CA1229046A - Antimycotic agents for single gynaecological treatment - Google Patents
Antimycotic agents for single gynaecological treatmentInfo
- Publication number
- CA1229046A CA1229046A CA000456237A CA456237A CA1229046A CA 1229046 A CA1229046 A CA 1229046A CA 000456237 A CA000456237 A CA 000456237A CA 456237 A CA456237 A CA 456237A CA 1229046 A CA1229046 A CA 1229046A
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- Prior art keywords
- pharmaceutically acceptable
- agent according
- antimycotic agent
- active ingredient
- present
- Prior art date
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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
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
-
- 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)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Gynecology & Obstetrics (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
* * *
The invention relates to antimycotic agents containing azole derivatives, such as clotrimazole, bifonazole, or lombazole, with the active compounds having a mean particle diameter of 4 to 20 µm ? 10 %, preferably 5 µm ? 10 %. The antimycotic agents of the invention provide greater bioavailability, thus making possible single dosage adminstration in gynaecological treatment.
* * *
The invention relates to antimycotic agents containing azole derivatives, such as clotrimazole, bifonazole, or lombazole, with the active compounds having a mean particle diameter of 4 to 20 µm ? 10 %, preferably 5 µm ? 10 %. The antimycotic agents of the invention provide greater bioavailability, thus making possible single dosage adminstration in gynaecological treatment.
Description
2904~i The present invention relates to novel formula-tions of the known ant;mycot;c azole der;vat;ves, which exh;b;t greater b;oavai~ability of the active compounds and thus make poss;ble gynaecolog;caL treatment which need only be administered once.
Numerous formulat;ons of ant;mycotic azole deriva-tives have already been disclosed for the treatment of vaginal infections with fungi. Using these formulations, 14 to 3 days of therapy are required for complete elimination of vaginal infection. This is attributable to, inter alia, the active compounds contained in the customary vaginal formulations being only partly soluble ;n aqueous media.
In order to shorten the duration of therapy, it is necessary, particularly for the elimination of the organisms in the vag;nal d;scharge~ to have a certain depot effect and a greater b;oava;lab;l;ty of the active compounds. The known formulations are suitable for this only to a restr;cted extent because only a small port;on of the available supply of active compound dissolves in the volume of fluid in the vagina. If the intention is now to achieve a shortening of the duration of therapy, for example to one day with a single administration, by further increasing the concentrat;on of active compound, care must be taken that the bioavailability of the active compound is opt;mal~
It has now been found that those types of cream, foam or spray formulat;ons of ant;mycot;c a~ole deriva-tlves, wh;ch contain the active compound ;n a very finely ground form, preferably in part;cle s;zes with a mean ~(~/c~ t-~s~
particle diameter of 5 ~ + 10%, the customary formulat-ing auxiliaries and/or an acid andlor a buffer system comprising an organic acid and/or its salts, exhibit opt;mal release of the active compound and thus make possible a duration of therapy shortened to a single Le A 22 374 ., ~.~
lZ29~4ç;
administration.
Active compounds which can be formulated in this manner are all derivatives having antimycotic activity, in particular imidazole and triazole derivatives. They are present in the agents according to the invention in amounts of from 1%
to 10%, preferably from 5 to 10%.
The compounds of the formulae given below may be mentioned as examples:
I ~ C ~ clotrimazole ~ N
II ~ ~ CH ~ bifonazole 1~
~3 III ~ ~ f ~ lombazole cN ~
Numerous other azole derivatives having anti-mycotic activity have been disclosed in DE-OS (German Published Specification) 2,430,039. They can likewise be used as active compounds in the agents according to the invention.
- 2a -~2~
The present invention is therefore directed to an antimycotic agent with greater bioavailability of the active ingredient which comprises as 1 to 10% of one or more antimy-cotically effective azole compounds or pharmaceutically accept-able salts thereof, in admixture with one or more pharmaceutically acceptable formulation auxiliaries, with a pharmaceutically acceptable acid or with a pharmaceutically acceptable buffer system, wherein the active ingredient is present in the form of particles whose size is 5 ~m 1 10%.
