CA1175355A - Antimycotic agents which have a good release of active compound and are in the form of elastic liquid plasters - Google Patents
Antimycotic agents which have a good release of active compound and are in the form of elastic liquid plastersInfo
- Publication number
- CA1175355A CA1175355A CA000391480A CA391480A CA1175355A CA 1175355 A CA1175355 A CA 1175355A CA 000391480 A CA000391480 A CA 000391480A CA 391480 A CA391480 A CA 391480A CA 1175355 A CA1175355 A CA 1175355A
- Authority
- CA
- Canada
- Prior art keywords
- active compound
- formulation according
- antimycotic
- agent
- formulations
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- 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
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- 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
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
-
- 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
-
- 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
Abstract
"Antimycotic agents which have a good release of active compound and are in the form of elastic liquid plasters"
ABSTRACT OF THE DISCLOSURE
The inventnion relates to formulations of anti-mycotic active compounds, said formulations containg a spreading agent, a solubilising agent and a film-forming agent which is soluble in both water and organic solvents to provide high bioavailability of the active compounds and make short-term therapy possible.
Le A 20 574-CA
ABSTRACT OF THE DISCLOSURE
The inventnion relates to formulations of anti-mycotic active compounds, said formulations containg a spreading agent, a solubilising agent and a film-forming agent which is soluble in both water and organic solvents to provide high bioavailability of the active compounds and make short-term therapy possible.
Le A 20 574-CA
Description
The present in~ention relates to certain novel antimycotic formulations of antimycotic active compounds which may in them-selves be known, w~hich have a depot action, in spite of film formation, and a relatively high bioavailability of the active compounds and thereby make short-term therapy possible.
Formula~ions of antimycotic derivatives for the treatment of mycoses in humans, above all mycoses of the skin, have already been disclosed. Using these formulations, a therapy period of ~ 21 days has been required for a complete cure.
In order to shorten the period of therapy, a certain depot action and a relatively high bioavailability of the active compounds are required, in particular to eliminate the germs and ln order to achieve a mycological cure. The kno~n formulations are suitable for this only to a limited extent, 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 example to one day and a single application, is to be achieved without a further increase in the concentration of active compound, optimum bioavailability of the active compound must be ensured.
According to the present invention we provide a formula, tion which comprises an antimycotically effective amount of an antimycotic compound and inert pharmaceutical carrier containing a film-forming agent which is soluble or swellable both in water and in organic solvents, a spreading agent and a solubilising agent. In a preferred embodiment we provide an antimycotic formulation which comprises an antimycotically active compound, 1~75~35S
Formula~ions of antimycotic derivatives for the treatment of mycoses in humans, above all mycoses of the skin, have already been disclosed. Using these formulations, a therapy period of ~ 21 days has been required for a complete cure.
In order to shorten the period of therapy, a certain depot action and a relatively high bioavailability of the active compounds are required, in particular to eliminate the germs and ln order to achieve a mycological cure. The kno~n formulations are suitable for this only to a limited extent, 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 example to one day and a single application, is to be achieved without a further increase in the concentration of active compound, optimum bioavailability of the active compound must be ensured.
According to the present invention we provide a formula, tion which comprises an antimycotically effective amount of an antimycotic compound and inert pharmaceutical carrier containing a film-forming agent which is soluble or swellable both in water and in organic solvents, a spreading agent and a solubilising agent. In a preferred embodiment we provide an antimycotic formulation which comprises an antimycotically active compound, 1~75~35S
2 to 10% of a spreadin~ a~ent ! 1 to 8% of a solubllising agent and, as a film-forming agent, a quick-drying polyvinylpyrrolidone, a terpolymer of 30% of vinyipyrrolldone, 40% of vinyl acetate and 30% of vinyl propionate, or a ~lnylpyrrolidone~vinyl acetate copolymer, which is soluble or swellable both in water and in organlc solvents. The formulatio~ can also contain any desired further formulation au~iliary or auxiliarles, - la -1~753SS
The formulations according to the present invention make possible optimum release of -the active compound and hence a therapy period which is shortened to one day by high concentrations of the active compound being achieved.
This effect is achieved by the presence of spreading-oils and solubilising agents and by the addition of adherent film-forming agents which allow the release of active compounds to be increased up to ten-fold and the action of the active compound thereby to be increased.
The formulations according to the invention, which are elastic liquid plaster formulations, represent a new ~ application principle for dermal treatment of mycoses which~
in addition to being very effective in applying the active compounds, provides, as a result of sealing the infection site, protection against infection of the surrounding area.
The formulations according to the invention are particularly-suitable for the treatment of nail mycoses.
