CA1209916A - Antimycotic agents in the form of gel systems with high release of active compound - Google Patents
Antimycotic agents in the form of gel systems with high release of active compoundInfo
- Publication number
- CA1209916A CA1209916A CA000441948A CA441948A CA1209916A CA 1209916 A CA1209916 A CA 1209916A CA 000441948 A CA000441948 A CA 000441948A CA 441948 A CA441948 A CA 441948A CA 1209916 A CA1209916 A CA 1209916A
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- Canada
- Prior art keywords
- antimycotic
- compound
- gel
- active compound
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- 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
-
- 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
-
- 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
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The invention provides for novel antimycotic agents in gel form for the treatment of fungal infections of the oral cavity. The gel form of the invention provides a depot effect, good adhesion properties and relatively high bioavailability of the active compounds. The gels of the invention make possible the use of short term therapy.
The invention provides for novel antimycotic agents in gel form for the treatment of fungal infections of the oral cavity. The gel form of the invention provides a depot effect, good adhesion properties and relatively high bioavailability of the active compounds. The gels of the invention make possible the use of short term therapy.
Description
1~()9 9~L6 The present invention relates to novel gel formulations of the known antimycotic azole derivatives which show improved release of the active com-pounds and thus make short-term therapy possible.
Formulations of antimycotic derivatives for the treatment of mycoses in humans, especially mycoses of the skin, have already been disclosed. Using these formulations, a 14 to 21-day therapy period is necessary for c~mplete healing.
In order to shorten the duration of therapy a certain depot efect and a greater bioavailability of the active compounds are necessary especially in order to eliminate the organisms and achieve mycological healing. The known formulations have only restricted suitability for this purpose because only a small proportion cf the amount of active compound present dissolves in the volume of fluid at the site of infection. If it is no~desired to shorten the duration of therapy by means of or without a further increase in the concentration of active compound, care must be taken that the bioavailability of the active compound is optimal.
It has now been found that those gel formulations of antimycotic azole derivatives which contain, in addition to customary formulating agents, 1-5% of benzyl alcohol and 2.5-35% of spreading agent and gel-forming agent release the active co~pound to a greater extent and thus permit shortening of the duration of therapy to 1 day. This effect of the improved release of active compound can extend up to a power of ten.
Thus, the present invention provides an antimycotic gel with improved release of the active compound, containing an antimycotic azole compound and customary formulation auxiliaries, characterised in that it contains 1-5% of benzyl ,, ~!;
Le A 22 000 --1~9~16 alcohol, 2.5-35% of spreading agent and, as the gel-forming agent, either a) 10-30% of cetylstearyl alcohol oxyethylated with about 3~ mols of ethylene oxide or b) 1-5% of polyacrylic acid, polymethacrylic acid or a salt of polyacrylic acid or polymethacrylic acid.
Active compounds which can be formulated in this manner are any com-pounds having antimycotic activity, especially imidazole and triazole deriva-tives. They are present in the agents according to the invention in amounts preferably from 0.05% to 1%, most preferably 0.1 to 1%.
The compounds of the formulae below may be mentioned as examples:
[~
I ~ C ~ clotrimazole ~ ~N
II T bifonazole N
III ~ I ~ lombazole Cl L N
,., ~2~9 916 Numerous other azole derivatives having antimycotic activity have been disclosed in DE-OS (German Published Specification) 2,430,039. They can like-wise be used as active compounds in the agen~s according to the invention.
Spreading agents are understood as comprising oily liquids which distribute themselves particularly well on the skin. (R. Keymer, Pharm. Ind.
32 ~1980), 577-581). The following compounds are especially suitable as spreading agents for the agents according to the invention:
Silicone oils of various viscosities.
Æsters of fatty acids, such as ethyl stearate, di-n-butyl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated C16-C18 fatty alcohols, isopropyl myristate, isopropyl palmitate, esters of caprylic/capric acid with saturated fatty alcohols of chain length C12-C18, isopropyl stearate, isopropyl isostearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate, ~axy esters of fatty acids, such as artificial duck preen gland fat, dibutyl phthalate, diisopropyl adipate1 mixtures of esters related to the latter, polyol esters of fatty acids etc.
Triglycerides, such as caprylic/capric acid triglyceride, triglyceride mixtures with vegetable fatty acids of chain length C~-C12 or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated fatty acids which may possibly also contain hydroxyl groups, monoglycerides of C8/C10 fatty acids etc.
