Abstract:
An object is to provide means for precisely treating vaginitis caused by intracellular parasite, protozoa, and/or fungus. A pharmaceutical composition for vaginitis, comprising a compound represented by the following general formula (1) as an active ingredient: (1) (In the formula, R represents a halogen atom or a hydrogen atom, and X represents a halogen atom.)

Description:
TECHNICAL FIELD 
       [0001]    The present invention relates to a pharmaceutical composition. In particular, the present invention relates to a pharmaceutical composition preferably usable for vaginitis or colpitis. 
       BACKGROUND ART 
       [0002]    Patients infected with vaginitis (colpitis) are increased in relation to STD in recent years. As for  Chlamydia  vaginitis, for example, it is also reported that about 70% of specimens had the pathogen according to a fixed point investigation performed by a certain public health center in the Tokyo metropolitan area (see, for example, http://idsc.tokyo-eiken.go.jp/diseases/sti/).  Trichomonas  vaginitis as well as  Chlamydia  vaginitis is also classified into STD. It is said that  Trichomonas  vaginitis is increased as accompanied with the increase in illicit sexual act in the same manner as  Chlamydia  vaginitis. Tetracycline, new quinolone, and macrolide antibiotic are effective on  Chlamydia  vaginitis. On the other hand, the therapeutic agent is only metronidazole for  Trichomonas  vaginitis. Further, as for the oral administration of metronidazole, the response rate is low with respect to the vaginitis, it is difficult to exterminate protozoa especially in vagina, and it is inevitable to rely on any vaginal tablet. However, it is said that the efficacy of the vaginal tablet is low to exterminate protozoa from outer labia. In this sense, any therapeutic means, which is effective on  Trichomonas  vaginitis, has not been obtained in the present circumstances, although such means is demanded. The situation as described above also arises identically in relation to  Chlamydia  provided that the therapeutic agent is merely changed to tetracycline antibiotic, new quinolone antibiotic, and/or macrolide antibiotic. It is affirmed that any technique, which can cure or treat vaginitis caused by the pathogenic microorganism by means of one medicament (agent or drug), has not been obtained in the present circumstances, although such a technique is demanded. 
         [0003]    Further, in recent years, it has been confirmed that fungi such as  Candida  and  Aspergillus  co-exist in many cases in relation to  Trichomonas  vaginitis (see, for example, Non-Patent Document 1 and Non-Patent Document 2). Even when  Trichomonas  vaginitis is cured, it is not rare that  Candida  vaginitis or  Aspergillus  vaginitis is newly caused. That is, any agent or drug, which can also treat or cure fungal vaginitis simultaneously with  Trichomonas  vaginitis, is not obtained, although the agent or drug is demanded. In the experience of the present inventors, the co-existence of  Candida albicans  was confirmed for 71 strains of clinically isolated 143 strains of  Trichomonas vaginalis . In other words, about 50% of  Trichomonas  strains co-existed with  Candida , in other words, caused the multiple infection in vaginitis. The situation as described above also arises in relation to  Chlamydia  in the same manner as described above. The multiple infection of  Chlamydia  and  Trichomonas  and the multiple infection of  Chlamydia  and fungus are present. Such multiple infection is considered to be one of the factors to which the most careful attention should be paid when the medical treatment is performed. 
         [0004]    On the other hand, it is known that a compound such as lanoconazole or luliconazole, which is represented by the general formula (1), has the antifungal action (see, for example, Patent Document 1, Patent Document 2, and Patent Document 3). It has been known that lanoconazole and lysozyme or clotrimazole are combined and used for the medical treatment of  Candida  vaginitis (see, for example, Patent Document 4). However, nothing has been known at all about the fact that the compound as described above is singly used as an active ingredient and the compound as described above is used to cure or prevent vaginitis caused by any fungus such as  Candida, Aspergillus  or the like, vaginitis caused by protozoa such as  Trichomonas  or the like, vaginitis caused by intracellular parasite such as  Chlamydia  or the like, and a combination of vaginitis caused by any fungus, protozoa such as  Trichomonas  or the like, and intracellular parasite such as  Chlamydia  or the like. 
         [0005]    Any compound is scarcely known, which is known as an antifungal agent and which simultaneously has an antiprotozoal action and an anticlamydial action. For example, it is known that bifonazole, miconazole, amorolfin, and butenafine, which are known as antifungal agents against athlete&#39;s foot or the like, do not have the antiprotozoal action and the anticlamydial action. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0006]    (In the formula, R represents a hydrogen atom or a halogen atom, and X represents a halogen atom.) 
         [0000]    
       
                 
         
             
             
         
       
     
       PRECEDING TECHNICAL DOCUMENTS 
     Patent Documents 
       [0000]    
       
         Patent Document 1: JP2007-84496A; 
         Patent Document 2: JP2009-515958W; 
         Patent Document 3: JP09-100279A; 
         Patent Document 4: JP08-198773A. 
       