The formulations according to the invention can be eitherasolution or a spray.
- 20 Active compounds which can be formulated in this manner are any of the compounds having an antimycotic action, in particular imidazole derivatives and triazole derivatives. They are present in the agents according to the invention in amounts of 0.05 - 1~o~ preferably 0~1-1o~
; 25 by weight.
The compounds with the following formulae may be mentioned as preferred examples:
,- ~
(I) ~ C ~ clotrimazole, I Cl Le A 20 574 ~L~753SS
~ CH ~
(II) ~ trifonazole and ~ N~
(III) H lombazole k~ c ~
\J ~ I ' >~
I Cl N ~
Numerous ether azole derivatives having an anti-mycotic action are known from DE-OS (German Published Specification) 2,430,039. They can likewise be used as the active compound in the agents according to the invention.
By spreading agents there are understood oily liquids which are particularly readily distributed on the skin [R.
Keymer, Parrn. Ind. 32 (1970) 577 - 581]. The compounds which follow are particularly suitable as spreading agents for the agents according to the invention:
Silicone oils of various viscosities;
, Fatty acid esters, ~such as ethyl stearate, di-n-butyl 15 ~ adipat;e, lauric acid hexyl 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 ac d ~; esters of saturated fatty alcohols of C12 C18 chain length ~ ~ 20 isopropyl stearate, oleic acid oleyl ester, oleic acid -~ decyl ester, ethyl oleate, lactic acid ethyl ester, waxy~ fatty acid esters, such as synthesised duck uropygial gland .
~ Le A 20 574 fat, dibutyl phthalate, adipic acid diisopropyl ester and ester mixtures related to the latter;
Triglycerides, such as caprylic/capric acid triglyceride, triglyceride mixtures with vegetable fatty acids of C8-C12 chain length or other specially selected naturally occurring fatty acids, partial glyceride mixtures of saturated or unsaturated fatty acids which optionally also contain hydroxyl groups and monoglycerides of C8/C10- fatty acids;
Fatty alcohols, such as isotridecyl alcohol, cetyl stearyl alcohol and oleyl alcohol; and Fatty acids, such a:s,~for example, oleic acid.
The compounds which follow are particularly suitable spreading-oils: isopropyl myristate, isopropyl palmitate, isopropyl stearate, capr.ylic/capric acid esters of saturated fatty alcohols of C12-C18 chain length, waxy fatty acid esters, such as synthesised duck uropygial gland fat, silicone oils, an isopropyl myristate/isopropyl palmitate/isopropyl stearate mixture and coconut oil acid isopropyl ester.
Preferred suitable solubilising agents for use in the formulations according to the present invention are benzyl alcohol, 2-octyl-dodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, dipr.opyl-ene and tripropylene glycol and waxes and other additivesused in cosmetics.
- The gel-forming and film-forming agents are those macromolecular compounds, as defined previously, which can dissolve or start to swell both in water and in organic solvents and form a type of film after drying.
Suita~le solvents are water and any of the water-miscible solvents. Possible solvents are, for example, alkanols (such as ethanol and isopropyl alcohol), propyl-ene glycol, Methylcellosolve, Cellusolve, esters, Le A 20 574 -.
~L~L7S35S
morpholines, dioxane, dimethylsulphoxide, dimethylformamide, tetrahydrofuran and cyclohexanone.
One or more solvents can be employed in the pre-paration of the formulations according to the invention.
The auxiliaries which follow can, _nter alia, be used as appropriate in practice to establish an optimum formulation: glycerol, viscous paraffin, highly liquid paraffin, triethanolamine, collagen, allantoin, novant-isolic acid and perfume oils~
Further auxiliaries which are suitable are:
(a) Substances which, for example, can stabilise a sus-pension, for example colloidal silicic acid or montmorillo-nites;
(b) Surface-active agents (including emulsifiers and 15 ~ 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. cat1onic surface-active agents, such as cetyl tri-methylammonium chloride;
The formulations according to the present invention make possible optimum release of -the active compound and hence a therapy period which is shortened to one day by high concentrations of the active compound being achieved.
This effect is achieved by the presence of spreading-oils and solubilising agents and by the addition of adherent film-forming agents which allow the release of active compounds to be increased up to ten-fold and the action of the active compound thereby to be increased.
The formulations according to the invention, which are elastic liquid plaster formulations, represent a new ~ application principle for dermal treatment of mycoses which~
in addition to being very effective in applying the active compounds, provides, as a result of sealing the infection site, protection against infection of the surrounding area.
The formulations according to the invention are particularly-suitable for the treatment of nail mycoses.
The formulations according to the invention can be eitherasolution or a spray.