Fatty alcohols, such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol and oleyl alcohol.
Fatty acids, such as, for example, oleic acid.
The following are spreading oils which are particularly well suited:
~%~ 6 isopropyl myristate, isopropyl palmitate, esters of caprylic/capric acid with saturated fatty alcohols of chain length C12-Cl8, waxy fatty acid esters such as artificial duck preen gland fat, silicone oils, isopropyl myristate/isopropyl stearate/isopropyl palmitate mixture, isopropyl stearate and isopropyl iso-stearate.
The following additional auxiliaries and/or formulation base auxiliaries can be used in the production Df the agents according to the invention: glycerol, high viscosity paraffin, low viscosity paraffin, triethanolamine, collagen, allantoin, novantisolic acid and perfume oils.
The gel-f~rming agent used is cetylstearyl alcohol with about 30 mols of ethylene oxide, optionally mixed with polyol esters of fatty acids, in concentrations of 10-30%.
Additional suitable gel-forming agents arethosemacromolecular com-pounds which can dissolve or swell in both water and organic solvents.
If a classification of macromolecular auxiliaries is followed ~Keipert et al., Die Pharmazie 28, 145-18~ (1973~), then, in particular, ionic macromolecules and their salt forms are used. These are, inter alia, poly-acrylic acid, polymethacrylic acid and their salts,such as, for example, a slightly crosslinked polyacrylic acid of extremely high molecular weight which forms a clear gel structure by the addition of an alkali. In the cases of polymethacrylic acid and/or its salts, 1-5% is necessary.
Suitable solvents are water and all solvents which are miscible with water. Suitable examples are alkanols, such as ethanol and isopropyl alcohol, benzyl alcohol, propylene glycol, methylcellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulphoxide, dimethylformamide, te~rahydrofuran and cyclohexanone.
~209!911~
It is also possible to employ one or more solvents in the produc-tion of the formulations according to the invention.
The antimycotic gels according to the invention are prepared by a process in which a mixture including one or more antimycotic azole compounds 1 - 5% benzyl alcohol, 2.5 - 35% of spreading agent and, as a gel-forming agent, either a) lO - 30% of cetylstearyl alcohol oxyethylated with about 30 mols of ethylene oxide or b) l - 5% of polyacrylic acid~ polymethacrylic acid or a salt of polyacrylic acid or polymethacrylic acid is melted at 110C under a nitrogen atmosphere, combined with water and cooled down to 25 under slow stirring. The azole derivative is used preferably in an amount of 0.05 to 1%, most preferably of 0.1 - 1%.
The water phase consists of 35 - 55% demineralised water.
Examp~e 1 Phase I
Clotrimazole 1.000 g Polyol esters of fatty acids 23.000 g Cetylstearyl alcohol oxyethylated with about ` 30 mols of ethylene oxide 16.000 g Isopropyl myristate 10.000 g Benzyl alcohol 3.000 g The mixture is heated to 100C with stirring.
Phase II
Demineralised water heated ~o 100C 47.00 g Phase II is slowly stirred into phase I at at least 95C. Any loss of water is compensated for at 60C and slow stirring is continued down to 50C.
The mixture is then cooled down from 50C to 25C without stirring (in order to ~ ,"
avoid inclusion of air and not adversely to affect the gel formation) The procedure in Examples 2-6 is analogous.
