Process for production of vaginal tampons containing pharmaceutical active compound
This is a division of application Ser. No. 460,083 filed Jan. 21, 1983 now abandoned. 
    
    
     The present invention relates to novel formulations of the known antimycotic azole derivatives, which exhibit a higher release of the active compounds and thereby make short-term therapy possible. 
     Formulations of antimycotic azole derivatives, which form tampons, for the treatment of vaginal infections with fungi have already been disclosed [Current Therapeutic Research, Vol. 23, No.6, June 1978, 661-665]. With these formulations, 14 to 3 days therapy time are necessary to complete vaginal clean-up. This is attributable, inter alia, to the fact that the active compound contained in the known tampon formulations is only partially soluble in aqueous media. However, it is desirable to have tampons available with which briefer therapy is possible. 
     In order to achieve a shortening of the duration of therapy for vaginal mycoses, particularly for eliminating the organisms, and in order to achieve a reliable mycological clean-up, a higher release of the active compounds in the aqueous medium is required. The known formulations are only suitable to limited extent for this purpose, since only a small proportion of the active compound available dissolves in the volume of liquid at the site of infection. The tampons are coated with a carrier material which consists of a base which only melts above body temperature and in which the active compound is present in the form of coarse crystals and is unchanged at body temperature. 
     In tampons coated in this manner, the active compound is slowly and gradually dissolved out and there exists the danger that the released active compound is absorbed again in the swelling tampons. For this reason, in vitro release results exhibit an effectiveness which fluctuates very widely and differs locally on the tampon. If it is now intended to achieve a shortening of the duration of therapy, for example to one day with administration three times, by or without further increase in the concentration of active compound, care must be taken that the bioavailability of the active compound is optimal. 
     It has not been found that those tampon formulations of antimycotic azole derivatives which contain the active compound in an impregnated form, only melting at body temperature, or dissolved form, such as, for example, in suppository bases or their combinations with emulsifiers and/or spreading agents and/or solubilisers, release the active compound to a greater extent and thereby make possible a shortening of the duration of therapy to 1 day. This effect of the higher release of active compound can extend up to a power of ten. 
     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 tampons according to the invention in amounts of 50-300 mg, preferably of 100-200 mg. 
     The compounds of the formulae below may be mentioned as examples: 
     