- 20 Active compounds which can be formulated in this manner are any of the compounds having an antimycotic action, in particular imidazole derivatives and triazole derivatives. They are present in the agents according to the invention in amounts of 0.05 - 1~o~ preferably 0~1-1o~
; 25 by weight.
The compounds with the following formulae may be mentioned as preferred examples:
,- ~
(I) ~ C ~ clotrimazole, I Cl Le A 20 574 ~L~753SS
~ CH ~
(II) ~ trifonazole and ~ N~
(III) H lombazole k~ c ~
\J ~ I ' >~
I Cl N ~
Numerous ether azole derivatives having an anti-mycotic action are known from DE-OS (German Published Specification) 2,430,039. They can likewise be used as the active compound in the agents according to the invention.
By spreading agents there are understood oily liquids which are particularly readily distributed on the skin [R.
Keymer, Parrn. Ind. 32 (1970) 577 - 581]. The compounds which follow are particularly suitable as spreading agents for the agents according to the invention:
Silicone oils of various viscosities;
, Fatty acid esters, ~such as ethyl stearate, di-n-butyl 15 ~ adipat;e, lauric acid hexyl 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 ac d ~; esters of saturated fatty alcohols of C12 C18 chain length ~ ~ 20 isopropyl stearate, oleic acid oleyl ester, oleic acid -~ decyl ester, ethyl oleate, lactic acid ethyl ester, waxy~ fatty acid esters, such as synthesised duck uropygial gland .
~ Le A 20 574 fat, dibutyl phthalate, adipic acid diisopropyl ester and ester mixtures related to the latter;
Triglycerides, such as caprylic/capric acid triglyceride, triglyceride mixtures with vegetable fatty acids of C8-C12 chain length or other specially selected naturally occurring fatty acids, partial glyceride mixtures of saturated or unsaturated fatty acids which optionally also contain hydroxyl groups and monoglycerides of C8/C10- fatty acids;
Fatty alcohols, such as isotridecyl alcohol, cetyl stearyl alcohol and oleyl alcohol; and Fatty acids, such a:s,~for example, oleic acid.
The compounds which follow are particularly suitable spreading-oils: isopropyl myristate, isopropyl palmitate, isopropyl stearate, capr.ylic/capric acid esters of saturated fatty alcohols of C12-C18 chain length, waxy fatty acid esters, such as synthesised duck uropygial gland fat, silicone oils, an isopropyl myristate/isopropyl palmitate/isopropyl stearate mixture and coconut oil acid isopropyl ester.
Preferred suitable solubilising agents for use in the formulations according to the present invention are benzyl alcohol, 2-octyl-dodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, dipr.opyl-ene and tripropylene glycol and waxes and other additivesused in cosmetics.
- The gel-forming and film-forming agents are those macromolecular compounds, as defined previously, which can dissolve or start to swell both in water and in organic solvents and form a type of film after drying.
Suita~le solvents are water and any of the water-miscible solvents. Possible solvents are, for example, alkanols (such as ethanol and isopropyl alcohol), propyl-ene glycol, Methylcellosolve, Cellusolve, esters, Le A 20 574 -.
~L~L7S35S
morpholines, dioxane, dimethylsulphoxide, dimethylformamide, tetrahydrofuran and cyclohexanone.
One or more solvents can be employed in the pre-paration of the formulations according to the invention.
The auxiliaries which follow can, _nter alia, be used as appropriate in practice to establish an optimum formulation: glycerol, viscous paraffin, highly liquid paraffin, triethanolamine, collagen, allantoin, novant-isolic acid and perfume oils~
Further auxiliaries which are suitable are:
(a) Substances which, for example, can stabilise a sus-pension, for example colloidal silicic acid or montmorillo-nites;
(b) Surface-active agents (including emulsifiers and 15 ~ 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. cat1onic surface-active agents, such as cetyl tri-methylammonium chloride;
3. ampholytic surface-active agents, such as di-Na-N-lauryl-~ -iminodiprnpionate or lecithin; and
4. non-ionic surface-active agents, for example poly-oxyethylated castor oil, polyoxyethylated sorbitane mono-cleate, sorbitane monostearate, cetyl alcohol, glycerol monostearate, polyoxyethylene stearate and alkylphenol ~ polyglycol ethers;
;~ (c) Stabilisers for preventing the chemical degradation ~ 30 which occurs in the case of some active compounds~ such ;~ as antioxidants, for example tocopherols and butyl-hydroxyanisole; and (d) Agueous solutions which have been rendered acid can be stabilised by the addition of preservatives which are .
Le A 20 574 .1753~5 customary in cosmetics, for example p-hydroxybenzoic acid esters.
