988-03-25 | 1989-10-02 | Nippon Nohyaku Co Ltd | Antimycotic cream composition for external use |
| JPH0725675B2 (en) * | 1989-05-08 | 1995-03-22 | ホーユー株式会社 | Liquid mycosis agent |
| BG95755A (en) * | 1991-01-19 | 1993-12-24 | Hoechst Aktiengesellschaft | METHOD OF OBTAINING PREPARATIVE FORM FOR APPLICATION BY IRRIGATION OF ANTHELMINTIC AGENTS |
| KR20020045152A (en) * | 2000-12-08 | 2002-06-19 | 류정열 | Clamp-holder for hose-clamp |
| US20080092561A1 (en) * | 2004-07-09 | 2008-04-24 | Pandura Farms Pty Ltd. | Sequential Cooling Methods and Apparatus |
| US9981069B2 (en) | 2007-06-20 | 2018-05-29 | The Trustees Of Columbia University In The City Of New York | Bio-film resistant surfaces |
| US9511040B2 (en) | 2007-06-20 | 2016-12-06 | The Trustees Of Columbia University In The City Of New York | Skin and surface disinfectant compositions containing botanicals |
| EP2166840B1 (en) | 2007-06-20 | 2017-01-11 | The Trustees of Columbia University in the City of New York | Bio-film resistant surfaces |
| US9687429B2 (en) | 2007-06-20 | 2017-06-27 | The Trustees Of Columbia University In The City Of New York | Antimicrobial compositions containing low concentrations of botanicals |
| JP2012532141A (en) * | 2009-06-30 | 2012-12-13 | ザ トラスティース オブ コロンビア ユニバーシティ イン ザ シティ オブ ニューヨーク | Antimicrobial / preservative composition containing plant components |
| EP2773334B1 (en) | 2011-11-03 | 2019-08-28 | The Trustees of Columbia University in the City of New York | Composition with sustained antimicrobial activity |
| US9968101B2 (en) | 2011-11-03 | 2018-05-15 | The Trustees Of Columbia University In The City Of New York | Botanical antimicrobial compositions |
| WO2013086094A1 (en) | 2011-12-06 | 2013-06-13 | The Trustees Of Columbia University In The City Of New York | Broad spectrum natural preservative composition |
| CN111423328B (en) * | 2020-04-02 | 2022-04-15 | 广州隽沐生物科技股份有限公司 | Preparation method of decyl oleate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3502594A (en) * | 1965-12-28 | 1970-03-24 | Gerhard W Ahrens | Synergistic antioxidant composition for natural oleaginous materials |
| US3483008A (en) * | 1966-08-01 | 1969-12-09 | Daniel A Naeve | Method of preparing a water-soluble protein lotion |
| DE2333355C2 (en) * | 1973-06-30 | 1984-01-19 | Bayer Ag, 5090 Leverkusen | Antimicrobial agents |
| DE2430039C2 (en) * | 1974-06-22 | 1983-11-10 | Bayer Ag, 5090 Leverkusen | Climbazole in cosmetic products |
| 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 |
| DE2628421A1 (en) * | 1976-06-24 | 1978-01-05 | Bayer Ag | ANTIMICROBIAL AGENTS |
| DE2811916A1 (en) * | 1978-03-18 | 1979-09-27 | Bayer Ag | Antimycotic 1-phenoxy-1-azolyl-4-halo-2-acyloxy-butane derivs. - prepd. by acylation of corresp. 1-imidazolyl-or 1-triazolyl-2-butanol derivs. |
-
1980
- 1980-12-05 DE DE19803045913 patent/DE3045913A1/en not_active Withdrawn
-
1981
- 1981-11-19 NO NO813930A patent/NO158922C/en unknown
- 1981-11-27 EP EP81109946A patent/EP0054205B1/en not_active Expired
- 1981-11-27 DE DE8181109946T patent/DE3168402D1/en not_active Expired
- 1981-11-27 AT AT81109946T patent/ATE11219T1/en not_active IP Right Cessation
- 1981-12-02 IL IL64434A patent/IL64434A0/en not_active IP Right Cessation
- 1981-12-03 FI FI813883A patent/FI813883L/en not_active Application Discontinuation
- 1981-12-04 CA CA000391479A patent/CA1180661A/en not_active Expired
- 1981-12-04 ES ES507726A patent/ES507726A0/en active Granted
- 1981-12-04 DK DK538481A patent/DK538481A/en not_active Application Discontinuation
- 1981-12-04 ZA ZA818430A patent/ZA818430B/en unknown
- 1981-12-04 JP JP56194672A patent/JPS57120516A/en active Granted
- 1981-12-04 AU AU78263/81A patent/AU546451B2/en not_active Ceased
- 1981-12-05 KR KR1019810004748A patent/KR880000724B1/en active
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4721724A (en) * | 1985-06-05 | 1988-01-26 | Bayer Aktiengesellschaft | Formulations containing azole derivatives, and their use for atraumatic nail removal |
Also Published As
| Publication number | Publication date |
|---|---|
| KR830007071A (en) | 1983-10-12 |
| NO813930L (en) | 1982-06-07 |
| DE3045913A1 (en) | 1982-07-08 |
| DE3168402D1 (en) | 1985-02-28 |
| EP0054205B1 (en) | 1985-01-16 |
| JPS57120516A (en) | 1982-07-27 |
| AU7826381A (en) | 1982-06-10 |
| ES8400241A1 (en) | 1983-11-01 |
| ATE11219T1 (en) | 1985-02-15 |
| EP0054205A1 (en) | 1982-06-23 |
| NO158922B (en) | 1988-08-08 |
| IL64434A0 (en) | 1982-03-31 |
| JPH0380775B2 (en) | 1991-12-26 |
| AU546451B2 (en) | 1985-09-05 |
| ZA818430B (en) | 1982-11-24 |
| NO158922C (en) | 1988-11-23 |
| KR880000724B1 (en) | 1988-04-29 |
| ES507726A0 (en) | 1983-11-01 |
| DK538481A (en) | 1982-06-06 |
| FI813883L (en) | 1982-06-06 |
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Legal Events
| Date | Code | Title | Description |
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| MKEX | Expiry |