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     ##STR1##                Chlortriamzole                               
II                                                                        
     ##STR2##                Bifonazole                                   
III                                                                       
     ##STR3##                Lombazole                                    
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     Numerous other azole derivatives having antimycotic activity are disclosed in DE-OS (German Published Specification) No. 2,430,039. They can equally serve as active compounds in the agents according to the invention. 
     The carrier material for impregnation must comply with the following requirements: 
     Sufficient consistency at room temperature, homogeneity, sufficient ability to dissolve the active compound, sufficient ability to release it, suitable melting characteristics and uniform in vitro effectiveness. 
     The following possible combinations are suitable for impregnation: 
     Suppository bases with emulsifier. 
     Suppository bases with emulsifier+lactic acid. 
     Suppository bases with solubilisers. 
     Suppository bases with spreading agents. 
     Suppository bases with spreading agent and solubiliser. 
     Solid spreading agents melting at body temperature. 
     Solid spreading agents melting at body temperature with spreading oils. 
     Solid spreading agents melting at body temperature with spreading oils and solubiliser. 
     Solid solvents melting at room temperature, for example ethylene carbonate. 
     Solid solvents melting at body temperature with additional solubilisers. 
     The following suppository bases are suitable as carrier material for the agents according to the invention: 
     Mixtures of triglycerides of natural saturated fatty acids of chain length C 10  -C 18 , triglycerides of mixtures of natural saturated plant fatty acids of chain length C 10  -C 18 , glycerol esters of mixtures of plant saturated fatty acids, lauric acid predominating. Suppository bases having a very low hydroxyl number. Bases free of hydroxyl groups. The abovementioned bases with emulsifier, for example non-ionic emulsifiers, such as saturated C 16  -C 18  fatty alcohol etherified with 25 mol of ethylene oxide etc. 
     Mixtures of mono-, di- and triglycerides of saturated natural fatty acids of chain length C 12  -C 18 , with or without emulsifiers. 
     Mixtures of mono-, di- and triglycerides, fatty alcohols, wax esters, etc. 
     For the agents according to the invention, the following compounds are, for example, suitable as solid spreading agents melting at body temperature: myristyl lactate, cetyl lactate, myristyl myristate and similar compounds. 
     Spreading agents are understood to include oily fluids which distribute particularly well on the skin [R. Keymer, Pharm. Ind. 32, 577-581 (1970)]. 
     For the agents according to the invention, the following compounds are particularly suitable as spreading agents or oils: 
     Silicone oils of various viscosity. 
     Fatty acid esters, such as ethyl stearate, di-n-butyl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid of moderate chain length with saturated fatty alcohols C 16  -C 18 , isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of separated fatty alcohols of chain length C 12  -C 18 , isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, wax-like fatty acid esters, such as artificial duck preen gland fat, dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter and the like. 
     Triglycerides, such as caprylic/capric acid triglyceride, mixtures of triglycerides with plant fatty acids of chain length C 8  -C 12  or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated fatty acids, possibly also containing hydroxyl groups, monoglycerides of C 8  /C 10  fatty acids and the like. 
     Fatty alcohols, such as isotridecyl alcohol, cetylstearyl alcohol and oleyl alcohol. 
     Fatty acids, such as, for example, oleic acid. 
     The following are particularly well suited spreading oils: isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated fatty alcohols of chain length C 12  -C 18 , wax-like fatty acid esters such as artificial duck preen gland fat, silicone oils and isopropyl myristate/isopropyl stearate/isopropyl palmitate mixture. 
     Glycerol, high viscosity paraffin and low viscosity paraffin. 
     For the agents according to the invention, the following agents are suitable as emulsifiers: 
     Colloidal-disperse mixture of cetylstearyl alcohol and sodium cetylstearyl sulphate, polyethylene stearate, cetylstearyl alcohol with about 12 mol of ethylene oxide, cetylstearyl alcohol with about 30 mol of ethylene oxide, fatty alcohol C 16  -C 18  etherified with 25 mol of ethylene oxide, sorbitan and glycerol fatty acid esters, ethoxylated castor oil and cetylstearyl alcohol with addition of non-ionic emulsifier. 
     The following other auxiliaries and/or formulation base auxiliaries can be used in manufacturing the agents according to the invention: 
     Surfactant (contains emulsifiers and wetting agent), for example 
     1. anion-active, such as Na lauryl sulphate, fatty alcohol ether sulphates, mono/dialkylpolyglycol ether orthophosphates-monoethanolamine salt; 
     2. cation-active, such as cetyltrimethylammonium chloride; 
     3. ampholytic, such as di-Na N-lauryl-β-ininodipropionate or lecithin; 
     4. non-ionic, for example polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate or cetyl alcohol. Glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers and similar compounds. 
     For the agents according to the invention, ethylene carbonate and polyethylene glycols having moderate molecular weights are suitable as solid solvents only melting at body temperature. 
     The following compounds can be employed as solubilisers: 
     2-Octyldodecanol, benzyl alcohol, ethyl lactate, propylene glycol, di- and tripropylene glycol and the like. 
     All qualities of commercially available, specially treated, compressed cotton can be used as the tampon. 
     The tampons according to the invention are manufactured in the following manner: 
     (a) Coating 
     The basic material consisting of active compound and formulating auxiliaries, melted and cooled down to 40° C., was weighed in portions of 2.0 g into 3 cm high glass vessels having a diameter of 1.5 cm. The pre-cooled tampons were pressed into the material so that they were surrounded at the level of the glass rim by the solidifying material. 
     The glass vessels with the tampons were wrapped in aluminium foil for protection from moisture and placed in a refrigerator to complete solidification. The coated tampons could subsequently be easily removed from the glass vessels. 
     (b) Impregnation 
     The basic material consisting of active compound and formulating auxiliaries, melted and cooled down to 40° C., was injected, using a pre-warmed 2 ml injection syringe, the capacity of which had previously been calibrated to 2.0 g by injection into tared tampons, from the point into pre-warmed tampons which were still wrapped in protective foil. 
     In order to prevent the basic material solidifying too rapidly, which would make uniform impregnation difficult, the impregnated tampons were placed with the point at the bottom in pre-warmed vessels and thus cooled down slowly. 
     The process described according to (b) makes possible on the large-scale a rapid, uncomplicated and more exact manufacture. The tampons impregnated by this process, compared to tampons coated according to (a), show a more uniform vitro release of active compound and thus also exhibit a better therapeutic effectiveness. 
     The impregnation material must comply with the following requirements: sufficient consistency up to 32° C., homogeneity, sufficient ability to dissolve the active compound, sufficient ability to release it, suitable melting characteristics and good in vitro effectiveness. 
    