The following Examples illustrate formulations according to the present invention (in these Examples M.W.
indicates the weight average molecular weight).
Example_1 Trifonazole 3.000 9 Benzyl alcohol 4.000 9 Isopropyl myristate 6.000 9 10 Vinylpyrrolidone/vinyl acetate copolymer12.500 9 Isopropanol to 100 ml The individual components were mixed with one another : at room temperature and thereby dissolved. The formulations of Examples 2 to 14 were prepared in the same way.
Example 2 Trifonazole 1.00 9 2-Octyldodencanol 2.00 9 Isopropyl myristate 6.00 9 Vinylpyrrolidone/vinyl acetate copolymer 10.00 9 ~ 20 Isopropanol to100 ml : Example 3 Lombazole 1.00 9 Benzyl alcohol 5.00 9 Isopropyl stearate 6.00 9 25 Vinylpyrrolidone/vinyl acetate copolymer 10.00 9 Isopropanol to100 ml ~: : Example 4 Lombazole 0.10 9 Benzyl alcohol 6.00 9 : 30 Isopropyl myristate 6.00 9 Vinylpyrrolidonetvinyl acetate copoljmer 10.00 9 Isopropanol . to100 ml Example 5 . Clotrimazole 1.00 9 Le A 20 574 __ -~L1L~53SS
Benzyl alcohol 5.00 9 Isopropyl myristate 6. no 9 Vinylpyrrolidone/vinyl acetate copolymer 12.50 9 Isopropanol to 100 ml Example 6 Clotrimazole . 1.00 9 Benzyl alcohol 6.00 9 Isopropyl myristate 6.00 g Vinylpyrrolidone/vinyl acetate copolymer 10.00 9 10 Isopropanol to100 ml Example 7 Clotrimazole 1.00 9 2-Octyldodecanol 2.00 9 Isopropyl myristate 6.00 9 15 Vinylpyrrolidone/vinyl acetate copolymer 10.00 9 Isopropanol , to100 ml Example 8 Clotrimazole 1.00 9 Benzylalcohol 4.00 9 20 Isopropyl myristate 6.00 9 Vinylpyrrolidone/vinyl acetate copolymer 12.50 9 Isopropanol to 100 ml Example ~
: Lombazole 1.00 9 25 2-Octyldodecanol 8.00 9 Isopropyl stearate/isopropyl myristate/
isopropyl palmitate 2.00 9 ; : Vinylpyrrolidone/Yinyl acetate copolymer 10.00 9 : Isopropanol to100 ml Example 10 Lnmoazole 0.10 9 2-Octyldodecanol 1.00 9 Isopropyl myristate 10.00 9 Vinylpyrrolidone/vinyl acetate copolymer 4 10.00 9 ~: : 35 Isopropancl to 100 ml Le A 20 574 ~753S5 o Example 11 Clotrimazole 1.0 9 Benzyl alcohol 5.0 9 Isopropyl myristate 6.0 9
;~ (c) Stabilisers for preventing the chemical degradation ~ 30 which occurs in the case of some active compounds~ such ;~ as antioxidants, for example tocopherols and butyl-hydroxyanisole; and (d) Agueous solutions which have been rendered acid can be stabilised by the addition of preservatives which are .
Le A 20 574 .1753~5 customary in cosmetics, for example p-hydroxybenzoic acid esters.
The following Examples illustrate formulations according to the present invention (in these Examples M.W.
indicates the weight average molecular weight).
Example_1 Trifonazole 3.000 9 Benzyl alcohol 4.000 9 Isopropyl myristate 6.000 9 10 Vinylpyrrolidone/vinyl acetate copolymer12.500 9 Isopropanol to 100 ml The individual components were mixed with one another : at room temperature and thereby dissolved. The formulations of Examples 2 to 14 were prepared in the same way.