In particular, it has been found that those types of vaginal cream or spray formulations which contain the active compound in a very finely ground form, that is to ,, c:
~ 2~g~6 say in particle sizes 5 m~ + 10X, or contain the compound of the formula II, and which also contain lactic acid and calc;um acetate, or of the formulae I and III, and ~hich also contain primary or tertiary sodium citrate, release the active compound so optimally that a single administra-tion can be brought to cure vaginal mycoses, for example those caused by cand;da spec;es and torulops;s species.
These types of formulat;ons are sat;sfactor;ly tolerated.
Moreover, other buffer systems and/or the acids or the acidic salts alone affect the formulations in the indicated favourabLe manner. These may be as follcws:
citric acid / primary Na citrate / tertiary Na citrate lactic acid / Na lactate DL tartaric acid / K Na tartrate adipic acid ascorbic acid / 1/2 Na salt or Na salt of ethylenedi-aminetetraacetic acid fumaric acid glyco/
glyc^r^lL buffer potassium hydrogen phthalate buffer tartrate buffer tKHC2H406) phosphate buffer ln this context, the customary formulating auxi-liaries are understood to include those given belo~.
In the first place, spreading agents or o~ls are suitable.
Silicone oils of various viscosities.
Fatty acid esters, such as ethyl stearate, di-n-butyl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length ~ith saturated C16~C18 fatty alcohols, isopropyl myristate, isopropyl palmitate, caprylic/capric esters of saturated fatty alcohols of cha;n length C12-C18, isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, ~axy fatty acid esters, such as artificial duck preen gland oil, dibutyl phthalate, diisopropyl adipate, Le A 22 374 ester m;xtures related to the latter, and others.
Triglycerides, such as caprylictcapric triglycerides, triglyceride mixtures with vegetable fatty acids of chain length C8-C12 or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsatu-rated fatty acids, which may possibly also contain hydrox-yl groups, monoglycerides of C8-C10 fatty acids, and others.
Fatty alcohols, such as isotridecyl alcohol, cetylstearyl alcohol or oleyl alcohol.
Fatty acids, such as, for example, ole;c acid.
Particularly well suited spreading oils are the following: isopropyl myristate, isopropyl pa~mitate, caprylic/capric esters of saturated fatty alcohols of chain length C12-C18, waxy fatty acid esters, such as artificial duck preen gland oil, silicone o;ls, and mix-tures of ;sopropyl myristate/isopropyl stearatetisopropyl palmitate.
Glycerol, high-viscosity paraffin and low-viscos-ity paraffin.
The following agents are suitable as emulsifiersfor the agents according to the invention:
Polyoxyethylene-sorbitan fatty acid esters, colloidal disperse mixture of cetylstearyl alcohol and sodium cetylstearyl sulphate, polyethylene stearate, cetylstearyl alcohol etherified with about 12 mol of ethylene oxide, cetylstearyl alcohol etherified with about 30 mol of ethylene oxide, and C16-C18 fattY a etherified with 25 mol of ethylene oxide, sorbitan and glycerol fatty acid esters, ethoxylated castor oil, and cetylstearyl alcohol w;th the addition of a non-ionic emulsifier.
The following other auxiliaries and/or formulating bases can be used for the preparation of the agents according to the invention:
Surfactants tincluding emulsifiers and wetting agents), Le A 22 374 - 5 - 12~9~
for example 1. anionic, such as Na lauryL suLphate, fatty aLcohoL
ether suLphates, and the monoethanoLamine saLt of mono-aLkyL/dialkyl polyglycol ether orthophosphates;
Numerous formulat;ons of ant;mycotic azole deriva-tives have already been disclosed for the treatment of vaginal infections with fungi. Using these formulations, 14 to 3 days of therapy are required for complete elimination of vaginal infection. This is attributable to, inter alia, the active compounds contained in the customary vaginal formulations being only partly soluble ;n aqueous media.