    
     PREPARATION EXAMPLES 
     Example 1 
     
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Chlortrimazole (coated)                                                   
                      200    mg/tampon                                    
Mixture of mono-, di- and                                                 
                      1,450  mg                                           
triglycerides of saturated                                                
natural fatty acids of chain                                              
length C.sub.12 -C.sub.18                                                 
Cetylstearyl alcohol with non-                                            
                      150    mg                                           
ionic emulsifier                                                          
Lactic acid           200    mg                                           
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     Example 2 
     
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Clotrimazole (coated)                                                     
                     200    mg/tampon                                     
Mixture of mono-, di- and                                                 
                     1,600  mg                                            
triglycerides of saturated                                                
natural fatty acids of chain                                              
length C.sub.12 -C.sub.18                                                 
Benzyl alcohol       200    mg                                            
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     Example 3 
     
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Clotrimazole (coated)                                                     
                     200    mg/tampon                                     
Mixture of mono-, di- and                                                 
                     1,650  mg                                            
triglycerides of saturated                                                
fatty acids of chain                                                      
length C.sub.12 -C.sub.18                                                 
Benzyl alcohol       150    mg                                            
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     The following Examples 4-43 deal with impregnated formulations. 
     Example 4 
     
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Clotrimazole         200    mg/tampon                                     
Triglyceride mixture of                                                   
                     800    mg                                            
natural saturated fatty acids                                             
of chain length C.sub.10 -C.sub.18                                        
Benzyl alcohol       200    mg                                            
Myristyl myristate   800    mg                                            
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     Example 5 
     
         ______________________________________                                    
Clotrimazole         200    mg/tampon                                     
Mixture of mono-, di- and                                                 
                     800    mg                                            
triglycerides of saturated                                                
fatty acids of chain                                                      
length C.sub.12 -C.sub.18                                                 
Ethyl lactate        200    mg                                            
Benzyl alcohol       100    mg                                            
Myristyl myristate   700    mg                                            
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     Example 6 
     
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Clotrimazole        200    mg/tampon                                      
Benzyl alcohol      80     mg                                             
Myristyl lactate    860    mg                                             
Myristyl myristate  860    mg                                             
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     Example 7 
     
         ______________________________________                                    
Clotrimazole          200    mg/tampon                                    
Mixture of mono-, di- and                                                 
                      800    mg                                           
triglycerides of saturated fatty                                          
acids of chain length C.sub.12 -C.sub.18                                  
Ethyl lactate         200    mg                                           
Myristyl myristate    800    mg                                           
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     Example 8 
     
         ______________________________________                                    
Clotrimazole         200    mg/tampon                                     
Mixture of mono-, di- and                                                 
                     800    mg                                            
triglycerides of saturated                                                
fatty acids of chain                                                      
length C.sub.12 -C.sub.18                                                 
Ethyl lactate        200    mg                                            
Myristyl lactate     800    mg                                            
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     Example 9 
     