Example 2 Trifonazole 1.00 9 2-Octyldodencanol 2.00 9 Isopropyl myristate 6.00 9 Vinylpyrrolidone/vinyl acetate copolymer 10.00 9 ~ 20 Isopropanol to100 ml : Example 3 Lombazole 1.00 9 Benzyl alcohol 5.00 9 Isopropyl stearate 6.00 9 25 Vinylpyrrolidone/vinyl acetate copolymer 10.00 9 Isopropanol to100 ml ~: : Example 4 Lombazole 0.10 9 Benzyl alcohol 6.00 9 : 30 Isopropyl myristate 6.00 9 Vinylpyrrolidonetvinyl acetate copoljmer 10.00 9 Isopropanol . to100 ml Example 5 . Clotrimazole 1.00 9 Le A 20 574 __ -~L1L~53SS
Benzyl alcohol 5.00 9 Isopropyl myristate 6. no 9 Vinylpyrrolidone/vinyl acetate copolymer 12.50 9 Isopropanol to 100 ml Example 6 Clotrimazole . 1.00 9 Benzyl alcohol 6.00 9 Isopropyl myristate 6.00 g Vinylpyrrolidone/vinyl acetate copolymer 10.00 9 10 Isopropanol to100 ml Example 7 Clotrimazole 1.00 9 2-Octyldodecanol 2.00 9 Isopropyl myristate 6.00 9 15 Vinylpyrrolidone/vinyl acetate copolymer 10.00 9 Isopropanol , to100 ml Example 8 Clotrimazole 1.00 9 Benzylalcohol 4.00 9 20 Isopropyl myristate 6.00 9 Vinylpyrrolidone/vinyl acetate copolymer 12.50 9 Isopropanol to 100 ml Example ~
: Lombazole 1.00 9 25 2-Octyldodecanol 8.00 9 Isopropyl stearate/isopropyl myristate/
isopropyl palmitate 2.00 9 ; : Vinylpyrrolidone/Yinyl acetate copolymer 10.00 9 : Isopropanol to100 ml Example 10 Lnmoazole 0.10 9 2-Octyldodecanol 1.00 9 Isopropyl myristate 10.00 9 Vinylpyrrolidone/vinyl acetate copolymer 4 10.00 9 ~: : 35 Isopropancl to 100 ml Le A 20 574 ~753S5 o Example 11 Clotrimazole 1.0 9 Benzyl alcohol 5.0 9 Isopropyl myristate 6.0 9
5 Polyvinylpyrrolidone 12.5 9 Isopropanol to 100 ml Example 12 Lombazole 1.0 9 Benzyl alcohol 5.0 9 Isopropyl myristate/isopropyl palmitate/
isopropyl stearate mixture 6.0 9 Polyvinylpyrrolidone 12.5 9 Isopropanol to 100 ml Example 13 15 Clotrimazole 1.0 9 Benzyl alcohol 2.0 9 Isopropyl myristate 6.0 9 Terpolymer of 30O of vinylpyrrolidone, 40O of vinyl acetate and 30u of vinyl propionate 12.5 9 20 Isopropanol to 100 ml Example 14 Lombazole 1.0 9 Benzyl alcohol 5.0 9 Mixture of isopropyl myristate/isopropyl : 25 stearate and isopropyl palmitate 6.0 9 Terpolymer of 30~ of vinylpyrrolidone, : ~ 40O of vinyl acetate and 30O of vinyl : propionate 12.5 9 Isopropanol to 100 ml Example 15 ~: Sprays ~: The active compound solutions prepared according to Examples 1 to 14 could also be processed to sprays. For this purpose, for example, 60 to 90O of active compound solution was mixed with 10 to 40O of a customary propellant, for example N2, N20, C02, propane, butane or a halogenated hydrocarbon.
Le A 20 574 ~L~L7535S
_ 9 _ The following Example illustrates the activity of certain formulations according to the present invention.
Example A: ~estin~the.acti.vit~ of ~he a~ents accordin~to ~he invention on Trlchop~to~-infected.guineapi~, .. . . . .
_______________ _________________ _ Trichophyton-infected Pirbright white guineapigs with an average weigh-t of 600 9 were used as a test model for a compara-tive examination of the activity of the agents according to the invention. The backs of the animals were shaved with electric hair-clippers such that hair stubble about 1/10 mm long remained.
Infection with Trichophyton mentagrophytes was effected by lightly rubbing in a spore suspension 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, whicn contained 1 - 3 x 1b5 infectious fungus particles, were applied per animal.
In the case of this mode of infection, the first symptoms of dermatophytosis show as readdening and scaling of the skin 2-3 days after infection. In the case of untreated animals, the dermatophytosis is mos-t pronounced about 14 days after infection: Loss of hair in patches and blocdy integumentary defects within a phlogistically changed, scaly edge zone.
The formulations to be tested were applied locally once, on the 2nd day after infection, to the reddened infection sites on the animals. In each case 0~5 ml of the formulations (= 5 mg of active compound as 1o strength formulation) was applied. The course of the infection was evaluated daily up to the 20th day after in~ection.
The results are giv_n in the following table (in which + = weak action, ++ = action, +++ = good action, ++++ = very good action).