In order to shorten the duration of therapy, it is necessary, particularly for the elimination of the organisms in the vag;nal d;scharge~ to have a certain depot effect and a greater b;oava;lab;l;ty of the active compounds. The known formulations are suitable for this only to a restr;cted extent because only a small port;on of the available supply of active compound dissolves in the volume of fluid in the vagina. If the intention is now to achieve a shortening of the duration of therapy, for example to one day with a single administration, by further increasing the concentrat;on of active compound, care must be taken that the bioavailability of the active compound is opt;mal~
It has now been found that those types of cream, foam or spray formulat;ons of ant;mycot;c a~ole deriva-tlves, wh;ch contain the active compound ;n a very finely ground form, preferably in part;cle s;zes with a mean ~(~/c~ t-~s~
particle diameter of 5 ~ + 10%, the customary formulat-ing auxiliaries and/or an acid andlor a buffer system comprising an organic acid and/or its salts, exhibit opt;mal release of the active compound and thus make possible a duration of therapy shortened to a single Le A 22 374 ., ~.~
lZ29~4ç;
administration.
Active compounds which can be formulated in this manner are all derivatives having antimycotic activity, in particular imidazole and triazole derivatives. They are present in the agents according to the invention in amounts of from 1%
to 10%, preferably from 5 to 10%.
The compounds of the formulae given below may be mentioned as examples:
I ~ C ~ clotrimazole ~ N
II ~ ~ CH ~ bifonazole 1~
~3 III ~ ~ f ~ lombazole cN ~
Numerous other azole derivatives having anti-mycotic activity have been disclosed in DE-OS (German Published Specification) 2,430,039. They can likewise be used as active compounds in the agents according to the invention.
- 2a -~2~
The present invention is therefore directed to an antimycotic agent with greater bioavailability of the active ingredient which comprises as 1 to 10% of one or more antimy-cotically effective azole compounds or pharmaceutically accept-able salts thereof, in admixture with one or more pharmaceutically acceptable formulation auxiliaries, with a pharmaceutically acceptable acid or with a pharmaceutically acceptable buffer system, wherein the active ingredient is present in the form of particles whose size is 5 ~m 1 10%.
In particular, it has been found that those types of vaginal cream or spray formulations which contain the active compound in a very finely ground form, that is to ,, c:
~ 2~g~6 say in particle sizes 5 m~ + 10X, or contain the compound of the formula II, and which also contain lactic acid and calc;um acetate, or of the formulae I and III, and ~hich also contain primary or tertiary sodium citrate, release the active compound so optimally that a single administra-tion can be brought to cure vaginal mycoses, for example those caused by cand;da spec;es and torulops;s species.
These types of formulat;ons are sat;sfactor;ly tolerated.
Moreover, other buffer systems and/or the acids or the acidic salts alone affect the formulations in the indicated favourabLe manner. These may be as follcws:
citric acid / primary Na citrate / tertiary Na citrate lactic acid / Na lactate DL tartaric acid / K Na tartrate adipic acid ascorbic acid / 1/2 Na salt or Na salt of ethylenedi-aminetetraacetic acid fumaric acid glyco/
glyc^r^lL buffer potassium hydrogen phthalate buffer tartrate buffer tKHC2H406) phosphate buffer ln this context, the customary formulating auxi-liaries are understood to include those given belo~.
In the first place, spreading agents or o~ls are suitable.
Silicone oils of various viscosities.
Fatty acid esters, such as ethyl stearate, di-n-butyl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length ~ith saturated C16~C18 fatty alcohols, isopropyl myristate, isopropyl palmitate, caprylic/capric esters of saturated fatty alcohols of cha;n length C12-C18, isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, ~axy fatty acid esters, such as artificial duck preen gland oil, dibutyl phthalate, diisopropyl adipate, Le A 22 374 ester m;xtures related to the latter, and others.