         ______________________________________                                    
Clotrimazole          200    mg/tampon                                    
Triglyceride mixture of natural                                           
                      800    mg                                           
saturated fatty acids of                                                  
chain length C.sub.10 -C.sub.18                                           
Ethyl lactate         200    mg                                           
Benzyl alcohol        100    mg                                           
Myristyl myristate    700    mg                                           
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     Example 10 
     
         ______________________________________                                    
Clotrimazole         200    mg/tampon                                     
Mixture of mono-, di- and                                                 
                     1,000  mg                                            
triglycerides of saturated                                                
fatty acids of chain length                                               
C.sub.12 -C.sub.18                                                        
Benzyl alcohol       100    mg                                            
Isopropyl myristate  100    mg                                            
Myristate lactate    400    mg                                            
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     Example 11 
     
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Clotrimazole         200    mg/tampon                                     
Mixture of mono-, di- and                                                 
                     600    mg                                            
triglycerides of saturated                                                
fatty acids of chain length                                               
C.sub.12 -C.sub.18                                                        
Benzyl alcohol       100    mg                                            
Hexyl laurate        300    mg                                            
Myristyl myristate   800    mg                                            
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     Example 12 
     
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Clotrimazole          200    mg/tampon                                    
Mixture of mono-, di- and                                                 
                      1,600  mg                                           
triglycerides of saturated fatty                                          
acids of chain length C.sub.12 -C.sub.18                                  
Ethyl lactate         200    mg                                           
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     Example 13 
     
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Clotrimazole        200    mg/tampon                                      
Benzyl alcohol      100    mg                                             
Hexyl laurate       300    mg                                             
Myristyl myristate  1,400  mg                                             
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     Example 14 
     
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Clotrimazole        200    mg/tampon                                      
Ethylene carbonate  1,800  mg                                             
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     Example 15 
     
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Clotrimazole        200    mg/tampon                                      
Benzyl alcohol      100    mg                                             
Ethylene carbonate  1,700  mg                                             
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     Example 16 
     
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Clotrimazole        200    mg/tampon                                      
Ethylene carbonate  1,700  mg                                             
2-Octyldodecanol    100    mg                                             
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     Example 17 
     
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Clotrimazole         100    mg/tampon                                     
Mixture of mono-, di- and                                                 
                     844.6  mg                                            
triglycerides of chain                                                    
length C.sub.12 -C.sub.18                                                 
Ethyl lactate        211.0  mg                                            
Benzyl alcohol       105.4  mg                                            
Myristyl myristate   739.0  mg                                            
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     Example 18 
     
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Clotrimazole         100    mg/tampon                                     
Triglyceride mixture of                                                   
                     844.6  mg                                            
natural saturated fatty acids                                             
of chain length C.sub.10 -C.sub.18                                        
Ethyl lactate        211.0  mg                                            
Benzyl alcohol       105.4  mg                                            
Myristyl myristate   739.0  mg                                            
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     Example 19 
     
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Clotrimazole        100     mg/tampon                                     
Mixture of mono-, di- and                                                 
                    1,055.2 mg                                            
triglycerides of chain                                                    
length C.sub.12 -C.sub.18                                                 
Ethyl lactate       211.0   mg                                            
Benzyl alcohol      105.4   mg                                            
Myristyl lactate    423.0   mg                                            
Isopropyl myristate 105.4   mg                                            
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     Example 20 
     
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Clotrimazole         100    mg/tampon                                     
Mixture of mono-, di- and                                                 
                     633.4  mg                                            
triglycerides of saturated                                                
fatty acids of chain length                                               
C.sub.12 -C.sub.18                                                        
Ethyl lactate        211.0  mg                                            
Benzyl alcohol       105.4  mg                                            
Myristyl myristate   633.4  mg                                            
Hexyl laurate        316.8  mg                                            
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     Example 21 
     