Le A 20 574 Ac~on ~n Trichophyton-Agent of ~;Xample i;nfecte~ guineapigs___ 1. +++
2 +~++
3 +++~
4 +~++
+~+
isopropyl stearate mixture 6.0 9 Polyvinylpyrrolidone 12.5 9 Isopropanol to 100 ml Example 13 15 Clotrimazole 1.0 9 Benzyl alcohol 2.0 9 Isopropyl myristate 6.0 9 Terpolymer of 30O of vinylpyrrolidone, 40O of vinyl acetate and 30u of vinyl propionate 12.5 9 20 Isopropanol to 100 ml Example 14 Lombazole 1.0 9 Benzyl alcohol 5.0 9 Mixture of isopropyl myristate/isopropyl : 25 stearate and isopropyl palmitate 6.0 9 Terpolymer of 30~ of vinylpyrrolidone, : ~ 40O of vinyl acetate and 30O of vinyl : propionate 12.5 9 Isopropanol to 100 ml Example 15 ~: Sprays ~: The active compound solutions prepared according to Examples 1 to 14 could also be processed to sprays. For this purpose, for example, 60 to 90O of active compound solution was mixed with 10 to 40O of a customary propellant, for example N2, N20, C02, propane, butane or a halogenated hydrocarbon.
Le A 20 574 ~L~L7535S
_ 9 _ The following Example illustrates the activity of certain formulations according to the present invention.
Example A: ~estin~the.acti.vit~ of ~he a~ents accordin~to ~he invention on Trlchop~to~-infected.guineapi~, .. . . . .
_______________ _________________ _ Trichophyton-infected Pirbright white guineapigs with an average weigh-t of 600 9 were used as a test model for a compara-tive examination of the activity of the agents according to the invention. The backs of the animals were shaved with electric hair-clippers such that hair stubble about 1/10 mm long remained.
Infection with Trichophyton mentagrophytes was effected by lightly rubbing in a spore suspension 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, whicn contained 1 - 3 x 1b5 infectious fungus particles, were applied per animal.
In the case of this mode of infection, the first symptoms of dermatophytosis show as readdening and scaling of the skin 2-3 days after infection. In the case of untreated animals, the dermatophytosis is mos-t pronounced about 14 days after infection: Loss of hair in patches and blocdy integumentary defects within a phlogistically changed, scaly edge zone.
The formulations to be tested were applied locally once, on the 2nd day after infection, to the reddened infection sites on the animals. In each case 0~5 ml of the formulations (= 5 mg of active compound as 1o strength formulation) was applied. The course of the infection was evaluated daily up to the 20th day after in~ection.
The results are giv_n in the following table (in which + = weak action, ++ = action, +++ = good action, ++++ = very good action).
Le A 20 574 Ac~on ~n Trichophyton-Agent of ~;Xample i;nfecte~ guineapigs___ 1. +++
2 +~++
3 +++~
4 +~++
+~+
6 ++++
7 ++++
8 +~++
10 9 +-~++
1 1 +++-~
12 ++++
14 ++++
When formulations which contained water-insoluble polymers, for example methacrylates, instead of the polymers mentioned were used instead of the ~ormulations according to the invention, the mycosis is aggravated.
~ When formulations which, in addition to the active compound, contained only the polymers mentioned and neither spreadlng agents nor solubilising agents were used, only a weak :: :
action is achieved.
~:
:: :
_ 10 ~
10 9 +-~++
1 1 +++-~
12 ++++
14 ++++
When formulations which contained water-insoluble polymers, for example methacrylates, instead of the polymers mentioned were used instead of the ~ormulations according to the invention, the mycosis is aggravated.
~ When formulations which, in addition to the active compound, contained only the polymers mentioned and neither spreadlng agents nor solubilising agents were used, only a weak :: :
action is achieved.
~:
:: :
_ 10 ~
Claims (10)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A formulation which comprises an antimycotically effective amount of antimycotic compound and inert pharmaceutical carrier containing a film-forming agent which is soluble or swellable both in water and in organic solvents, a spreading agent and a solubilising agent,
2. A formulation of claim 1, containing 2 to 10% of a spreading agent, 1 to 8% of a solubilising agent and, as a film-forming agent, polyvinylpyrrolidone, a terpolymer of 30%
vinylpyrrolidone, 40% of vinyl acetate and 30% of vinyl propionate, or a vinylpyrrolidone/vinyl acetate copolymer, which is soluble or swellable both in water or in organic solvents.
vinylpyrrolidone, 40% of vinyl acetate and 30% of vinyl propionate, or a vinylpyrrolidone/vinyl acetate copolymer, which is soluble or swellable both in water or in organic solvents.
3. A formulation according to claim 1 in which the anti-mycotic active compound is present in an amount of 0.05 to 1%
by weight.
by weight.
4. A formulation according to claim 1 in which the anti-mycotic is present in an amount of 0.1 to 1% by weight.
5. A formulation according to claim 1 or 2, in which the antimycotic active compound is an imidazole derivative or a triazole derivative.