Triglycerides, such as caprylictcapric triglycerides, triglyceride mixtures with vegetable fatty acids of chain length C8-C12 or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsatu-rated fatty acids, which may possibly also contain hydrox-yl groups, monoglycerides of C8-C10 fatty acids, and others.
Fatty alcohols, such as isotridecyl alcohol, cetylstearyl alcohol or oleyl alcohol.
Fatty acids, such as, for example, ole;c acid.
Particularly well suited spreading oils are the following: isopropyl myristate, isopropyl pa~mitate, caprylic/capric esters of saturated fatty alcohols of chain length C12-C18, waxy fatty acid esters, such as artificial duck preen gland oil, silicone o;ls, and mix-tures of ;sopropyl myristate/isopropyl stearatetisopropyl palmitate.
Glycerol, high-viscosity paraffin and low-viscos-ity paraffin.
The following agents are suitable as emulsifiersfor the agents according to the invention:
Polyoxyethylene-sorbitan fatty acid esters, colloidal disperse mixture of cetylstearyl alcohol and sodium cetylstearyl sulphate, polyethylene stearate, cetylstearyl alcohol etherified with about 12 mol of ethylene oxide, cetylstearyl alcohol etherified with about 30 mol of ethylene oxide, and C16-C18 fattY a etherified with 25 mol of ethylene oxide, sorbitan and glycerol fatty acid esters, ethoxylated castor oil, and cetylstearyl alcohol w;th the addition of a non-ionic emulsifier.
The following other auxiliaries and/or formulating bases can be used for the preparation of the agents according to the invention:
Surfactants tincluding emulsifiers and wetting agents), Le A 22 374 - 5 - 12~9~
for example 1. anionic, such as Na lauryL suLphate, fatty aLcohoL
ether suLphates, and the monoethanoLamine saLt of mono-aLkyL/dialkyl polyglycol ether orthophosphates;
2. cationic, such as cetyltrimethylammonium chloride;
3. ampholytic, such as di-N-Na N-lauryl ~-jminodipropjon-ate or lecithin;
Example 1 Clotrimazole active compound, 10 micronised 5 ~ ~ 10X 10.00 g Sorbitan fatty acid ester 2.00 9 Polyoxyethylene-sorbitan fatty acid ester 1.50 9 Artif;cial spermaceti 3.00 9 CetylstearyL aLcohoL 3.50 9 15 Isopropyl myristate 13.50 9 8enzyL aLcohoL 1.00 9 Dem;neraLised water 65.50 g Phase I.
MeLt, stir and mix up to 70C the sorbitan fatty acid ester and part quantities of the polyoxyethylene-sorbitan fatty acid ester, artificial spermaceti, cetyl-stearyL alcohol and isopropyl myristate.
Phase II.
Mix benzyl alcohol with water, boil and cool to 75C.
Slowly stir phase II into phase I and cool to 25C. Dissolve phase III, that is to say the remaining quantity of polyoxyethylene-sorbitan fatty acid ester, in water at 50C, cool to 25C, add micronised clotrima-zole active compound, stir, suspend and add to phase I +II.
The process is carried out in an analogous manner for Examples Z to 5.