     
       Non-Patent Documents 
       [0000]    
       
         Non-Patent Document 1: Zdrodowska-Stefanow B, Klosowska W M, Ostaszewska-Puchalska I, Bulhak-Koziol V, Kotowicz B; “ Ureaplasma urealyticum  and  Mycoplasma hominis  infection in women with urogenital diseases.” Adv Med Sci. 2006; 51:250-3. 
         Non-Patent Document 2: Mittal A, Rastogi S, Reddy B S, Verma S, Salhan S, Gupta E; “Enhanced immunocompetent cells in chlamydial cervicitis.” J Reprod Med. 2004; 49(8):671-7 
       
     
       SUMMARY OF THE INVENTION 
     Technical Problem 
       [0013]    The present invention has been made under the circumstances as described above, an object of which is to provide means for precisely treating vaginitis caused by intracellular parasite, protozoa, and/or fungus. 
       Solution to Problem 
       [0014]    Taking the foregoing circumstances into consideration, the present inventors have repeatedly performed diligent researches and efforts in order to seek for means for precisely treating vaginitis caused by intracellular parasite, protozoa, and/or fungus. As a result, it has been found out that the compound such as luliconazole and lanoconazole, which is represented by the general formula (1) described above, has the action or function to inhibit the growth of intracellular parasite such as  Chlamydia  or the like, protozoa such as  Trichomonas  or the like, and fungus such as  Candida, Aspergillus  or the like. It has been found out that vaginitis, which is caused by intracellular parasite, protozoa, and/or fungus, can be precisely treated by using the compound as described above as an active ingredient. Thus, the invention has been completed. That is, the present invention is as follows. 
         [0015]    &lt;1&gt; A pharmaceutical composition for vaginitis, comprising a compound represented by the following general formula (1) as an active ingredient: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0016]    (In the formula, R represents a halogen atom or a hydrogen atom, and X represents a halogen atom.) 
         [0017]    &lt;2&gt; The pharmaceutical composition for vaginitis as defined in &lt;1&gt;, wherein the compound represented by the general formula (1) is luliconazole or lanoconazole: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0018]    &lt;3&gt; The pharmaceutical composition for vaginitis as defined in &lt;1&gt; or &lt;2&gt;, wherein the vaginitis is caused by a pathogen selected from intracellular parasite, protozoa, and fungus. 
         [0019]    &lt;4&gt; The pharmaceutical composition for vaginitis as defined in &lt;3&gt;, wherein the protozoa is protozoa belonging to genus  Trichomonas.    
         [0020]    &lt;5&gt; The pharmaceutical composition for vaginitis as defined in &lt;3&gt; or &lt;4&gt;, wherein the fungus is fungus belonging to genus  Candida  and/or fungus belonging to genus  Aspergillus.    
         [0021]    &lt;6&gt; The pharmaceutical composition for vaginitis as defined in any one of &lt;3&gt; to &lt;5&gt;, wherein the intracellular parasite is intracellular parasite belonging to genus  Chlamydia.    
         [0022]    &lt;7&gt; The pharmaceutical composition for vaginitis as defined in any one of &lt;1&gt; to &lt;6&gt;, wherein a content of the compound represented by the general formula (1) is 1 to 60% by mass with respect to a total amount of the pharmaceutical composition. 
         [0023]    &lt;8&gt; The pharmaceutical composition for vaginitis as defined in any one of &lt;1&gt; to &lt;7&gt;, further containing 40 to 99% by mass of an arbitrary component for preparing a pharmaceutical preparation. 
         [0024]    &lt;9&gt; The pharmaceutical composition for vaginitis as defined in any one of &lt;1&gt; to &lt;8&gt;, wherein the pharmaceutical composition is a suppository, a tablet, or a gel. 
         [0025]    &lt;10&gt; An antiprotozoal agent, comprising a compound represented by a general formula (1) as an active ingredient. 
         [0026]    &lt;11&gt; The antiprotozoal agent as defined in &lt;10&gt;, wherein the protozoa is protozoa belonging to genus  Trichomonas.    
         [0027]    &lt;12&gt; An anti-intracellular parasite agent, comprising a compound represented by a general formula (1) as an active ingredient. 
         [0028]    &lt;13&gt; The anti-intracellular parasite agent as defined in &lt;12&gt;, wherein the intracellular parasite is intracellular parasite belonging to genus  Chlamydia.    
       Advantageous Effects of Invention 
       [0029]    According to the present invention, it is possible to provide means for precisely treating vaginitis caused by intracellular parasite, protozoa, and/or fungus. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0030]      FIG. 1  shows drawings (photographs) illustrating observation results of  Chlamydia  inclusion bodies after the luliconazole treatment, as obtained by the fluorescence staining by using  Chlamydia  FA reagent “Seiken”. Panel (A) shows the observation result of  Chlamydia  inclusion bodies after a treatment with 8 μg/mL of luliconazole, panel (B) shows the observation result of  Chlamydia  inclusion bodies after a treatment with 16 μg/mL of luliconazole, and panel (C) shows the observation result of  Chlamydia  inclusion bodies after a treatment with 32 μg/mL of luliconazole. In (A) and (B), dot-shaped  Chlamydia  inclusion bodies stained apple green were observed. No inclusion body was found in (C). 
       