Example 2 Bifonazole 1.00 g Polyol esters of fatty acids 20.00 g Cetylstearyl alcohol oxyethylated with about 30 mols of ethylene oxide 16.00 g Isopropyl myristate 10.00 g Benzyl alcchol 3.00 g Lactic acid 1.50 g Demin.eralised water 48.50 g Example 3 Clotrimazole 1.00 g Polyol esters of fatty acids 20.00 g Cetylstearyl alcohol oxyethylated with about 30 mols of ethylene oxide 20.00 g Isopropyl isostearate 5.00 g 96% strength ethanol 3.00 g Benzyl alcohol 1.00 g Demineralised water 50,00 g Example 4 Bifonazole 1.00 g Polyol esters of fatty acids 23.00 g Cetylstearyl alcohol oxyethylated with about 30 mols of ethylene oxide 12.00 g Isopropyl myristate 10.00 g Benzyl alcohol 3.00 g Demineralised water 51O00 g Example 5 Lombazole 1.00 g Polyol esters of fatty 20.00 g Cetylstearyl alcohol oxyethylated with about 3~ mols of ethylene oxide 20.00 g `` 12099~Ç~
Isopropyl isostearate 5.00 g Ethanol 3.50 g Benzyl alcohol 1.00 g Demineralised water 49.50 g Example 6 Bifonazole 1.00 g Polyol esters of fatty acids 20.00 g Cetylstearyl alcohol oxyethylated with about 30 mols of ethylene oxide20.00 g Isopropyl myristate 5.00 g Benzyl alcohol 5.00 g Demineralised water 49.00 g Example 7 Phase I
Clotrimazole 1.00 g dissolved in isopropanol 40.00 g then the following are stirred in and dissolved Polyol esters of fatty acids 4.00 g Benzyl alcohol 3.00 g Diisopropyl adipate 4.00 g Phase II
Carbopol* 940 (a high polymer polyacrylate) 1.50 g is introduced, with stirring into 46.10 g demineralised water The mixture is allowed to swell for about 2h and neutralised with 45~ strength NaOH0.40 g Phase I is slowly worked, in portions with stirring, into phase II.
The procedure in Examples 8 and 9 is analogous.
*Trade Mark ~`
3~
, . , Example 8 __ __ Lombazole 1.00 9 Polyol esters sf fatty ac;ds4.00 9 Isopropyl myristate 4.00 g 5 Benzyl alcohol 1.00 9 Isopropanol 45.00 9 Carhopo~ ~40 1.50 g 45X strength NaOH 0.40 9 Demineralised water 43.10 g 10 Example 9 eifonazole 1.00 9 Polyol esters of fatty acids4.00 9 Isopropyl esters of coconut fatty acid 4.00 g Benzyl alc Q hol 5.00 9 15 Isopropanol 45.00 g Carbopol 940 1.50 9 45X strength NaOH 0.40 9 Dem;neral;sed water 3~.10 g Test of the efficacy of the agents according to the invention on gu;neapigs ;nfected ~ith trichophyton.
The test model ~hich ~e used for the comparative test of the efficacy of the formulations according to the invention was Pirbrigth white gu;neapigs of average ~eight 60û 9 infected with trichophyton. The backs of the animals were shaved with an electric ha;r-cutting machine so that the remaining stubble was about 1t10 mm long~
The infection uith Trichophyton mentagrophytes ~as carried out by gently rubbing a suspension of spores O of the pathogen, ~hich had been germinated ;n Sabouraud's nutrient solution for 24 hours, into an area of about 2 x
Formulations of antimycotic derivatives for the treatment of mycoses in humans, especially mycoses of the skin, have already been disclosed. Using these formulations, a 14 to 21-day therapy period is necessary for c~mplete healing.
In order to shorten the duration of therapy a certain depot efect and a greater bioavailability of the active compounds are necessary especially in order to eliminate the organisms and achieve mycological healing. The known formulations have only restricted suitability for this purpose because only a small proportion cf the amount of active compound present dissolves in the volume of fluid at the site of infection. If it is no~desired to shorten the duration of therapy by means of or without a further increase in the concentration of active compound, care must be taken that the bioavailability of the active compound is optimal.
It has now been found that those gel formulations of antimycotic azole derivatives which contain, in addition to customary formulating agents, 1-5% of benzyl alcohol and 2.5-35% of spreading agent and gel-forming agent release the active co~pound to a greater extent and thus permit shortening of the duration of therapy to 1 day. This effect of the improved release of active compound can extend up to a power of ten.
Thus, the present invention provides an antimycotic gel with improved release of the active compound, containing an antimycotic azole compound and customary formulation auxiliaries, characterised in that it contains 1-5% of benzyl ,, ~!;
Le A 22 000 --1~9~16 alcohol, 2.5-35% of spreading agent and, as the gel-forming agent, either a) 10-30% of cetylstearyl alcohol oxyethylated with about 3~ mols of ethylene oxide or b) 1-5% of polyacrylic acid, polymethacrylic acid or a salt of polyacrylic acid or polymethacrylic acid.
Active compounds which can be formulated in this manner are any com-pounds having antimycotic activity, especially imidazole and triazole deriva-tives. They are present in the agents according to the invention in amounts preferably from 0.05% to 1%, most preferably 0.1 to 1%.