Example 2 35 aifonazole active compound, micronised 5 ~ ~ 10X 10.00 g Le A 22 374 - 6 - ~2~90~$
Sorbitan fatty acid ester 2.00 9 Polyoxyethylene-sorbitan fatty acid ester 1.50 9 Artificial spermaceti 3.00 9 Cetylstearyl alcohol 3.50 9 5 Isopropyl myristate 13.50 9 Lactic acid 1.00 g Ca lactate 0.50 g 8enzyl alcohol 1.00 g Dem;neralised water 64.00 g 10 Example 3 Lombazole act;ve compound, A micron;sed 5 ~ + 10% 10.00 9 Sorbitan fatty acid ester 2.00 9 Polyoxyethylene-sorbitan fatty acid ester 1.50 9 15 Artificial spermaceti 3 00 9 Cetylstearyl alcohol 6.00 9 Isopropyl myristate 13,50 9 Lactic acid 1.00 9 Tertiary Na citrate 1.00 g 20 aenzyl alcohol 1.00 g Demineralised water 61.00 g Example 4 Clotr;mazole active compound, ~m m;cron;sed 5 ~ + 10X 10.00 9 25 Sorb;tan fatty ac;d ester 2.00 9 Polyoxyethylene-sorbitan fatty acid ester 1.50 9 Art;f;cial spermacet; 3.00 9 Cetylstearyl alcohol 3.50 9 Isopropyl myr;state 13.50 9 30 8enzyl alcohol 1.00 g Primary Na c;trate 0.03 9 Demineral;sed water 65.47 g Example 5 8ifonazole active compound, 35 micronised 5 ~ + 10X 5.00 9 Sorb;tan fatty acid ester 2.00 9 Le A 22 374 --, ~229G~
Polyoxyethylene-sorbitan fatty acid ester 1.50 9 Art;f;cial spermacet; 3.00 g Cetylstearyl alcohol 6.00 9 Isopropyl myr;state 13.50 9 5 Benzyl alcohol 1.00 9 ~act;c ac;d 0.50 9 Calc;um lactate 0.25 9 Dem;neral;sed water 67.25 9 The for~ulations thus made up are filled into 10 applicators.
Example 6 Part A Clotrimazole active compound, A m;cronised 5 ~ + 10X10.000 9 Anhydrous glycerol 1.000 9 Pr;mary Na citrate 0.025 9 Deminer~alised water 84.775 9 Solbrol M 0.150 9 Part B Cetylstearyl alcohol, with the add;tion of non-ionic emulsifier 2.000 9 Sodium cetylstearyl sulphate1.000 9 Decyl oLeate 1.000 9 Solbrol~P o.o50 9 Heat part B to 60C and stir. For part A, dis-solve Solbrol~M at 90C, cool to 60C, and add gly-cerol and Na citrate. Stir part A into part B under v~acuum, add clotr~mazole at 40C, suspend and cool to 25C. Fill into aluminium canisters: 9Z parts of emul-sion and 8 parts of propellant gas 12/114 ~40:60).
The sprays thus prepared are admin1stered in the upside down position. Volume of foam about 40-45 ml.
Test of the efficacy of the agents according to the invention on guinea-p;gs infected w1th tr;chophyton.
::
The test model used by us to compare the efficacy of the formulations according to the invention was P~rbrigth~ ~h;te guinea-pigs, of mean weight ~00 9~ wh;ch w~ere~infected ~;th trichophyton. The backs of th`e animals Le A;22 374 r~ ~ m ~r t~
~, :
.
.
- 8 - ~229~46 were sheared with an electric hair cutter such that the stubble remaining was about 1/10 mm long. Infection ~ith Trichophyton mentagrophytes was carried out by gently rubbing into an area about 2 x 2 cm in size on the shorn backs of the animals a suspension of spores of the patho-gen which had been germinated in Sabouraud's nutrient solution for 24 hours. 0.5 ml of suspension of organisms which contained 1 - 3 x 105 ;nfectious fungal particles was applied to each animal.
Using th;s mode of infection, the first symptoms of dermatophytosis emerged 2-3 days after infection as reddening and scal;ng of the skin. The dermatophytosis ;s maximally pronounced in untreated animals about 14 days after infect;on: areas of hair loss and bleeding damage to the ;ntegument with;n a scaly edge zone having inflam-matory changes.
The formulations to be tested were applied once, on the 2nd day after infection, topically to the reddened site of infection on the animals, and gently rubbed in using a horn spatula.
In each case, 0.5 9 of the formulations = 50 mg of act;ve compound was appl;ed. The course of the infec-tion was assessed da;ly up to the 20th day after ;nfec-t;on.