    
    
     DESCRIPTION OF EMBODIMENTS 
     &lt;1&gt; Compound Represented by General Formula (1) 
       [0031]    The pharmaceutical composition of the present invention is characterized in that the pharmaceutical composition contains the compound represented by the general formula (1) and the pharmaceutical composition is usable for vaginitis. In the general formula (1)′, the group represented by R is a hydrogen atom or a halogen atom. The halogen atom can be preferably exemplified, for example, by chlorine atom, bromine atom, fluorine atom, and iodine atom. The group represented by R is especially preferably a hydrogen atom or a chlorine atom. The group represented by X represents a halogen atom. The halogen atom can be preferably exemplified, for example, by chlorine atom, bromine atom, fluorine atom, and iodine atom. The group represented by X is especially preferably a chlorine atom. The compound represented by the general formula (1) is especially preferably luliconazole (R═X═Cl; (R)-(−)-(E)-[4-(2,4-dichlorophenyl)-1,3-dithiolane-2-ylidene]-1-imidazolyl acetonitrile) and lanoconazole (R═H, X═Cl; 4-(2-chlorophenyl)-1,3-dithiolane-2-ylidene-1-imidazolyl acetonitrile), and luliconazole is especially preferred. The compound as described above suppresses the growth of intracellular parasite such as  Chlamydia  or the like and protozoa such as  Trichomonas  or the like, and the compound as described above also suppresses the growth of fungus such as  Candida, Aspergillus  or the like. 
         [0032]    The compound as described above can be synthesized, for example, in accordance with a method described in JP60-218387A. That is, 1-cyanomethylimidazole and carbon disulfide are reacted to obtain a compound of (III) which is reacted with a compound of the general formula (II) having a leaving group. Thus, it is possible to obtain the compound represented by the general formula (1) as described above. The leaving group as described above can be preferably exemplified, for example, by methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, and halogen atom. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0033]    In the formula, Y, Y′ represent the leaving group such as methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, and halogen atom, and M represents alkali metal. 
         [0034]    In order that the compound represented by the general formula (1) exhibits the anti-intracellular parasite action, the anti-protozoa action (antiprotozoal action), and the antifungal action, it is preferable that the compound represented by the general formula (1) is contained in the pharmaceutical composition of the present invention usually by 0.5 to 80% by mass and more preferably by 1 to 60% by mass with respect to the total amount of the pharmaceutical composition. 
       &lt;2&gt; Pharmaceutical Composition of the Present Invention 
       [0035]    The pharmaceutical composition of the present invention can contain any arbitrary component for preparing a pharmaceutical preparation, other than the compound represented by the general formula (1) described above. It is preferable that the component for preparing the pharmaceutical preparation is the residual part or the balance of the compound represented by the general formula (1). The component for preparing the pharmaceutical preparation is usually 20 to 99.5% by mass and preferably 40 to 99% by mass in a total amount with respect to the total amount of the pharmaceutical composition of the present invention. 
         [0036]    The component for preparing the pharmaceutical preparation can be preferably exemplified as follows, for example, in the case of the tablet. That is, it is possible to preferably exemplify excipients such as lactose, croscarmellose and the like; alkali agents such as sodium carbonate, sodium hydrogencarbonate and the like; acid agents such as citric acid, lactic acid, tartaric acid and the like; coating agents such as hydroxypropyl methylcellulose, triethyl citrate and the like; binding agents such as gum arabic and the like; disintegrating agents such as starch, hydroxypropyl cellulose, croscarmellose and the like; sugar coating agents such as sucrose, maltitol and the like; surfactants such as POE-cured castor oil, POE sorbitan fatty acid ester and the like; plasticizers such as triethyl citrate, caprylic capric monoglyceride, diethylene glycol monoethyl ether and the like; and lubricants such as magnesium stearate, talc and the like. As for the tablet, it is also possible to adopt a form of vaginal tablet as well as tablet for oral administration. When the form of vaginal tablet is adopted, it is preferable to provide a foam tablet or effervescent tablet obtained by the tablet making after coating alkaline granules and acidic granules in order to facilitate the disintegration performance. 