6. A formulation according to claim 1, 2 or 3, in which the antimycotic active compound is clotrimazole, of the formula
7. A formulation according to claim 1, 2 or 3, in which the antimycotic active compound is trifonazole, of the formula
8. A formulation according to claim 1, 2 or 3, in which the antimycotic active compound is lombazole, of the formula
9. A formulation according to claim 1 in the form of solution.
10. A formulation according to claim 1 in the form of a spray.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19803045914 DE3045914A1 (en) | 1980-12-05 | 1980-12-05 | ANTIMYCOTIC AGENTS WITH HIGH ACTIVE SUBSTANCE RELEASE IN THE FORM OF ELASTIC LIQUID PLASTERS |
| DEP3045914.4 | 1980-12-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1175355A true CA1175355A (en) | 1984-10-02 |
Family
ID=6118423
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000391480A Expired CA1175355A (en) | 1980-12-05 | 1981-12-04 | Antimycotic agents which have a good release of active compound and are in the form of elastic liquid plasters |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0055397B1 (en) |
| JP (1) | JPS57122015A (en) |
| KR (1) | KR880000738B1 (en) |
| AT (1) | ATE9060T1 (en) |
| AU (1) | AU546449B2 (en) |
| CA (1) | CA1175355A (en) |
| DE (2) | DE3045914A1 (en) |
| DK (1) | DK538281A (en) |
| FI (1) | FI813885L (en) |
| IL (1) | IL64436A (en) |
| NO (1) | NO813932L (en) |
| ZA (1) | ZA818431B (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4957730A (en) * | 1985-12-19 | 1990-09-18 | Hoechst Aktiengesellschaft | Antimycotic nail varnish |
| US5116603A (en) * | 1989-01-31 | 1992-05-26 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Oral antifungal preventative, and method of use |
| US5264206A (en) * | 1987-06-16 | 1993-11-23 | Hoechst Aktiengesellschaft | Nail lacquer with antimycotic activity, and a process for the preparation thereof |
| US6143794A (en) * | 1998-04-17 | 2000-11-07 | Bertek Pharmaceuticals, Inc. | Topical formulations for the treatment of nail fungal diseases |
| US6962691B1 (en) | 1999-05-20 | 2005-11-08 | U & I Pharmaceuticals Ltd. | Topical spray compositions |
| EP1931309A2 (en) | 2005-09-29 | 2008-06-18 | Novartis AG | Antifungal composition |
| US7462362B2 (en) | 2003-03-21 | 2008-12-09 | Nexmed Holdings, Inc. | Antifungal nail coat and method of use |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CA1241602A (en) * | 1984-02-23 | 1988-09-06 | Ortho Pharmaceutical Corporation | Antifungal aerosol solution |
| FR2568773B1 (en) * | 1984-08-10 | 1989-03-03 | Sandoz Lab | NEW NASAL ADMINISTRATIVE PHARMACEUTICAL COMPOSITIONS |
| EP0175671A1 (en) * | 1984-08-23 | 1986-03-26 | Kuhlemann & Co. | Pharmaceutical preparation and method for the administration of this pharmaceutical preparation |
| JPS61151117A (en) * | 1984-12-25 | 1986-07-09 | Bayer Yakuhin Kk | Gelatinous antimycotic preparation |
| DE3522550A1 (en) * | 1985-06-24 | 1987-01-02 | Klinge Co Chem Pharm Fab | SPRAYABLE PHARMACEUTICAL PREPARATION FOR TOPICAL APPLICATION |
| 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 |
| JPH01230514A (en) * | 1987-11-25 | 1989-09-14 | Osaka Aerosol Ind Corp | Aerosol type patch external use |
| DE3802046A1 (en) * | 1988-01-25 | 1989-08-03 | Robert P Hielscher | Hygiene paper (prevention of dermatomycosis - mycosis pedis) |
| JP2555555B2 (en) * | 1991-07-03 | 1996-11-20 | 武田薬品工業株式会社 | Antifungal topical formulation |
| FR2732223B1 (en) * | 1995-03-30 | 1997-06-13 | Sanofi Sa | PHARMACEUTICAL COMPOSITION FOR TRANSDERMAL ADMINISTRATION |
| FR2742989B1 (en) * | 1995-12-29 | 1998-01-23 | Adir | BIOADHESIVE PHARMACEUTICAL COMPOSITION FOR THE CONTROLLED RELEASE OF ACTIVE INGREDIENTS |
| KR20000064607A (en) * | 1996-03-16 | 2000-11-06 | 훽스트 악티엔게젤샤프트 | Topical preparation for nail psoriasis treatment |