The results of the tests are clear from the table below.
Agent of Example Effect on gu;nea-pigs _ _infected with tr;chophyton x x x x 2 xxxx 3 xxxx
Example 1 Clotrimazole active compound, 10 micronised 5 ~ ~ 10X 10.00 g Sorbitan fatty acid ester 2.00 9 Polyoxyethylene-sorbitan fatty acid ester 1.50 9 Artif;cial spermaceti 3.00 9 CetylstearyL aLcohoL 3.50 9 15 Isopropyl myristate 13.50 9 8enzyL aLcohoL 1.00 9 Dem;neraLised water 65.50 g Phase I.
MeLt, stir and mix up to 70C the sorbitan fatty acid ester and part quantities of the polyoxyethylene-sorbitan fatty acid ester, artificial spermaceti, cetyl-stearyL alcohol and isopropyl myristate.
Phase II.
Mix benzyl alcohol with water, boil and cool to 75C.
Slowly stir phase II into phase I and cool to 25C. Dissolve phase III, that is to say the remaining quantity of polyoxyethylene-sorbitan fatty acid ester, in water at 50C, cool to 25C, add micronised clotrima-zole active compound, stir, suspend and add to phase I +II.
The process is carried out in an analogous manner for Examples Z to 5.
Example 2 35 aifonazole active compound, micronised 5 ~ ~ 10X 10.00 g Le A 22 374 - 6 - ~2~90~$
Sorbitan fatty acid ester 2.00 9 Polyoxyethylene-sorbitan fatty acid ester 1.50 9 Artificial spermaceti 3.00 9 Cetylstearyl alcohol 3.50 9 5 Isopropyl myristate 13.50 9 Lactic acid 1.00 g Ca lactate 0.50 g 8enzyl alcohol 1.00 g Dem;neralised water 64.00 g 10 Example 3 Lombazole act;ve compound, A micron;sed 5 ~ + 10% 10.00 9 Sorbitan fatty acid ester 2.00 9 Polyoxyethylene-sorbitan fatty acid ester 1.50 9 15 Artificial spermaceti 3 00 9 Cetylstearyl alcohol 6.00 9 Isopropyl myristate 13,50 9 Lactic acid 1.00 9 Tertiary Na citrate 1.00 g 20 aenzyl alcohol 1.00 g Demineralised water 61.00 g Example 4 Clotr;mazole active compound, ~m m;cron;sed 5 ~ + 10X 10.00 9 25 Sorb;tan fatty ac;d ester 2.00 9 Polyoxyethylene-sorbitan fatty acid ester 1.50 9 Art;f;cial spermacet; 3.00 9 Cetylstearyl alcohol 3.50 9 Isopropyl myr;state 13.50 9 30 8enzyl alcohol 1.00 g Primary Na c;trate 0.03 9 Demineral;sed water 65.47 g Example 5 8ifonazole active compound, 35 micronised 5 ~ + 10X 5.00 9 Sorb;tan fatty acid ester 2.00 9 Le A 22 374 --, ~229G~
Polyoxyethylene-sorbitan fatty acid ester 1.50 9 Art;f;cial spermacet; 3.00 g Cetylstearyl alcohol 6.00 9 Isopropyl myr;state 13.50 9 5 Benzyl alcohol 1.00 9 ~act;c ac;d 0.50 9 Calc;um lactate 0.25 9 Dem;neral;sed water 67.25 9 The for~ulations thus made up are filled into 10 applicators.
Example 6 Part A Clotrimazole active compound, A m;cronised 5 ~ + 10X10.000 9 Anhydrous glycerol 1.000 9 Pr;mary Na citrate 0.025 9 Deminer~alised water 84.775 9 Solbrol M 0.150 9 Part B Cetylstearyl alcohol, with the add;tion of non-ionic emulsifier 2.000 9 Sodium cetylstearyl sulphate1.000 9 Decyl oLeate 1.000 9 Solbrol~P o.o50 9 Heat part B to 60C and stir. For part A, dis-solve Solbrol~M at 90C, cool to 60C, and add gly-cerol and Na citrate. Stir part A into part B under v~acuum, add clotr~mazole at 40C, suspend and cool to 25C. Fill into aluminium canisters: 9Z parts of emul-sion and 8 parts of propellant gas 12/114 ~40:60).