         [0037]    It is also possible to preferably exemplify, for example, the suppository or the gel to be directly administered into the vagina. In the case of the suppository, it is possible to preferably exemplify hydrocarbons such as Vaseline, solid paraffin, microcrystalline wax, liquid paraffin and the like; esters such as Witepsol, spermaceti, carnauba wax, Japan tallow, beeswax, jojoba oil, octyldodecyl oleate and the like; triglycerides such as olive oil, coconut oil, glyceryl triisostearate, glyceryl tristearate and the like; higher alcohols such as oleyl alcohol, behenyl alcohol, stearyl alcohol and the like; lipophilic surfactants such as monoglyceryl stearate, monoglyceryl oleate, sorbitan fatty acid ester and the like; and solvents such as N-alkyl-2-pyrrolidone, alkylene carbonate, benzyl alcohol and the like. As for the gel, it is possible to preferably exemplify polyhydric alcohols such as glycerol, 1,3-butanediol, propylene glycol, polyethylene glycol and the like; volatile solvents such as ethanol, acetone, methyl ethyl ketone and the like; and thickening/gelling agents such as (ammonium acryloyldimethyltaurate/VP) copolymer, (ammonium acryloyldimethyltaurate/beheneth-25 methacrylate) crosspolymer, ethyl cellulose, carboxyvinyl polymer, hydroxypropyl methylcellulose and the like. 
         [0038]    The pharmaceutical composition of the present invention can be produced on the basis of any conventional method by using the compound represented by the general formula (1) described above and arbitrary components for preparing the pharmaceutical preparation. 
         [0039]    As for the pharmaceutical composition of the present invention, it is possible to use any one of the pharmaceutical preparations as described above. It is especially preferable to use the pharmaceutical preparation having the form capable of being directly administered into the vagina. The compound of the present invention is not absorbed into the body in the vagina, and the effect thereof is not decreased, unlike metronidazole. Therefore, the compound of the present invention can sufficiently exhibit the effect in relation to the mode as described above. 
         [0040]    A preferred mode of application can be appropriately selected while considering, for example, the body weight, the age, the sexuality, and the symptoms or condition of the patient. However, in the ordinary case of an adult, it is appropriate to perform the administration once or several times per day in the vagina so that the administration amount of the compound represented by the general formula (1) is 0.1 to 10 g, and such a treatment is performed for about 1 day to 3 weeks. 
         [0041]    The compound represented by the general formula (1) has the anti-intracellular parasite action, the anti-protozoa action (antiprotozoal action), and the antifungal action against the intracellular parasite, the protozoa, and the fungus. The pharmaceutical composition of the present invention has been achieved on the basis of such knowledge acquired by the present inventors. 
         [0042]    That is, the disease, to which the pharmaceutical composition of the present invention is applicable, can be the vaginitis which is caused by a pathogen selected from intracellular parasite, protozoa, and/or fungus (for example, vaginitis diagnosed that the pathogen is intracellular parasite, protozoa, and/or fungus). 
         [0043]    In this context, the “pharmaceutical composition for vaginitis caused by the pathogen of protozoa of the present invention” can be applied to the vaginitis in which the pathogen is protozoa and the vaginitis in which the pathogen is protozoa and intracellular parasite and/or fungus. In consideration of the present circumstances in which, for example, there are many cases of the co-existence of protozoa and intracellular parasite and/or fungus or the secondary infection of protozoa, it is also preferable to apply the “pharmaceutical composition for vaginitis caused by the pathogen of protozoa of the present invention” to the vaginitis caused by the pathogen of fungus and/or intracellular parasite, in view of the suppression of any potential infection of protozoa and the prevention of any secondary infection. Further, the application to the vaginitis caused by the pathogen of fungus and/or intracellular parasite for the purpose as described above is also included in the scope of the present invention. 
         [0044]    Further, the “pharmaceutical composition for vaginitis caused by the pathogen of fungus of the present invention” can be applied to the vaginitis in which the pathogen is fungus and the vaginitis in which the pathogen is fungus and protozoa and/or intracellular parasite. In consideration of the present circumstances in which, for example, there are many cases of the co-existence of fungus and protozoa and/or intracellular parasite or the secondary infection of fungus, it is also preferable to apply the “pharmaceutical composition for vaginitis caused by the pathogen of fungus of the present invention” to the vaginitis caused by the pathogen of protozoa and/or intracellular parasite, in view of the suppression of any potential infection of fungus and the prevention of any secondary infection. Further, the application to the vaginitis caused by the pathogen of protozoa and/or intracellular parasite for the purpose as described above is also included in the scope of the present invention. 