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Clotrimazole        100    mg/tampon                                      
Benzyl alcohol      105    mg                                             
Ethylene carbonate  1,795  mg                                             
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     Example 22 
     
         ______________________________________                                    
Clotrimazole         100    mg/tampon                                     
Polyglycol with a molecular                                               
                     450    mg                                            
weight of 1,000                                                           
Polyglycol with a molecular                                               
                     1,350  mg                                            
weight of 1,500                                                           
Benzyl alcohol       100    mg                                            
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     Example 23 
     
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Clotrimazole         100    mg/tampon                                     
Mixture of mono-, di- and                                                 
                     900    mg                                            
triglycerides of saturated                                                
fatty acids of chain length                                               
C.sub.12 -C.sub.18                                                        
Ethyl lactate        200    mg                                            
Benzyl alcohol       100    mg                                            
Myristyl myristate   700    mg                                            
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     Example 24 
     
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Clotrimazole          100    mg/tampon                                    
Triglyceride mixture of natural                                           
                      800    mg                                           
saturated fatty acids of chain                                            
length C.sub.10 -C.sub.18 with                                            
addition of 2% of a non-ionic                                             
emulsifier                                                                
Ethyl lactate         300    mg                                           
Benzyl alcohol        100    mg                                           
Myristyl myristate    700    mg                                           
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     Example 25 
     
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Clotrimazole          100    mg/tampon                                    
Triglyceride mixture of natural                                           
                      800    mg                                           
saturated fatty acids of chain                                            
length C.sub.10 -C.sub.18                                                 
Ethyl lactate         400    mg                                           
Myristyl myristate    700    mg                                           
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     Example 26 
     
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Clotrimazole         100    mg/tampon                                     
Triglycerides of saturated                                                
                     500    mg                                            
fatty acids of chain length                                               
C.sub.12 -C.sub.18                                                        
Ethyl lactate        100    mg                                            
Isopropyl myristate  200    mg                                            
Myristyl lactate     400    mg                                            
Myristyl myristate   500    mg                                            
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     Example 27 
     
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Clotrimazole         100    mg/tampon                                     
Triglycerides of saturated                                                
                     800    mg                                            
fatty acids of chain length                                               
C.sub.12 -C.sub.18                                                        
Ethyl lactate        400    mg                                            
Benzyl alcohol       100    mg                                            
Isopropyl myristate  300    mg                                            
Myristyl lactate     300    mg                                            
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     Example 28 
     
         ______________________________________                                    
Clotrimazole         100    mg/tampon                                     
Triglycerides of saturated                                                
                     900    mg                                            
fatty acids of chain length                                               
C.sub.12 -C.sub.18                                                        
Ethyl lactate        400    mg                                            
Isopropyl myristate  300    mg                                            
Myristyl lactate     300    mg                                            
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     Example 29 
     
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Clotrimazole         100    mg/tampon                                     
Triglycerides of saturated                                                
                     500    mg                                            
fatty acids of chain length                                               
C.sub.12 -C.sub.18                                                        
Ethyl acetate        200    mg                                            
Benzyl alcohol       100    mg                                            
Hexyl laurate        200    mg                                            
Myristyl lactate     400    mg                                            
Myristyl myristate   500    mg                                            
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     Example 30 
     
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Clotrimazole         100    mg/tampon                                     
Triglycerides of saturated                                                
                     900    mg                                            
fatty acids of chain length                                               
C.sub.12 -C.sub.18                                                        
Ethyl lactate        200    mg                                            
Benzyl alcohol       100    mg                                            
Hexyl laurate        300    mg                                            
Myristyl lactate     400    mg                                            
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     Example 31 
     
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Clotrimazole         100    mg/tampon                                     
Triglycerides of saturated                                                
                     900    mg                                            
fatty acids of chain length                                               
C.sub.12 -C.sub.18                                                        
Ethyl lactate        400    mg                                            
Hexyl laurate        300    mg                                            
Myristyl lactate     300    mg                                            
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     Example 32 
     