The sprays thus prepared are admin1stered in the upside down position. Volume of foam about 40-45 ml.
Test of the efficacy of the agents according to the invention on guinea-p;gs infected w1th tr;chophyton.
::
The test model used by us to compare the efficacy of the formulations according to the invention was P~rbrigth~ ~h;te guinea-pigs, of mean weight ~00 9~ wh;ch w~ere~infected ~;th trichophyton. The backs of th`e animals Le A;22 374 r~ ~ m ~r t~
~, :
.
.
- 8 - ~229~46 were sheared with an electric hair cutter such that the stubble remaining was about 1/10 mm long. Infection ~ith Trichophyton mentagrophytes was carried out by gently rubbing into an area about 2 x 2 cm in size on the shorn backs of the animals a suspension of spores of the patho-gen which had been germinated in Sabouraud's nutrient solution for 24 hours. 0.5 ml of suspension of organisms which contained 1 - 3 x 105 ;nfectious fungal particles was applied to each animal.
Using th;s mode of infection, the first symptoms of dermatophytosis emerged 2-3 days after infection as reddening and scal;ng of the skin. The dermatophytosis ;s maximally pronounced in untreated animals about 14 days after infect;on: areas of hair loss and bleeding damage to the ;ntegument with;n a scaly edge zone having inflam-matory changes.
The formulations to be tested were applied once, on the 2nd day after infection, topically to the reddened site of infection on the animals, and gently rubbed in using a horn spatula.
In each case, 0.5 9 of the formulations = 50 mg of act;ve compound was appl;ed. The course of the infec-tion was assessed da;ly up to the 20th day after ;nfec-t;on.
The results of the tests are clear from the table below.
Agent of Example Effect on gu;nea-pigs _ _infected with tr;chophyton x x x x 2 xxxx 3 xxxx
4 xxxx xxxx xxxx .
xxxx: very good effect xxx: good effect Le A 22 374 ~2Z9 !)~6 _ 9 _ xx: effect x: ~eak effect 0: no effect L~ A 22 374
xxxx: very good effect xxx: good effect Le A 22 374 ~2Z9 !)~6 _ 9 _ xx: effect x: ~eak effect 0: no effect L~ A 22 374
Claims (13)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. An antimycotic agent with greater bioavailability of the active ingredient which comprises as active ingredient 1 to 10% of one or more antimycotically effective azole compounds or pharmaceutically acceptable salts thereof, in admixture with one or more pharmaceutically acceptable formulation auxiliaries, with a pharmaceutically acceptable acid or with a pharmaceutically acceptable buffer system, wherein the active ingredient is present in the form of particles whose mean size is 5 µm + 10%.
2. An antimycotic agent according to claim 1 wherein there is present a pharmaceutically acceptable acid or a pharmaceutically acceptable buffer system comprising an organic acid and/or its salt.
3. An antimycotic agent according to claim 1 which contains, as active ingredient, clotrimazole of the formula
4. An antimycotic agent according to claim 1 which contains, as active ingredient, bifonazole of the formula
5. An antimycotic agent according to claim 1 which contains, as active ingredient, lombazole of the formula
6. An antimycotic agent according to claim 1 or 2, which is in the form of a cream.
7. A antimycotic agent according to claim 3, 4 or 5, which is in the form of a cream.
8. An antimycotic agent according to claim 1 or 2, characterised in that it is a spray.
9. An antimycotic agent according to claim 3, 4 or 5, characterised in that it is a spray.
10. An antimycotic agent according to claim 1 or 2, wherein the active ingredient is present in a suspended form.
11. An antimycotic agent according to claim 3, 4 or 5, wherein the active ingredient is present in a suspended form.
12. A process for preparing an antimycotic agent according to claim 1 which comprises admixing an antimycotically effective azole compound or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable formulation auxiliaries, with a pharmaceutically acceptable acid or with a pharmaceutically acceptable buffer system, the azole compound or salt thereof being in the form of particles whose mean size is 5µm ? 10% and being present in an amount of 1 to 10%, at a temperature between room temperature and 70°C.