         [0045]    Similarly, it is also possible to treat intracellular parasite. That is, the “pharmaceutical composition for vaginitis caused by the pathogen of intracellular parasite of the present invention” can be applied to the vaginitis in which the pathogen is intracellular parasite and the vaginitis in which the pathogen is intracellular parasite and fungus and/or protozoa. In consideration of the present circumstances in which, for example, there are many cases of the co-existence of intracellular parasite and fungus and/or protozoa or the secondary infection of intracellular parasite, it is also preferable to apply the “pharmaceutical composition for vaginitis caused by the pathogen of intracellular parasite of the present invention” to the vaginitis caused by the pathogen of fungus and/or protozoa, in view of the suppression of any potential infection of intracellular parasite and the prevention of any secondary infection. Further, the application to the vaginitis caused by the pathogen of fungus and/or protozoa for the purpose as described above is also included in the scope of the present invention. 
         [0046]    The “pharmaceutical composition for vaginitis caused by the pathogen of intracellular parasite, protozoa, and fungus of the present invention” can be applied not only to the vaginitis in which the pathogen is intracellular parasite, protozoa, and fungus but also to the vaginitis in which the pathogen is protozoa, the vaginitis in which the pathogen is fungus, and the vaginitis in which the pathogen is intracellular parasite, in view of the suppression of any potential infection of intracellular parasite, protozoa, or fungus and the prevention of any secondary infection. Further, the application to the vaginitis caused by the pathogen of protozoa, the vaginitis caused by the pathogen of fungus, and the vaginitis caused by the pathogen of intracellular parasite for the purpose as described above is also included in the scope of the present invention. 
         [0047]    The fungus, which is the objective or target of the present invention, is not specifically limited, which is exemplified, for example, by fungi belonging to the genus  Candida  such as  Candida albicans  and the like and the genus  Aspergillus.    
         [0048]    The protozoa, which is the objective or target of the present invention, is not specifically limited, which is exemplified, for example, by protozoas belonging to the genus  Trichomonas  such as  Trichomonas vaginalis  and the like. 
         [0049]    The intracellular parasite, which is the objective or target of the present invention, is not specifically limited, which is exemplified, for example, by intracellular parasites belonging to the genus  Chlamydia  such as  Chlamydia trachomatis  and the like. 
       EXAMPLES 
       [0050]    The present invention will be explained in further detail below as exemplified by Examples. However, the present invention is not limited to Examples described below. 
       Example 1 
       [0051]    The effect on  Trichomonas vaginalis  was investigated for luliconazole of the compound represented by the general formula (1). That is, 5×10 6  cells of clinically isolated  Trichomonas vaginalis  were seeded in  Trichomonas  medium F (6.5 mL, contained in tube) produced by Fujiyakuhin Co., Ltd. containing Neutral Red as a marker, and the preculture was carried out for 72 hours (preculture). It was confirmed that  Trichomonas  grew, the acid was actively produced, and Neutral Red was changed to be yellow. After that, the preculture was added to  Trichomonas  medium F by every 100 μL in order to carry out the main culture, to which 0.5 mL of a test solution was added. In this situation, the number of protozoas in the solution of preculture was 1.5×10 5  cells/mL. Three series of test solutions were prepared, in which the luliconazole concentrations were 200 μM (final concentration: 35.2 μM), 100 μM (final concentration: 17.6 μM), and 50 μM (final concentration: 8.8 μM), as luliconazole dissolved in 10% methanol saline solution. 0.5 mL of vehicle was added as a control. As for the vehicle, 10% methanol saline solution (final concentration: 0 μM) was used. Stirring was sufficiently performed after the addition, followed by culturing at 37° C. for 72 hours. After the completion of the cultivation, the color was discriminated, and the state of protozoas was observed by using an inverted microscope. Results are shown in Table 1. Accordingly, it is appreciated that luliconazole inhibits the growth of  Trichomonas  at 8.8 μM. In other words, it has been revealed that luliconazole is a substance which can inhibit the growth with respect to  Trichomonas  and which is clinically applicable, except for metronidazole. Further, it is also revealed that the minimum growth inhibitory concentration (MIC) is in the vicinity of 8.8 μM. 
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 Final  
                   