| BR0007997A (en) * | 1999-02-05 | 2001-10-30 | Cipla Ltd | Topical medical spray composition, dispenser containing a composition, preparation process for a dispenser, and use of a composition |
| JP4513921B2 (en) * | 2008-12-09 | 2010-07-28 | ソニー株式会社 | Optical body and manufacturing method thereof, window material, blind, roll curtain, and shoji |
| US8697753B1 (en) | 2013-02-07 | 2014-04-15 | Polichem Sa | Method of treating onychomycosis |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3476853A (en) * | 1965-04-13 | 1969-11-04 | Colgate Palmolive Co | Sprayed opaque bandage composition |
| DE1642063A1 (en) * | 1967-11-16 | 1970-07-16 | Henkel & Cie Gmbh | Wound dressing spray |
| 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 |
-
1980
- 1980-12-05 DE DE19803045914 patent/DE3045914A1/en not_active Withdrawn
-
1981
- 1981-11-19 NO NO813932A patent/NO813932L/en unknown
- 1981-11-27 DE DE8181109948T patent/DE3165710D1/en not_active Expired
- 1981-11-27 EP EP81109948A patent/EP0055397B1/en not_active Expired
- 1981-11-27 AT AT81109948T patent/ATE9060T1/en not_active IP Right Cessation
- 1981-12-02 IL IL64436A patent/IL64436A/en unknown
- 1981-12-03 FI FI813885A patent/FI813885L/en not_active Application Discontinuation
- 1981-12-04 CA CA000391480A patent/CA1175355A/en not_active Expired
- 1981-12-04 AU AU78261/81A patent/AU546449B2/en not_active Expired - Fee Related
- 1981-12-04 JP JP56194673A patent/JPS57122015A/en active Pending
- 1981-12-04 ZA ZA818431A patent/ZA818431B/en unknown
- 1981-12-04 DK DK538281A patent/DK538281A/en not_active Application Discontinuation
- 1981-12-05 KR KR1019810004749A patent/KR880000738B1/en active
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4957730A (en) * | 1985-12-19 | 1990-09-18 | Hoechst Aktiengesellschaft | Antimycotic nail varnish |
| US5264206A (en) * | 1987-06-16 | 1993-11-23 | Hoechst Aktiengesellschaft | Nail lacquer with antimycotic activity, and a process for the preparation thereof |
| US5116603A (en) * | 1989-01-31 | 1992-05-26 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Oral antifungal preventative, and method of use |
| US5989522A (en) * | 1989-01-31 | 1999-11-23 | Yissum Research & Development Company Of The Hebrew University Of Jerusalem | Oral antifungal preventative, and method of use |
| US6143794A (en) * | 1998-04-17 | 2000-11-07 | Bertek Pharmaceuticals, Inc. | Topical formulations for the treatment of nail fungal diseases |
| US6962691B1 (en) | 1999-05-20 | 2005-11-08 | U & I Pharmaceuticals Ltd. | Topical spray compositions |
| US7462362B2 (en) | 2003-03-21 | 2008-12-09 | Nexmed Holdings, Inc. | Antifungal nail coat and method of use |
| EP2106805A1 (en) | 2003-03-21 | 2009-10-07 | Nexmed Holdings, Inc. | Antifungal nail coat and method of use |
| EP1931309A2 (en) | 2005-09-29 | 2008-06-18 | Novartis AG | Antifungal composition |
| EP1931309B1 (en) * | 2005-09-29 | 2012-09-26 | Novartis AG | Antifungal composition |
| US10525003B2 (en) | 2005-09-29 | 2020-01-07 | GSK Consumer Healthcare S.A. | Antifungal composition |
Also Published As
| Publication number | Publication date |
|---|---|
| DK538281A (en) | 1982-06-06 |
| IL64436A0 (en) | 1982-03-31 |
| FI813885L (en) | 1982-06-06 |
| AU546449B2 (en) | 1985-09-05 |
| ATE9060T1 (en) | 1984-09-15 |
| EP0055397B1 (en) | 1984-08-22 |
| IL64436A (en) | 1985-03-31 |
| ZA818431B (en) | 1982-11-24 |
| DE3165710D1 (en) | 1984-09-27 |
| EP0055397A1 (en) | 1982-07-07 |
| JPS57122015A (en) | 1982-07-29 |
| DE3045914A1 (en) | 1982-07-22 |
| KR830007072A (en) | 1983-10-14 |
| AU7826181A (en) | 1982-06-10 |
| NO813932L (en) | 1982-06-07 |
| KR880000738B1 (en) | 1988-05-04 |
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