The compounds of the formulae below may be mentioned as examples:
[~
I ~ C ~ clotrimazole ~ ~N
II T bifonazole N
III ~ I ~ lombazole Cl L N
,., ~2~9 916 Numerous other azole derivatives having antimycotic activity have been disclosed in DE-OS (German Published Specification) 2,430,039. They can like-wise be used as active compounds in the agen~s according to the invention.
Spreading agents are understood as comprising oily liquids which distribute themselves particularly well on the skin. (R. Keymer, Pharm. Ind.
32 ~1980), 577-581). The following compounds are especially suitable as spreading agents for the agents according to the invention:
Silicone oils of various viscosities.
Æsters of fatty acids, such as ethyl stearate, di-n-butyl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated C16-C18 fatty alcohols, isopropyl myristate, isopropyl palmitate, esters of caprylic/capric acid with saturated fatty alcohols of chain length C12-C18, isopropyl stearate, isopropyl isostearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate, ~axy esters of fatty acids, such as artificial duck preen gland fat, dibutyl phthalate, diisopropyl adipate1 mixtures of esters related to the latter, polyol esters of fatty acids etc.
Triglycerides, such as caprylic/capric acid triglyceride, triglyceride mixtures with vegetable fatty acids of chain length C~-C12 or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated fatty acids which may possibly also contain hydroxyl groups, monoglycerides of C8/C10 fatty acids etc.
Fatty alcohols, such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol and oleyl alcohol.
Fatty acids, such as, for example, oleic acid.
The following are spreading oils which are particularly well suited:
~%~ 6 isopropyl myristate, isopropyl palmitate, esters of caprylic/capric acid with saturated fatty alcohols of chain length C12-Cl8, waxy fatty acid esters such as artificial duck preen gland fat, silicone oils, isopropyl myristate/isopropyl stearate/isopropyl palmitate mixture, isopropyl stearate and isopropyl iso-stearate.
The following additional auxiliaries and/or formulation base auxiliaries can be used in the production Df the agents according to the invention: glycerol, high viscosity paraffin, low viscosity paraffin, triethanolamine, collagen, allantoin, novantisolic acid and perfume oils.
The gel-f~rming agent used is cetylstearyl alcohol with about 30 mols of ethylene oxide, optionally mixed with polyol esters of fatty acids, in concentrations of 10-30%.
Additional suitable gel-forming agents arethosemacromolecular com-pounds which can dissolve or swell in both water and organic solvents.
If a classification of macromolecular auxiliaries is followed ~Keipert et al., Die Pharmazie 28, 145-18~ (1973~), then, in particular, ionic macromolecules and their salt forms are used. These are, inter alia, poly-acrylic acid, polymethacrylic acid and their salts,such as, for example, a slightly crosslinked polyacrylic acid of extremely high molecular weight which forms a clear gel structure by the addition of an alkali. In the cases of polymethacrylic acid and/or its salts, 1-5% is necessary.
Suitable solvents are water and all solvents which are miscible with water. Suitable examples are alkanols, such as ethanol and isopropyl alcohol, benzyl alcohol, propylene glycol, methylcellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulphoxide, dimethylformamide, te~rahydrofuran and cyclohexanone.
~209!911~
It is also possible to employ one or more solvents in the produc-tion of the formulations according to the invention.
The antimycotic gels according to the invention are prepared by a process in which a mixture including one or more antimycotic azole compounds 1 - 5% benzyl alcohol, 2.5 - 35% of spreading agent and, as a gel-forming agent, either a) lO - 30% of cetylstearyl alcohol oxyethylated with about 30 mols of ethylene oxide or b) l - 5% of polyacrylic acid~ polymethacrylic acid or a salt of polyacrylic acid or polymethacrylic acid is melted at 110C under a nitrogen atmosphere, combined with water and cooled down to 25 under slow stirring. The azole derivative is used preferably in an amount of 0.05 to 1%, most preferably of 0.1 - 1%.
The water phase consists of 35 - 55% demineralised water.
Examp~e 1 Phase I
Clotrimazole 1.000 g Polyol esters of fatty acids 23.000 g Cetylstearyl alcohol oxyethylated with about ` 30 mols of ethylene oxide 16.000 g Isopropyl myristate 10.000 g Benzyl alcohol 3.000 g The mixture is heated to 100C with stirring.
Phase II
Demineralised water heated ~o 100C 47.00 g Phase II is slowly stirred into phase I at at least 95C. Any loss of water is compensated for at 60C and slow stirring is continued down to 50C.
The mixture is then cooled down from 50C to 25C without stirring (in order to ~ ,"
avoid inclusion of air and not adversely to affect the gel formation) The procedure in Examples 2-6 is analogous.
Example 2 Bifonazole 1.00 g Polyol esters of fatty acids 20.00 g Cetylstearyl alcohol oxyethylated with about 30 mols of ethylene oxide 16.00 g Isopropyl myristate 10.00 g Benzyl alcchol 3.00 g Lactic acid 1.50 g Demin.eralised water 48.50 g Example 3 Clotrimazole 1.00 g Polyol esters of fatty acids 20.00 g Cetylstearyl alcohol oxyethylated with about 30 mols of ethylene oxide 20.00 g Isopropyl isostearate 5.00 g 96% strength ethanol 3.00 g Benzyl alcohol 1.00 g Demineralised water 50,00 g Example 4 Bifonazole 1.00 g Polyol esters of fatty acids 23.00 g Cetylstearyl alcohol oxyethylated with about 30 mols of ethylene oxide 12.00 g Isopropyl myristate 10.00 g Benzyl alcohol 3.00 g Demineralised water 51O00 g Example 5 Lombazole 1.00 g Polyol esters of fatty 20.00 g Cetylstearyl alcohol oxyethylated with about 3~ mols of ethylene oxide 20.00 g `` 12099~Ç~
Isopropyl isostearate 5.00 g Ethanol 3.50 g Benzyl alcohol 1.00 g Demineralised water 49.50 g Example 6 Bifonazole 1.00 g Polyol esters of fatty acids 20.00 g Cetylstearyl alcohol oxyethylated with about 30 mols of ethylene oxide20.00 g Isopropyl myristate 5.00 g Benzyl alcohol 5.00 g Demineralised water 49.00 g Example 7 Phase I
Clotrimazole 1.00 g dissolved in isopropanol 40.00 g then the following are stirred in and dissolved Polyol esters of fatty acids 4.00 g Benzyl alcohol 3.00 g Diisopropyl adipate 4.00 g Phase II
Carbopol* 940 (a high polymer polyacrylate) 1.50 g is introduced, with stirring into 46.10 g demineralised water The mixture is allowed to swell for about 2h and neutralised with 45~ strength NaOH0.40 g Phase I is slowly worked, in portions with stirring, into phase II.
The procedure in Examples 8 and 9 is analogous.
*Trade Mark ~`
3~
, . , Example 8 __ __ Lombazole 1.00 9 Polyol esters sf fatty ac;ds4.00 9 Isopropyl myristate 4.00 g 5 Benzyl alcohol 1.00 9 Isopropanol 45.00 9 Carhopo~ ~40 1.50 g 45X strength NaOH 0.40 9 Demineralised water 43.10 g 10 Example 9 eifonazole 1.00 9 Polyol esters of fatty acids4.00 9 Isopropyl esters of coconut fatty acid 4.00 g Benzyl alc Q hol 5.00 9 15 Isopropanol 45.00 g Carbopol 940 1.50 9 45X strength NaOH 0.40 9 Dem;neral;sed water 3~.10 g Test of the efficacy of the agents according to the invention on gu;neapigs ;nfected ~ith trichophyton.
The test model ~hich ~e used for the comparative test of the efficacy of the formulations according to the invention was Pirbrigth white gu;neapigs of average ~eight 60û 9 infected with trichophyton. The backs of the animals were shaved with an electric ha;r-cutting machine so that the remaining stubble was about 1t10 mm long~
The infection uith Trichophyton mentagrophytes ~as carried out by gently rubbing a suspension of spores O of the pathogen, ~hich had been germinated ;n Sabouraud's nutrient solution for 24 hours, into an area of about 2 x
2 cm on the shaven backs of the animals. 0.5 ml of the suspension of organisms ~hich contained 1 - 3 x 105 infectious fungal particles was applied to each animal.
Us;ng this method of infect;on, the first symp-toms of dermatophytosis appear 2 - 3 days after infection Le A 2Z 000 --` 120~9~6 as reddening and scaling of the skin. The dermatophytosis is maximal about 14 days after infect;on in untreated animals: areas of hair loss and haemorrhagic damage to the integument ~ith;n a sca~y edge zone ~ith inflammatory changes~
The formulations to be tested ~ere locally applied once, on the 2nd day after infection, to the reddened site of ;nfection on the an;mals and gently rubbed in us;ng a horn spatula.