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Clotrimazole         100    mg/tampon                                     
Triglycerides of saturated                                                
                     650    mg                                            
fatty acids of chain length                                               
C.sub.12 -C.sub.18                                                        
Ethyl lactate        220    mg                                            
Benzyl alcohol       110    mg                                            
Hexyl laurate        320    mg                                            
Myristyl myristate   600    mg                                            
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     Example 33 
     
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Clotrimazole          100    mg/tampon                                    
Triglycerides of saturated                                                
                      800    mg                                           
fatty acids of chain length                                               
C.sub.12 -C.sub.18                                                        
Triglyceride mixture of natural                                           
                      800    mg                                           
saturated fatty acids of chain                                            
length C.sub.10 -C.sub.18 with                                            
addition of 2% of non-ionic                                               
emulsifier                                                                
Ethyl lactate         300    mg                                           
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     Example 34 
     
         ______________________________________                                    
Clotrimazole        100    mg/tampon                                      
Polyglycol molecular                                                      
                    350    mg                                             
weight 1,000                                                              
Polyglycol molecular                                                      
                    1,050  mg                                             
weight 1,500                                                              
Ethyl lactate       500    mg                                             
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     Example 35 
     
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Clotrimazole        100    mg/tampon                                      
Polyglycol molecular                                                      
                    400    mg                                             
weight 1,000                                                              
Polyglycol molecular                                                      
                    1,100  mg                                             
weight 1,500                                                              
Ethyl lactate       200    mg                                             
Benzyl alcohol      100    mg                                             
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     Example 36 
     
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Clotrimazole          100    mg/tampon                                    
Polyglycol molecular  360    mg                                           
weight 1,000                                                              
Polyglycol molecular  1,140  mg                                           
weight 1,500                                                              
Solubiliser of fatty acid                                                 
                      400    mg                                           
glycerol polyglycol esters                                                
and fatty acid polyglycol esters                                          
obtained by reaction of hydro-                                            
genated castor oil with E.O.,                                             
and polyethylene glycols and                                              
glycerol ethoxylate                                                       
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     Example 37 
     
         ______________________________________                                    
Clotrimazole         100    mg/tampon                                     
Ethyl lactate        300    mg                                            
Polyglycol molecular 400    mg                                            
weight 1,000                                                              
Polyglycol molecular 1,000  mg                                            
weight 1,500                                                              
Solubiliser as in Example 36                                              
                     200    mg                                            
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     Example 38 
     
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Bifonazole           100    mg/tampon                                     
Mixture of of mono-, di- and                                              
                     900    mg                                            
triglycerides of saturated                                                
fatty acids of chain length                                               
C.sub.12 -C.sub.18                                                        
Ethyl lactate        400    mg                                            
Hexyl laurate        300    mg                                            
Myristyl lactate     300    mg                                            
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     Example 39 
     
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Bifonazole           100    mg/tampon                                     
Triglyceride mixture of                                                   
                     800    mg                                            
natural saturated fatty acids                                             
of chain length C.sub.10 -C.sub.18                                        
with the addition of 2% of                                                
non-ionic emulsifier                                                      
Ethyl lactate        400    mg                                            
Benzyl alcohol       100    mg                                            
Myristyl myristate   700    mg                                            
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     Example 40 
     
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Bifonazole          100    mg/tampon                                      
Polyglycol molecular                                                      
                    400    mg                                             
weight 1,000                                                              
Polyglycol molecular                                                      
                    1,000  mg                                             
weight 1,500                                                              
Ethyl lactate       200    mg                                             
Benzyl alcohol      100    mg                                             
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     Example 41 
     
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Lombazole            100    mg/tampon                                     
Mixture of mono-, di- and                                                 
                     900    mg                                            
triglycerides of saturated                                                
fatty acids of chain length                                               
C.sub.12 -C.sub.18                                                        
Ethyl lactate        400    mg                                            
Hexyl laurate        300    mg                                            
Myristyl lactate     300    mg                                            
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     Example 42 
     