13. A process according to claim 12 wherein the azole compound or salt thereof is subjected to comminution to obtain the required particle size, prior to admixture with other ingre-dients.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19833321043 DE3321043A1 (en) | 1983-06-10 | 1983-06-10 | ANTIMYCOTIC AGENTS FOR UNIQUE GYNAECOLOGICAL TREATMENT |
| DEP3321043.8 | 1983-06-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1229046A true CA1229046A (en) | 1987-11-10 |
Family
ID=6201182
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000456237A Expired CA1229046A (en) | 1983-06-10 | 1984-06-08 | Antimycotic agents for single gynaecological treatment |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0128459A3 (en) |
| JP (1) | JPS6016919A (en) |
| KR (1) | KR910004480B1 (en) |
| AU (1) | AU579102B2 (en) |
| CA (1) | CA1229046A (en) |
| DE (1) | DE3321043A1 (en) |
| DK (1) | DK284984A (en) |
| ZA (1) | ZA844349B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61229822A (en) * | 1985-03-29 | 1986-10-14 | フアイザー・インコーポレーテツド | Preventive of thiokonazole and related compounds for sexually contagious diseases |
| US6899890B2 (en) * | 2002-03-20 | 2005-05-31 | Kv Pharmaceutical Company | Bioadhesive drug delivery system |
| KR102385558B1 (en) * | 2021-05-31 | 2022-04-11 | 김동엽 | Apparatus for processing metal rod |
| KR102385557B1 (en) * | 2021-05-31 | 2022-04-11 | 김동엽 | Apparatus for cutting, bending, and sorting metal rod |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6048486B2 (en) * | 1976-01-01 | 1985-10-28 | 木場 常義 | antirheumatic agent |
| DE3070778D1 (en) * | 1979-08-11 | 1985-07-25 | Bayer Ag | Antimycotic agents with enhanced release of the active ingredients |
| DE3243544A1 (en) * | 1982-11-25 | 1984-05-30 | Bayer Ag, 5090 Leverkusen | Antimycotic compositions for single gynaecological treatment |
-
1983
- 1983-06-10 DE DE19833321043 patent/DE3321043A1/en not_active Withdrawn
-
1984
- 1984-05-30 EP EP84106152A patent/EP0128459A3/en not_active Withdrawn
- 1984-06-01 AU AU28936/84A patent/AU579102B2/en not_active Ceased
- 1984-06-07 JP JP59115610A patent/JPS6016919A/en active Pending
- 1984-06-08 CA CA000456237A patent/CA1229046A/en not_active Expired
- 1984-06-08 DK DK284984A patent/DK284984A/en not_active Application Discontinuation
- 1984-06-08 ZA ZA844349A patent/ZA844349B/en unknown
- 1984-06-09 KR KR1019840003253A patent/KR910004480B1/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| KR850000405A (en) | 1985-02-27 |
| EP0128459A2 (en) | 1984-12-19 |
| AU579102B2 (en) | 1988-11-17 |
| AU2893684A (en) | 1984-12-13 |
| KR910004480B1 (en) | 1991-06-29 |
| DE3321043A1 (en) | 1984-12-13 |
| EP0128459A3 (en) | 1986-07-09 |
| DK284984A (en) | 1984-12-11 |
| JPS6016919A (en) | 1985-01-28 |
| ZA844349B (en) | 1985-02-27 |
| DK284984D0 (en) | 1984-06-08 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |