PHARMACEUTICAL COMPOSITION FOR TREATING VAGINITIS OR PNEUMONIA

TECHNICAL FIELD

[0001]

The present invention relates to a pharmaceutical composition. In particular, the present invention relates to a pharmaceutical composition preferably usable to treat vaginitis (colpitis) and pneumonia.

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, Non-Patent Document 1) . 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 and macrolide antibiotics are effective for Chlamydia

vaginitis, while 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, and it is difficult to exterminate protozoa especially in vagina. Therefore, 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 for Trichomonas vaginitis, has not been obtained in the present

circumstances, although such means 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 2 and Non-Patent Document 3). Even when Trichomonas vaginitis is cured, it is not rare that Candida vaginitis and/or Aspergillus vaginitis is/are newly caused. That is, the following present circumstance also exists. 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. [0004]

On the other hand, pneumonia is caused in most cases by Pneumococci as accompanied, for example, with influenza principally. However, fungal pneumonia, which is caused, for example, by Candida and/or Aspergillus, is rapidly increased in recent years on account of the decrease in immunity by the chemotherapy for cancer or the decrease in immunity by the onset or crisis of AIDS. On the other hand, patients infected with Chlamydia pneumonia

(chlamydial pneumonia) or Trichomonas pneumonia

(trichomonal pneumonia) are increased as accompanied with any particular sexual act in relation to STD in recent years. Tetracycline and macrolide antibiotics are

effective for Chlamydia pneumonia, while the therapeutic agent is only metronidazole for Trichomonas pneumonia.

Further, as for metronidazole, a resistant strain against metronidazole is also found in Trichomonas (see, for example, Non-Patent Document 4). In this sense, any therapeutic means, which is effective for Trichomonas pneumonia, has not been obtained in the present

circumstances, although such means is demanded.

[0005]

Multiple infection, which is accompanied by

Trichomonas in the same manner as in vaginitis, is observed in pneumonia caused by the microorganism ( s ) of Candida and/or Aspergillus (see, for example, Non-Patent Documents 2 and 3) . Such multiple infection also makes it difficult to perform the medical treatment, in the same manner as in vaginitis .

[0006]

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, any action on Trichomonas and/or Chlamydia is known. In addition, the compounds as described above involve such a problem that the water solubility is poor. Therefore, it is feared that the action on the target pathogen may be restricted at the affected part. It has been demanded to develop any means for improving the inconvenience as described above. In relation to crotamiton, it is known that the optical isomerization of luliconazole is suppressed by using luliconazole and crotamiton in combination in an external preparation for skin (see, for example, Patent Document 5) . However, it is not known that crotamiton has an action to enhance the effect of the compound represented by the general formula (1) with respect to Trichomonas . [0007]

General formula (1)

[0008]

(In the formula, each of Ri and R ₂ independently represents hydrogen atom or halogen atom, and Ri and R2 are not simultaneously hydrogen atoms.)

[0009]

Luliconazole

[0010]

Lanoconazole PRECEDING TECHNICAL DOCUMENTS

Non-Patent Documents:

[0011]

Non-Patent Document 1: Homepage of Tokyo Metropolitan

Infectious Disease Surveillance Center, [online] , internet <URL: http: //idsc. tokyo-eiken. go. jp/diseases/sti/>;

Non-Patent Document 2: Zdrodowska-Stefanow B, Klosowska WM, 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 3: Mittal A, Rastogi S, Reddy BS, Verma S, Salhan S, Gupta E; "Enhanced immunocompetent cells in chlamydial cervicitis." J Reprod Med. 2004 ;49(8): 671-7; Non-Patent Document 4: Pal C, Bandyopadhyay U.; "Redox- active antiparasitic drugs" Antioxid Redox Signal. 2012; 17 (4) : 555-82.

Patent Documents:

[0012]

Patent Document 1 JP2004-521102W;

Patent Document 2 JP2002-514165 ;

Patent Document 3 JP2003-527308W;

Patent Document 4 JP08-198773A;

Patent Document 5 WO2007/102242.

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 enhance the action of the compound represented by the general formula (1) described above and provide a

pharmaceutical composition effective for pneumonia and vaginitis .

Solution to Problem

[0014]

Taking the foregoing circumstances into consideration, the present inventors sought for any pharmaceutical

composition which includes the compound represented by the general formula (1) described above as an active ingredient and which is effective for pneumonia and vaginitis. As a result, it has been found out that the compound as

described above is effective . not only for Candida and

Aspergillus but also for Trichomonas and Chlamydia, and the action is remarkably improved when the compound as

described above is formed into a pharmaceutical preparation together with crotamiton. Thus, the present invention has been completed. That is, the present invention is as follows .

[0015]

<1> A pharmaceutical composition for vaginitis or pneumonia, comprising a compound represented by the

foregoing general formula (1) and crotamiton. <2> The pharmaceutical composition as defined in <1>, wherein the compound represented by the general formula (1) is luliconazole .

<3> The pharmaceutical composition as defined in <1> or <2>, wherein a pathogen of vaginitis or pneumonia includes Trichomonas .

<4> The pharmaceutical composition according to any one of <1> to <3>, wherein the pharmaceutical composition is in a form of suppository or tablet.

Advantageous Effects of Invention

[0016]

According to the present invention, it is possible to enhance the action of the compound represented by the general formula (1) described above and provide the

pharmaceutical composition effective for pneumonia and vaginitis.

DESCRIPTION OF EMBODIMENTS

[0017]

(1) Compound represented by general formula (1) as

essential component of pharmaceutical composition of the present invention

The pharmaceutical composition of the present

invention is the composition for treating vaginitis and pneumonia, characterized in that the compound represented by the foregoing general formula (1) is contained. In the general formula (1), each the groups represented by R _x and R ₂ is hydrogen atom or halogen atom. However, Ri and R ₂ are not simultaneously hydrogen atoms. The halogen atom can be preferably exemplified, for example, by chlorine atom, bromine atom, fluorine ^' atom, and iodine atom. The group represented by Ri and R ₂ is especially preferably a

hydrogen atom or a chlorine atom. The compound represented by the general formula (1) is especially preferably

luliconazole (Ri = R ₂ = CI; (R) - (-) - (E) - [4- (2, 4- dichlorophenyl ) -1, 3-dithiolane-2-ylidene] -1-imidazolyl acetonitrile) and lanoconazole (R _x = H, R ₂ = CI; 4- (2- chlorophenyl ) -1, 3-dithiolane-2-ylidene-l-imidazolyl

acetonitrile) , and luliconazole is especially preferred. The compound as described above has the antifungal action, the anti-Trichomonas action, and the anti-Chlamydia action, and it is possible to treat pneumonia and vaginitis caused by multiple infection, with one component. The actions will be explained in Exemplary Tests described · later on.

[0018]

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.

[0019]

(ID ( 1 )

[0020]

In the formula, Y, Y' represent the leaving groups, and M represents alkali metal.

[0021]

In the pharmaceutical composition of the present invention, it is preferable that the compound represented by the general formula (1) is contained by 0.1 to 10% by mass, and it is more preferable that the compound

represented by the general formula (1) is contained by 0.5 to 5% by mass, for the following reason. That is, if the amount is excessively small, the distribution to the affected part is nonuniform in some cases. If the amount is excessively large, then the compound is crystallized at the part of administration, and the effect is deteriorated in some cases. [0022]

(2) Crotamiton as essential component of pharmaceutical composition of the present invention

The pharmaceutical composition of the present

invention is characterized in that the pharmaceutical composition contains crotamiton. The component as

described above has the action to enhance the action of the compound of the general formula (1) exerted on the pathogen which is protozoa such as Trichomonas or the like. It is considered that such an effect improves the orientation of the compound represented by the general formula (1) with respect to the pathogen. In order to express the action as described above, it is preferable that crotamiton is contained by 0.1 to 50% by mass, and it is more preferable that crotamiton is contained by 1 to 10% by mass in the pharmaceutical composition of the present invention. It is preferable that crotamiton is contained in an amount of 0.5 to 15 mass times the compound of the general formula (1), and it is more preferable that crotamiton is contained in an amount of 1 to 10 mass times the compound of the general formula (1), for the following reason. That is, if the amount of crotamiton is excessively small, the enhancing effect is not expressed in some cases. If the amount of crotamiton is excessively large, it is difficult to prepare the pharmaceutical preparation in some cases.

[0023]

(3) Pharmaceutical composition of the present invention The pharmaceutical composition of the present

invention is characterized in that the pharmaceutical composition contains the essential components as described above, and the pharmaceutical composition is usable to perform the treatment for vaginitis or pneumonia. The treatment herein includes, for example, the medical

treatment or therapy for the infected state to mitigate the symptom, the prevention of infection when there is any risk of infection, and the prevention of multiple infection when a patient is infected with at least one type of pathogen. In particular, the component represented by the general formula (1) also has the medical treatment effect with respect to protozoa such as Trichomonas or the like and intracellular parasite such as Chlamydia or the like, in addition to fungi such as Candida, Aspergillus or the like. Therefore, the compound represented by the general formula (1) is preferably applied to the infectious disease caused by the pathogen as described above and the multiple

infectious disease. In particular, the compound also effectively acts on those against which little

countermeasure has been hitherto available, including, for example, the multiple infection of fungus and protozoa, the multiple infection of fungus and intracellular parasite, the multiple infection of protozoa and intracellular parasite, and the multiple infection of fungus, protozoa, and intracellular parasite, which is preferred. Of course, the compound is also effective for the single infection of fungus, protozoa, or intracellular parasite.

[0024]

That is, the pharmaceutical composition of the present invention can treat, as the disease to be applied,

vaginitis and pneumonia caused by the pathogen of, for example, intracellular parasite, protozoa, and/or fungus (for example, vaginitis and pneumonia diagnosed that the pathogen is intracellular parasite, protozoa, and/or fungus). In this context, the pharmaceutical composition of the present invention has the action to enhance the action of the compound of the general formula (1) exerted on protozoa such as Trichomonas or the like. Therefore, the pharmaceutical composition of the present invention is preferably applicable to vaginitis and pneumonia in which the pathogen includes Trichomonas . The "pharmaceutical composition for vaginitis and pneumonia caused by the pathogen including Trichomonas of the present invention" can be applied to vaginitis and pneumonia in which the pathogen is protozoa and vaginitis and pneumonia 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 coexistence 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 and pneumonia caused by the pathogen including Trichomonas of the present invention" to vaginitis and pneumonia 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 vaginitis and pneumonia 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.

[0025]

The administration route of the pharmaceutical

composition of the present invention can be preferably exemplified, for example, by administration by inhalation, intravaginal administration, endorectal administration, oral administration, and intravascular administration. In particular, it is especially preferable to perform

intravaginal administration and endorectal administration.

[0026]

The agent form, which is useable for the

administration as described above, can be preferably exemplified, for example, by suppository, tablet, injection agent, and granule. Suppository and tablet can be

exemplified more _. preferably. Suppository is especially preferred. The pharmaceutical preparation as described above may be produced by treating the essential components as described above and the components for the

pharmaceutical preparation including, for example, base material, excipient, disintegrating agent, binding agent, dispersing agent, emulsifier, diluting agent, taste/odor- correcting agent, coloring agent, and coating agent, in accordance with an ordinary method. The preferred amount of administration of the pharmaceutical composition of the present invention differs depending on, for example, the agent form, the age of patient, the body weight, and the sexuality. However,, the amount of administration is preferably 10 to 5000 mg per one person per a day, while the amount is converted into the amount of the compound of the general formula (1) . It is preferable that the

administration is performed once a day or several times a day in a divided manner. The methods for producing the suppository and the tablet will be described in detail below .

[0027]

As for the suppository, it is possible to apply any one of the oily suppository and the aqueous suppository. As for the oily suppository, it is possible to use hard fat including, for example, Witepsol H series, Witepsol W series, Witepsol S series, Witepsol E series (each of which is produced by Cremer Oleo & Sasol) , Pharmasol A series, Pharmasol B series, Pharmasol N series (each of which is produced by NOF Corporation) , and Isocacao M series (each of which is produced by Kao Corporation) to which Vaseline, liquid paraffin, and/or oil such as olive oil is/are added so that, the melting point is adjusted to prepare a base material. The compound represented by the general formula (1), which is dissolved in crotamiton, may be dispersed therein, followed by being molded by being charged into a mold in a heated and softened state. As for the aqueous suppository, polyethylene glycols having different average molecular weights are heated and mixed, and the hardness is adjusted. The compound represented by the general formula

(1), which is dissolved in crotamiton, may be dispersed therein, followed by being molded by being charged into a mold in a heated and softened state. In the case of the vaginal suppository, it is preferable that the melting point is adjusted to 33 to 36°C. In the case of the rectal suppository, it is preferable that the melting point is adjusted to 35 to 39°C.

[0028]

The tablet can be prepared as follows. That is, an excipient such as lactose, starch, carmellose,

croscarmellose or the like and a binding agent such as hydroxypropyl cellulose, gum arabic, xanthan gum or the like are mixed with each other, which is subjected to the coating with the compound represented by the general formula (1) dissolved in crotamiton, followed by performing a tablet making process and, if desired, being coated with, for example, hydroxypropyl cellulose, sucrose or the like. In case of preparing an effervescent tablet, effervescent base material such as base component comprising sodium hydrogen carbonate, sodium carbonate, magnesium

bicarbonate, magnesium carbonate and calcium carbonate; and acid component comprising citric acid, ascorbic acid, succinic acid, adipic acid, fumaric acid, tartaric acid, malonic acid, malic acid and amino acid, is further used.

EXAMPLES

[0029]

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.

[0030]

<Test Example 1>

<Action on fungus>

An in vitro antifungal (antimicrobial) activity against Candida albicans was investigated. That is, the minimum growth inhibitory concentration (MIC) was measured by means of the broth microdilution method (medicament x2 dilution series) based on the use of BPMI 1640 (pH 7.0) buffered with 0.165 M morpholinopropanesulfonic acid

(morpholine propanesulphonic acid) . 100 μΐ. of a test microorganism yeast cell suspensions (1 to 5 x 10 ³

cells/mL) and 100 μΤ. of media previously added with respective compounds were dispensed into respective wells of flat-bottom microculture plate, followed by being cultured at 35°C for 48 hours. After that, the culture turbidities of the respective wells were measured at 630 nm. The minimum growth inhibitory concentration (MIC; μg/mL) was designated 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 a control culture (measured as a suspension) . Results are shown in Table 1.

[0031]

Table 1

[0032]

<Test Example 2>

<Action on Trichomonas>

The effect for Trichomonas vaginalis was investigated in relation to luliconazole and lanoconazole. That is, 5 x 10 ⁶ cells of clinically isolated Trichomonas vaginalis were seeded in Trichomonas medium F (6.5 mL, contained in tube) produced by Fuj iyakuhin Co., Ltd. containing Neutral Red as a marker, and the preculture was carried out for 72 hours. 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 μΐ _^ , to which 0.5 mL of a test solution was added. In this situation, the number of protozoans in the solution of preculture was 1.5 x 10 ⁵ cells/mL. 0.5 mL of vehicle was added as a control. As for the vehicle, 10% methanol saline solution was used. As a result, it was revealed that MIC of luliconazole was 3.2 μg/mL, and MIC of lanoconazole was 6.4 μς/ηΛ.

[0033]

<Test Example 3>

<Action on Chlamydia>

The anti-intracellular parasite action was

investigated by using Chlamydia trachomatis (D/UW3/Cx) . That is, Chlamydia trachomatis was cultured in the presence of x2 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 fluorescently stained as apple green with FITC-labeled anti-Chlamydia monoclonal antibody "Chlamydia Kit F" (DENKA SEIKEN Co., Ltd.), and the observation was performed by using a fluorescence microscope. The concentration, at which the fluorescent color of apple green was not observed at all, was designated as MIC. MIC of luliconazole with respect to Chlamydia trachomatis was 32 μg/mL.

[0034]

<Example 1>

<Effect of crotamiton on luliconazole>

Trichomonas vaginalis (clinically isolated strain) was used to investigate the effect of crotamiton on luliconazole . Luliconazole was dissolved in 0.5 mL of 10% ethanol solution together with crotamiton, followed by being added to "Trichomonas medium F" (produced by Fuji Pharma Co., Ltd.) to which 100 μΐ, of a culture medium of 1 x 10 ⁵ cells/mL of Trichomonas vaginalis was added. The cultivation was carried out at 37°C for 72 hours, followed by being cooled for 5 minutes with ice water. After that, the number of Trichomonas vaginalis cells in the medium was counted by using a hemocytometer . Results are shown in Table 2. Accordingly, it is appreciated that the coexistence of crotamiton enhances the effect of luliconazole against Trichomonas .

[0035]

Table 2

[0036]

<Example 2>

<Effect of crotamiton on lanoconazole>

The effect of crotamiton on lanoconazole was

investigated in the same manner as in Example 1. Results are shown in Table 3. Accordingly, it is appreciated that the co-existence of crotamiton enhances the effect of lanoconazole against Trichomonas .

[0037]

Table 3

[0038]

<Example 3>

A vaginal suppository was manufactured in accordance with a formulation shown below. 'That is, components of A were heated and dissolved. A preparation, which was obtained by heating and dissolving components of B, was gradually added thereto while stirring, thereby being dispersed. Stirring and cooling were performed until arrival at 60°C, followed by being poured into a mold. Cooling was performed spontaneously, followed by being solidified to obtain the vaginal suppository.

[0039]

Table 4

Component %

by mass

A

itepsol H15 60

Vaseline 29

B

Luliconazole 1

Crotamiton 10

Total 100

[0040]

<Example 4>

A vaginal suppository was prepared in accordance with a formulation shown below in the same manner as in Example 3. .

[0041]

Table 5

Component %

by mass

A

Witepsol H15 60

Vaseline 29

B

Lanoconazole 1

Crotamiton 10

Total 100

[0042]

<Example 5>

A rectal suppository was manufactured in accordance with a formulation shown below in the same manner as in Example 3. [0043]

Table 6

Component

by mass

A

Pharmasol N145 65 Liquid paraffin 24 B

Luliconazole 1 Crotamiton 10

Total 100

[0044]

<Example 6>

A rectal suppository was manufactured in accordance with a formulation shown below in the same manner as in Example 3.

[0045]

Table 7

Component % by mass

A

Pharmasol N145 65 Liquid paraffin 24 B

Lanoconazole 1

Crotamiton 10

Total 100

[0046]

<Example 7>

A tablet was prepared in accordance with a formulation shown below. That is, components of A were sufficiently mixed, to which solubilized components of B were sprayed to coat the components of A. A ^' component of C was mixed therewith,, followed by being humidified and granulated. Blowing and drying were performed at 40°C to manufacture granules which were subjected to the tablet making to obtain the tablet. The tablet was preferred as a vaginal tablet and an oral tablet.

[0047]

Table 8

Component % by mass

A

Lactose 65 Starch 20 B

Luliconazole 1 Crotamiton 10 C

Hydroxypropyl cellulose 4

Total 100

[0048]

<Example 8>

A tablet was manufactured in the same manner as in Example 7.

[0049]

Table 9

Component

by mass

A

Lactose 65

Starch 20

B

Lanoconazole 1

Crotamiton 10

C

Hydroxypropyl cellulose

Total 100

[0050]

<Example 9>

A vaginal suppository was prepared in accordance with a formulation shown below in the same manner as in Example 3.

[0051]

Table 10

Component

by mass

A

Witepsol S-55 98

B

Luliconazole 1

Crotamiton 1

Total 100

[0052]

<Example 10>

A vaginal suppository was prepared in accordance with a formulation shown below in the same manner as in Example 3.

[ 0053]

Table 11

Component

by mass

A

Witepsol S-55 98

B

Lanoconazole 1

Crotamiton 1

Total 100

[ 0054 ]

<Example 11>

A vaginal suppository was prepared in accordance with a formulation shown below in the same manner as in Example 3.

[0055]

Table 12

Component

by mass

A

Witepsol S-55 89.9

B

Luliconazole 0.1

Crotamiton 10

Total 100

[0056]

<Example 12>

A vaginal suppository was prepared in accordance with a formulation shown below in the same manner as in Example 3. [0057]

Table 13

Component

by mass

A

Witepsol S-55 89 B

Lanoconazole 0 Crotamiton 10

Total 100

[0058]

<Example 13>

A vaginal suppository was prepared in accordance with a formulation shown below in the same manner as, in Example 3.

[0059]

Table 14

Component

by mass

A

Witepsol S-55 89

B

Luliconazole 1

Crotamiton 10

Total 100

[0060]

<Example 14>

A vaginal suppository was prepared in accordance with a formulation shown below in the same manner as in Example 3.

[0061] Table 15

Component

by mass

A

itepsol S-55 89

B

Lanoconazole 1

Crotamiton 10

Total 100

[0062]

<Example 15>

An effervescent tablet was manufactured in accordance with a formulation shown below with a direct tableting method. That tablet was preferred as a vaginal

suppository.

[0063]

Table 16

Component

by mass

Lactose 55

Dried sodium hydrogen carbonate 24

Anhydrous citric acid 14

Carmellose 5

Luliconazole 1

Crotamiton 1

Total 100

[0064]

<Example 16>

An effervescent tablet was prepared in accordance with a formulation shown below in the same manner as in Example 11. [0065]

Table 17

Component % by mass

Lactose 55 Dried sodium hydrogen carbonate 24 Anhydrous citric acid 14 Carmellose ^' 5

Lanoconazole 1

Crotamiton 1

Total 100

INDUSTRIAL APPLICABILITY

[0066]

The present invention is applicable to

pharmaceuticals .