                   
               
               
                 concentration 
                 Color 
                 Result of microscopic observation 
               
               
                   
               
             
             
               
                 35.2 μM 
                 red 
                 no protozoa was observed 
               
               
                 17.6 μM 
                 red 
                 no protozoa was observed 
               
               
                  8.8 μM 
                 yellow 
                 protozoas were observed slightly 
               
               
                   0 μM 
                 yellow 
                 large number of protozoas were 
               
               
                   
                   
                 observed 
               
               
                   
               
             
          
         
       
     
       Example 2 
       [0052]    The same or equivalent investigation as that of Example 1 was performed while changing luliconazole to lanoconazole. As a result, it becomes clear that lanoconazole also inhibits the growth of  Trichomonas  as well as luliconazole. It has been revealed that lanoconazole is a substance which can inhibit the growth with respect to  Trichomonas  and which is clinically applicable, except for metronidazole. Further, it is revealed that the minimum growth inhibitory concentration (MIC) is in the vicinity of 17.6 μM. 
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 Final  
                   
                   
               
               
                 concentration 
                 Color 
                 Result of microscopic observation 
               
               
                   
               
             
             
               
                 35.2 μM 
                 red 
                 no protozoa was observed 
               
               
                 17.6 μM 
                 red 
                 protozoas were observed slightly 
               
               
                  8.8 μM 
                 yellow 
                 large number of protozoas were 
               
               
                   
                   
                 observed 
               
               
                   0 μM 
                 yellow 
                 large number of protozoas were 
               
               
                   
                   
                 observed 
               
               
                   
               
             
          
         
       
     
       Example 3 
     In Vitro Antifungal Activity on  Candida albicans    
       [0053]    The minimum growth inhibitory concentration (MIC) was measured by means of the broth microdilution method (medicament ×2 dilution series) based on the use of BPMI 1640 medium (pH 7.0) buffered with 0.165 M morpholinopropanesulfonic acid. 100 μL of test microorganism yeast cells/sterilized physiological saline suspensions (1 to 5×10 3  cells/mL) and 100 μL of media previously added with respective compounds and medium not added with, compounds as a control were dispensed into respective wells of flat-bottom microculture plate. After performing the cultivation at 35° C. for 48 hours, the culture turbidities of the respective wells were measured at 630 nm to determine the minimum growth inhibitory concentration (MIC 80 : μg/mL) as the minimum concentration of the compound at which the growth inhibition of 80% was exhibited with respect to the growth of the microorganism in the control culture (measured as the suspension). Results are shown in Table 3. It is appreciated that the excellent antifungal activity is exhibited in any case. Considering this fact in combination with Examples 1 and 2, it is clear that it is possible to simultaneously inhibit the growth of protozoa such as  Trichomonas  and the growth of fungus such as  Candida  by using the compound represented by the general formula (1). 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                   
                 Microbial strain 
                 Luliconazole 
                 Lanoconazole 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 IFO0197 
                 0.0625  
                 0.125 
               
               
                   
                 IFO0579 
                 0.0313 
                 0.0625 
               
               
                   
                 IFO1269 
                 0.0625 
                 0.0625 
               
               
                   
                 TIMM3164 
                 0.5 
                 0.5 
               
               
                   
               
             
          
         
       
     
       Example 4 
       [0054]    Vaginal tablets were manufactured in accordance with the following formulation. That is, Part A and Part B were granulated into granules respectively, and coating was performed while spraying hydroxypropyl methylcellulose and triethyl citrate dissolved in ethanol. After the completion of the coating, the blowing was performed with warm air at 40° C. to perform the drying. After the drying, granules A and granules B were mixed, followed by being manufactured into effervescent tablets in accordance with the tablet making process. 
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
             
             
               
                   
                 A 
                   
               
               
                   
                 (Granule component) 
                   
               
               
                   
                 Citric acid 
                  15 parts by mass 
               
               
                   
                 Lactic acid 
                  10 parts by mass 
               
               
                   
                 Luliconazole 
                  20 parts by mass 
               
               
                   
                 Hydroxypropyl cellulose 
                 0.5 part by mass 
               
               
                   
                 (Coating agent) 
                   
               
               
                   
                 Hydroxypropyl methylcellulose 
                   4 parts by mass 
               
               
                   
                 Triethyl citrate 
                 0.5 part by mass 
               
               
                   
                 B 
                   
               
               
                   
                 (Granule component) 
                   
               
               
                   
                 Sodium hydrogencarbonate 
                  25 parts by mass 
               
               
                   
                 Croscarmellose 
                  20 parts by mass 
               
               
                   
                 Hydroxypropyl cellulose 
                 0.5 part by mass 
               
               
                   
                 (Coating agent) 
                   
               
               
                   
                 Hydroxypropyl methylcellulose 
                   4 parts by mass 
               
               
                   
                 Triethyl citrate 
                 0.5 part by mass 
               
               
                   
               
             
          
         
       
     
       Example 5 
       [0055]    Vaginal tablets were manufactured in accordance with the following formulation. That is, Part A and Part B were granulated into granules respectively, and coating was performed while spraying hydroxypropyl methylcellulose and triethyl citrate dissolved in ethanol. After the completion of the coating, the blowing was performed with warm air at 40° C. to perform the drying. After the drying, granules A and granules B were mixed, followed by being manufactured into effervescent tablets in accordance with the tablet making process. 
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 5 
               
               
                   
               
             
             
               
                   
                 A 
                   
               
               
                   
                 (Granule component) 
                   
               
               
                   
                 Citric acid 
                  15 parts by mass 
               
               
                   
                 Lactic acid 
                  10 parts by mass 
               
               
                   
                 Lanoconazole 
                  20 parts by mass 
               
               
                   
                 Hydroxypropyl cellulose 
                 0.5 part by mass 
               
               
                   
                 (Coating agent) 
                   
               
               
                   
                 Hydroxypropyl methylcellulose 
                   4 parts by mass 
               
               
                   
                 Triethyl citrate 
                 0.5 part by mass 
               
               
                   
                 B 
                   
               
               
                   
                 (Granule component) 
                   
               
               
                   
                 Sodium hydrogencarbonate 
                  25 parts by mass 
               
               
                   
                 Croscarmellose 
                  20 parts by mass 
               
               
                   
                 Hydroxypropyl cellulose 
                 0.5 part by mass 
               
               
                   
                 (Coating agent) 
                   
               
               
                   
                 Hydroxypropyl methylcellulose 
                   4 parts by mass 
               
               
                   
                 Triethyl citrate 
                 0.5 part by mass 
               
               
                   
               
             
          
         
       
     
       Example 6 
       [0056]    The anti-intracellular parasite action was investigated by using  Chlamydia trachomatis  (D/UW3/Cx). That is,  Chlamydia trachomatis  was cultured in the presence of ×2 dilution series of 8 to 64 μg/ml of luliconazole by using HeLa 229 cells as the host. MEM added with 8% thermally inactivated FBS, to which 1 μg/ml of cyclohexamide was added, was used as the medium, and the culture was performed for 72 hours in 5% carbon dioxide gas at 37° C. After the culture,  Chlamydia  inclusion bodies were subjected to the fluorescent staining to be apple green with  Chlamydia  FA reagent “Seiken” (produced by DENKA SEIKEN Co., Ltd.), and the observation was performed by using a fluorescence microscope. Results are shown in  FIG. 1 . Accordingly, it is appreciated that MIC of luliconazole with respect to  Chlamydia trachomatis  is 32 μg/ml. 
       INDUSTRIAL APPLICABILITY 
       [0057]    The present invention is applicable to pharmaceuticals.