In each case, 0.5 9 of the formulations = 5 mg of act;ve compound ~as appl;ed. The course of infection was assessed each day up to the 20th day after infect;on.
The results of the tests can be seen in the table belo~.
15 Example of agent Effect on guineapigs infected with trichophyton ****
2 ****
Us;ng this method of infect;on, the first symp-toms of dermatophytosis appear 2 - 3 days after infection Le A 2Z 000 --` 120~9~6 as reddening and scaling of the skin. The dermatophytosis is maximal about 14 days after infect;on in untreated animals: areas of hair loss and haemorrhagic damage to the integument ~ith;n a sca~y edge zone ~ith inflammatory changes~
The formulations to be tested ~ere locally applied once, on the 2nd day after infection, to the reddened site of ;nfection on the an;mals and gently rubbed in us;ng a horn spatula.
In each case, 0.5 9 of the formulations = 5 mg of act;ve compound ~as appl;ed. The course of infection was assessed each day up to the 20th day after infect;on.
The results of the tests can be seen in the table belo~.
15 Example of agent Effect on guineapigs infected with trichophyton ****
2 ****
3 ****
3 ~***
****
6 ****
7 ****
8 ****
9 ****
****: very sood effect **: effect *** : good effect * : weak effect 0 : no effect If, instead of the formulations accord;ng to the invention, formulat;ons contain;ng no benzyl alcohol and no spreading agent are used, an effect corresponding to that of the formulat;ons according to the invention ;s only achieved after applicat;on three times.
Le A 22 000
3 ~***
****
6 ****
7 ****
8 ****
9 ****
****: very sood effect **: effect *** : good effect * : weak effect 0 : no effect If, instead of the formulations accord;ng to the invention, formulat;ons contain;ng no benzyl alcohol and no spreading agent are used, an effect corresponding to that of the formulat;ons according to the invention ;s only achieved after applicat;on three times.
Le A 22 000
Claims (11)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED IS FOLLOWS:
1. An antimycotic gel with improved release of the active compound, containing an antimycotic azole compound and customary formulation auxiliaries, characterised in that it contains 1-5% of benzyl alcohol, 2.5-35% of spreading agent and, as the gel-forming agent, either a) 10-30% of cetylstearyl alcohol oxyethylated with about 30 mols of ethylene oxide or b) 1-5% of polyacrylic acid, polymethacrylic acid or a salt of polyacrylic acid or polymethacrylic acid.
2. An antimycotic gel according to Claim 1, characterised in that it contains clotrimazole of the formula as the active compound.
3. An antimycotic gel according to Claim 1, characterised in that it contains bifonazole of the formula as the active compound.
4. An antimycotic gel according to Claim 1, characterised in that it contains lombazole of the formula as the active compound.
5. An antimycotic gel according to Claim 1, characterised in that it contains an antimycotic azole compound in an amount of 0.05-1%.
6. An antimycotic gel according to Claim 1, characterised in that it contains an antimycotic azole compound in an amount of 0.1-1%.
7. A process for the production of an antimycotic gel according to claim 1, characterized in that a mixture including one or more antimycotic azole compounds, 1-5% benzyl alcohol, 2.5-35% of spreading agent and, as a gel-forming agent, either a) 10-30% of cetylstearyl alcohol with about 30 mols of ethylene oxide or b) 1-5% of polyacrylic acid, polymethacrylic acid or a salt of or polymethacrylic acid is melted at 110°C under a nitrogen atmosphere, combined with water and cooled down to 25°C under slow stirring.
8. A process according to Claim 7, wherein the antimycotic compound is clotrimazole.
9, A process according to Claim 7 wherein the antimycotic compound is bifonazole.