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Lombazole             100    mg/tampon                                    
Triglyceride mixture of natural                                           
                      800    mg                                           
saturated fatty acids of chain                                            
length C.sub.10 -C.sub.18 with the                                        
addition of 2% of non-ionic                                               
emulsifier                                                                
Ethyl lactate         300    mg                                           
Benzyl alcohol        100    mg                                           
Myristyl myristate    700    mg                                           
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     Example 43 
     
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Lombazole           100    mg/tampon                                      
Polyglycol molecular                                                      
                    400    mg                                             
weight 1,000                                                              
Polyglycol molecular                                                      
                    1,100  mg                                             
weight 1,500                                                              
Ethyl lactate       200    mg                                             
Benzyl alcohol      100    mg                                             
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     Testing the effectiveness of the tampons according to the invention was carried out by sensitivity measurement in the agar diffusion test for Candida albicans and Torulopsis glabrata in accordance with the following method: 
     In order to measure the release of active compound, 2 each of the different vaginal tampons, impregnated in each case with 100 or 200 mg of the active compounds to be tested, were placed in 10 cm high glass beakers which were filled with Kimmig nutrient agar to a height of 5 cm. Before introducing the tampons, holes of the diameter of the tampons were bored in the centre of the agar dishes using sterile cork borers. 
     The surfaces of the agar in the dishes were then homogeneously inoculated with suspensions of organisms of C. albicans or T. glabrata. The density of organisms was 10 4  cells per cm 2 . 
     The test dishes thus prepared were incubated at 37° C. for 48 hours in an incubation chamber. 
     In order to obtain a time scale for release of the active compound from the vaginal tampons, of the 2 tampons employed in each case, one was removed from the culture dish after 3 hours and the other after 6 hours. 
     After the end of the incubation time, the zones of inhibition which had formed round the test holes due to the release of active compound from the tampons were measured. 
     The sizes of the zones of inhibition for the individual tampon formulations are compiled in the following table. 
     
                       TABLE                                                       
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Sizes of zones of inhibition for various vaginal formulations after       
exposure times of 3 and 6 hours for C. albicans and T. glabrata.          
          Size of zone of inhibition in mm .0. after an                   
          exposure time of 3 and 6 hours for                              
Formulation Candida albicans                                              
                          Torulopsis glabrata                             
Examples    3 hours 6 hours   3 hours                                     
                                    6 hours                               
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 1          32      32        27    29                                    
 2          37      37        neg.  trace                                 
 3          40      41        34    35                                    
 4          36      36        30    34                                    
 5          43      44        29    33                                    
 6          37      38        29    31                                    
 7          30      35        trace 25                                    
 8          32      33        trace 26                                    
 9          43      43        29    33                                    
10          45      45        30    34                                    
11          40      45        32    35                                    
12          30      39        24    27                                    
13          39      40        25    25                                    
14          35      35        29    31                                    
15          40      40        38    41                                    
16          39      39        35    37                                    
17          40      41        33    35                                    
18          40      40        32    35                                    
19          35      36        27    28                                    
20          39      39        30    29                                    
21          39      39        37    38                                    
23          33      34        28    29                                    
24          34      39        28    28                                    
25          33      34        trace trace                                 
26          32      36        30    30                                    
27          38      40        trace 30                                    
28          34      35        26    27                                    
29          33      36        28    32                                    
30          34      34        29    30                                    
31          32      33        27    28                                    
32          31      32        28    28                                    
33          30      33        trace trace                                 
34          32      37        neg.  trace                                 
35          33      39        29    32                                    
36          34      43        trace trace                                 
37          32      40        neg.  neg.                                  
Known tampons                                                             
            30      34        unclear zones of                            
[see Curr on                  inhibition, growing                         
Therapeutic                   together                                    
Research, Vo. 23,                                                         
No. 6, June 1978,                                                         
661-665]                                                                  
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