10. A process according to Claim 7 wherein the antimycotic compound is lombazole.
11. A process according to Claim 8, 9 or 10 wherein the amount of antimycotic compound is 0.05-1%.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823244027 DE3244027A1 (en) | 1982-11-27 | 1982-11-27 | ANTIMYCOTIC AGENTS WITH HIGH ACTIVE SUBSTANCE RELEASE IN THE FORM OF GEL SYSTEMS |
| DEP3244027.8 | 1982-11-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1209916A true CA1209916A (en) | 1986-08-19 |
Family
ID=6179276
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000441948A Expired CA1209916A (en) | 1982-11-27 | 1983-11-25 | Antimycotic agents in the form of gel systems with high release of active compound |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0113009A3 (en) |
| JP (1) | JPS59108713A (en) |
| KR (1) | KR840006767A (en) |
| AR (1) | AR231397A1 (en) |
| CA (1) | CA1209916A (en) |
| DE (1) | DE3244027A1 (en) |
| DK (1) | DK541783A (en) |
| ES (1) | ES527566A0 (en) |
| HU (1) | HU187612B (en) |
| IL (1) | IL70320A0 (en) |
| NO (1) | NO834083L (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61151117A (en) * | 1984-12-25 | 1986-07-09 | Bayer Yakuhin Kk | Gelatinous antimycotic preparation |
| US4837378A (en) * | 1986-01-15 | 1989-06-06 | Curatek Pharmaceuticals, Inc. | Topical metronidazole formulations and therapeutic uses thereof |
| JPH01246219A (en) * | 1988-03-25 | 1989-10-02 | Nippon Nohyaku Co Ltd | Antimycotic cream composition for external use |
| JPH01242525A (en) * | 1988-03-25 | 1989-09-27 | Nippon Nohyaku Co Ltd | Antifungal agent for external use |
| DE4234188C2 (en) * | 1992-10-10 | 1996-01-11 | Beiersdorf Ag | Antimycotic cosmetic and dermatological uses |
| IT1284874B1 (en) | 1996-08-02 | 1998-05-22 | Farmigea Spa | BIOADHESIVE COMPLEXES OF POLYCARBOPHIL AND AZOLIC ANTIFUNGAL OR ANTIPROTOZOAR DRUGS |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS52117416A (en) * | 1976-03-29 | 1977-10-01 | Nippon Kayaku Co Ltd | Novel ointment base |
| JPS5562008A (en) * | 1978-10-31 | 1980-05-10 | Sumitomo Chem Co Ltd | Preparation of cream |
| DE3045913A1 (en) * | 1980-12-05 | 1982-07-08 | Bayer Ag, 5090 Leverkusen | ANTIMYCOTIC AGENTS WITH HIGH ACTIVE SUBSTANCE RELEASE |
| DE3106635A1 (en) * | 1981-02-23 | 1982-09-09 | Bayer Ag | ANTIMYCOTIC AGENT WITH HIGH ACTIVE SUBSTANCE RELEASE IN THE FORM OF PEN |
| JPS5815909A (en) * | 1981-07-22 | 1983-01-29 | Toko Yakuhin Kogyo Kk | Antimycotic agent for external use |
-
1982
- 1982-11-27 DE DE19823244027 patent/DE3244027A1/en not_active Withdrawn
-
1983
- 1983-11-09 NO NO834083A patent/NO834083L/en unknown
- 1983-11-17 EP EP83111460A patent/EP0113009A3/en not_active Withdrawn
- 1983-11-24 HU HU834039A patent/HU187612B/en unknown
- 1983-11-24 IL IL70320A patent/IL70320A0/en unknown
- 1983-11-25 ES ES527566A patent/ES527566A0/en active Granted
- 1983-11-25 AR AR294927A patent/AR231397A1/en active
- 1983-11-25 CA CA000441948A patent/CA1209916A/en not_active Expired
- 1983-11-25 DK DK541783A patent/DK541783A/en not_active Application Discontinuation
- 1983-11-25 JP JP58220891A patent/JPS59108713A/en active Pending
- 1983-11-26 KR KR1019830005598A patent/KR840006767A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DK541783A (en) | 1984-05-28 |
| JPS59108713A (en) | 1984-06-23 |
| IL70320A0 (en) | 1984-02-29 |
| AR231397A1 (en) | 1984-11-30 |
| DK541783D0 (en) | 1983-11-25 |
| EP0113009A2 (en) | 1984-07-11 |
| DE3244027A1 (en) | 1984-05-30 |
| ES8406192A1 (en) | 1984-08-01 |
| KR840006767A (en) | 1984-12-03 |
| ES527566A0 (en) | 1984-08-01 |
| HU187612B (en) | 1986-02-28 |
| NO834083L (en) | 1984-05-28 |
| EP0113009A3 (en) | 1985-09-25 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |