Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
  • A61P33/08—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis for Pneumocystis carinii
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to a stabilized pharmaceutical composition in lyophilized form containing a cyclic polypeptide compound. More particularly, the present invention relates to a stabilized pharmaceutical composition in lyophilized form containing a cyclic polypeptide compound or its pharmaceutically acceptable salt and a stabilizer.
• the cyclic polypeptide compound of the present invention is represented by the general formula (I):
• R 1 is a hydrogen atom or an acyl group and R 2 and R 3 are, the same or different, a hydrogen atom or a hydroxyl group.
• the compound has an antimicrobial activity, particularly an antifungal activity and a ⁇ -1,3-glucan synthase inhibiting action, and is useful for preventing and treating various kinds of infectious diseases including Pneumocystis carinii infection, e.g., carinii pneumonia.
• cyclic polypeptide compounds represented by the above formula (I) a compound wherein R 1 is a hydrogen atom and R 2 and R 3 are hydroxyl groups and a compound wherein R 1 , R 2 and R 3 are hydrogen atoms are obtained by a fermentation process disclosed by European Patent No. 0462531 and processes disclosed by W097/32975 and by W097/47738.
• a compound wherein R 1 is an acyl group and its production process are disclosed by US Patent Nos. 5,376,634 and 5,569,646 and W096/ 11210 and WO99/40108.
• the cyclic polypeptide compounds (I) and their salts are generally unstable to light, humidity, acids, heat and the like. Therefore, desired is development of pharmaceutical preparations in which the cyclic polypeptide compounds and their salts are stabilized.
• the present invention provides a stabilized pharmaceutical composition in lyophilized form containing a cyclic polypeptide compound (I) or its pharmaceutically acceptable salt and a stabilizer.
• acyl group for R 1 in the formula (I) representing the cyclic polypeptide compound of the present invention is now explained.
• “lower” means having one to six carbon atoms unless otherwise indicated.
• the acyl group may be mentioned aliphatic acyl groups, aromatic acyl groups, aromatic- aliphatic acyl groups and heterocyclic acyl groups derived from aliphatic, aromatic, aromatic- aliphatic and heterocyclic carboxylic acids.
• aliphatic acyl groups include lower or higher alkanoyl groups such as formyl, acetyl, propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.; cycloalkanoyl groups such as cyclopentanoyl and cyclohexanoyl; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, t-
• lower alkanesulfonyl groups such as methanesulfonyl, ethane sulfonyl, etc.
• lower alkoxysulfonyl groups such as methoxy sulfonyl, ethoxy sulfonyl, etc.; and the like.
• aromatic acyl groups examples include aroyl groups such as benzoyl, toluoyl, naphthoyl and the like.
• aromatic-aliphatic acyl groups include ar (lower) alkanoyl groups such as phenylfCj-CgJalkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl(C 1 -C 6 )alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.) and the like; ar (lower) alkenoyl groups such as phenyl(C 3 -C 6 )alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentanoyl,
• heterocyclic acyl groups include heterocyclic carbonyl groups such as thenoyl, furoyl, nicotinoyl, etc.; heterocyclic(lower) alkanoyl groups such as heterocyclic acetyl, heterocyclic propanoyl, heterocyclic butanoyl, heterocyclic pentanoyl, heterocyclic hexanoyl, etc.; heterocyclic (lower) alkenoyl groups such as heterocyclic propenoyl, heterocyclic butenoyl, heterocyclic pentenoyl, heterocyclic hexenoyl, etc.; heterocyclic glyoxyloyl and the like.
• the acyl group for R 1 may have one or more suitable substituent(s). Among the above-mentioned examples for the acyl groups, an aroyl group which may have one or more suitable substituent(s) is particularly preferable.
• Suitable substituents in the acyl group include a heterocyclic group substituted by an aryl group having a lower alkoxy group, a heterocyclic group substituted by an aryl group having a lower alkoxy (lower) alkoxy group, a heterocyclic group substituted by an aryl group having a lower alkoxy (higher) alkoxy group, a heterocyclic group substituted by an aryl group having a cyclo (lower) alkyloxy group, a heterocyclic group substituted by an aryl group having a heterocyclic group, a heterocyclic group substituted by a cyclo (lower) alkyl group having a cyclo (lower) alkyl group, a heterocyclic group substituted by an aryl group having an aryl group substituted by a lower alkoxy (lower) alkoxy and a heterocyclic group substituted by an aryl group having a heterocyclic group substituted by a cyclo(lower)
• an unsaturated 3- to 8- membered heteromonocyclic group containing one to two oxygen atom(s) and one to three nitrogen atom(s) and substituted by phenyl having (C 4 - C 6 ) alkoxy an unsaturated condensed heterocyclic group containing one to two sulfur atom(s) and one to three nitrogen atom(s) and substituted by phenyl having (C 4 -C 6 )alkoxy
• an unsaturated 3- to 8-membered heteromonocyclic group containing one to two sulfur atom(s) and one to three nitrogen atom(s) and substituted by phenyl having (Cr C 4 )alkoxy(C 4 -C 6 )alkoxy an unsaturated 3- to 8-membered heteromonocyclic group containing one to two sulfur atom(s) and one to three nitrogen atom(s) and substituted by phenyl having (C x - C 4 )alkoxy(C 7
• an isoxazolyl group substituted by phenyl having pentyloxy an imidazothiadiazolyl group substituted by phenyl having pentyloxy, a thiadiazolyl group substituted by phenyl having methoxyhexyloxy, a thiadiazolyl group substituted by phenyl having methoxyoctyloxy, a thiadiazolyl group substituted by phenyl having methoxyheptyloxy, an imidazothiadiazolyl group substituted by phenyl having cyclohexyloxy, an imidazothiadiazolyl group substituted by phenyl having dimethylmorpholino, a piperazinyl group substituted by phenyl having methoxyheptyloxy, a piperazinyl group substituted by phenyl having methoxyoctyloxy, a piperazinyl group substituted by cyclohexyl having cyclohexyl having
• acyl group of R 1 may be a benzoyl group having isoxazolyl substituted by phenyl having pentyloxy, a benzoyl group having imidazothiadiazolyl substituted by phenyl having pentyloxy, a benzoyl group having thiadiazolyl substituted by phenyl having methoxyhexyloxy, a benzoyl group having thiadiazolyl substituted by phenyl having methoxyoctyloxy, a benzoyl group having thiadiazolyl substituted by phenyl having methoxyheptyloxy, a benzoyl group having imidazothiadiazolyl substituted by phenyl having cyclohexyloxy, a benzoyl group having imidazothiadiazolyl substituted by phenyl having dimethylmorpholino, a benzoyl group having piperazinyl substituted by phenyl having methyl
• the cyclic polypeptide compounds (I) having the above- mentioned acyl groups may be prepared from a compound having a hydrogen atom as R 1 and hydroxyl groups as R 2 and R 3 or a compound having hydrogen atoms as R 1 , R 2 and R 3 according to the US Patent Nos. 5,376,634 and 5,569, 646 and W096/ 11210 and WO99/40108.
• Suitable salts of the cyclic polypeptide compounds (I) are soluble in water and pharmaceutically acceptable salts including salts with bases and acid addition salts. Such a salt may be prepared by treating the cyclic polypeptide compound (I) with an appropriate base or acid according to the conventional method.
• salts with bases may be mentioned salts with inorganic bases such as alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, etc.), ammonium salts and the like; salts with organic bases such as organic amine salts (e.g., triethylamine salts, diisopropylethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, etc.); and the like.
• alkali metal salts e.g., sodium salts, potassium salts, etc.
• alkaline earth metal salts e.g., calcium salts, magnesium salts, etc.
• salts with organic bases such as organic amine salts (e.g., triethyl
• acid addition salts may be mentioned inorganic acid addition salts (e.g., hydrochlorides, hydrobromides, sulfates, phosphates, etc.); and organic carboxylic or sulfonic acid addition salts (e.g., formates, acetates, trifluoroacetates, maleates, tartrates, fumarates, methnesulfonates, benzenesulfonates, toluenesulfonates, etc.). Further, may also be mentioned salts with basic or acidic amino acids (e.g., salts with arginine, aspartic acid, glutamic acid, etc.).
• inorganic acid addition salts e.g., hydrochlorides, hydrobromides, sulfates, phosphates, etc.
• organic carboxylic or sulfonic acid addition salts e.g., formates, acetates, trifluoroacetates, maleates, tartrates, fumarates
• the cyclic polypeptide compounds (I) of the present invention also include possible conformers and a pair or more of stereoisomers such as geometric isomers and optical isomers which may exist due to asymmetric carbon atoms.
• the amount of the cyclic polypeptide compound (I) or its pharmaceutically acceptable salt contained in the composition for a single unit dosage of the present invention is 0.1 to 400 mg, more preferably 1 to 200 mg, still more preferably 10 to 100 mg, specifically 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 75, 80, 85, 90, 95 and 100 mg.
• the stabilizer may be mentioned polysaccharides, disaccharides, sodium chloride and a combination thereof.
• polysaccharide examples include dextran, starch, cellulose and hyaluronic acid; and examples of the disacharide are lactose, maltose and sucrose.
• the polysaccharide or disaccharide contained in the pharmaceutical composition of the present invention may be ⁇ - monohydrate, ⁇ -anhydride, ⁇ -anhydride or a combination thereof.
• the amount of the stabilizer used in the pharmaceutical composition of the present invention should be at least sufficient for stabilizing the cyclic polypeptide compound (I) or its pharmaceutically acceptable salt in the composition.
• one part by weight of the stabilizer with respect to one part by weight of the cyclic polypeptide compound (I) or its pharmaceutically acceptable salt in the present composition is sufficient at least.
• the stabilizer may also serve as a carrier or an excipient.
• the use amount of stabilizer does not have a particular upper limit and may be determined in consideration of the weight or volume of the composition with respect to a unit dose of the compound and the like.
• such amount is preferably 0.4 to 50 parts by weight, more preferably 0.6 to 20 parts by weight, still more preferably 0.8 to 10 parts by weight with respect to one part by weight of the cyclic polypeptide compound (I) or its pharmaceutically acceptable salt, though it varies depending upon the kind and the used amount of the cyclic polypeptide compound (I) or its pharmaceutically acceptable salt, its preparation form and/or the like. Specifically, it is more preferable that 1 to 20 parts, still more preferably 2 to 10 parts by weight of the disaccharide are used with respect to one part by weight of the cyclic polypeptide compound (I) or its pharmaceutically acceptable salt.
• 0.6 to 20 parts, still more preferably 0.8 to 10 parts by weight of sodium chloride are used with respect to one part by weight of the cyclic polypeptide compound (I) or its pharmaceutically acceptable salt.
• the pharmaceutical composition of the present invention may be produced according to methods known in the art with using additives if necessary.
• Basic Lecture on Development of Pharmaceuticals XI 20 Production of Pharmaceuticals (the second volume) (edited by Kyobunn Tsuda and Hisashi Nogami and published by Chizyo Shoten) is mentioned for reference.
• the lyophilized composition may be obtained by preparing an aqueous solution of the cyclic polypeptide compound (I) or its pharmaceutically acceptable salt and the stabilizer, optionally adding a pH adjustor (citric acid anhydrous, sodium hydroxide, etc.) as required to attain pH 4.0 - 7.5, preferably pH 4.5 - 7.0, and then lyophilizing the resulting solution in vial according to a conventional method.
• a pH adjustor citric acid anhydrous, sodium hydroxide, etc.
• the stabilized pharmaceutical composition in lyophilized form when dissolved in purified water, preferably gives a solution of pH 4.0 to 7.5, more preferably pH 4.5 to 7.0. It is preferable that the thus prepared composition in lyophilized form is sealed and stored with shading.
• the lyophilized composition can be loaded in each vial in the solution form before lyophilizing or in lyophilized powder form after lyophilizing. Since the cyclic polypeptide compound is not satisfactorily stable to humidity, it is necessary that the lyophilized composition of the present invention contains 3.4 % by weight or less of water, preferably 3.0 %, more preferably 2.0 %.
• the stabilized pharmaceutical composition in lyophilized form is dissolved in isotonic sodium chloride solution as required and used as an injection solution.
• the pharmaceutical composition of the present invention may be used as an injection preparation which requires some compounding before use.
• Example .1 Compound (II) 25 g Lactose 200 g anhydrous Citric acid in a suitable amount Sodium hydroxide in a suitable amount
• Lactose was dissolved in purified water (2000 ml) under heating below 50°C. After cooling below 20°C, the lactose solution was added with Compound (II) avoiding bubbling under gently stirring. After adding 2 % aqueous citric acid solution (9.5 ml), the solution was added with 0.4 % aqueous sodium hydroxide solution (about 24 ml) to adjust pH 5.5 followed by diluting with purified water to make a given volume (2500 ml). The resulting solution was dispensed into 1 ,000 vials of 10 mL volume, 2.5 ml per vial. The solution in the respective vials was lyophilized by using the lyophilizer (RL-603BS manufactured by Kyowa Shinku Co., Ltd) by the conventional method to obtain lyophilized compositions each containing 25 mg of Compound (II).
• Lyophilized compositions each containing 50 mg of Compound (II) were obtained in the same manner as in Example 1 except that the amount of Compound (II) used was 50 g.
• Lyophilized compositions each containing 25 mg of Compound (II) are obtained in the same manner as in Example 1 except that 150 g of maltose is used instead of lactose.
• Lyophilized compositions each containing 50 mg of Compound (II) are obtained in the same manner as in Example 1 except that the amount of Compound (II) used is 50 g instead of 25 g and 250 g of sucrose is used instead of lactose.
• Lyophilized compositions each containing 25 mg of Compound (II) are obtained in the same manner as in Example 1 except that 25 g of sodium chloride is used instead of lactose.
• Lyophilized compositions each containing 10 mg of Compound (II) are obtained in the same manner as in Example 1 except that the amount of Compound (II) used is 10 g instead of 25 g and 100 g of dextran is used instead of lactose.
• Example 7 Lyophilized compositions each containing 25 mg of Compound
• Test Example 2 The similar tests were conducted in the same manner as in Test
• Example 1 except that 100 mg of maltose, 50 mg of sucrose or 50 mg of glucose was used as a stabilizer. The results are shown in Table 2. (to be continued on the next page) Table 2
• Tests were carried out in the same manner as in Test example 1 except that 20 mg, 50 mg, 100 mg or 200 mg of lactose were added as a stabilizer.
• Table 3 shows the results of tests by observation of the appearance of compositions, the residual amount of Compound (II), the appearance of reconstituted solutions of compositions in 1 ml of water, and the like. Incidentally, it took 15 seconds to reconstitute the compositions in 1 ml of water.
• Table 3 shows the results of tests by observation of the appearance of compositions, the residual amount of Compound (II), the appearance of reconstituted solutions of compositions in 1 ml of water, and the like. Incidentally, it took 15 seconds to reconstitute the compositions in 1 ml of water.
• Tests were carried out in the same manner as in Test Example 1 except that 12.5 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound (II) were used with 200 mg of lactose.
• Table 4 shows the results of the tests on the residual amount of Compound (II) in the resulting compositions and the like. Regarding all the compositions, their appearance is a white mass, the time for reconstitutional dissolution was 15 seconds, and the color and the clarity of reconstituted solutions of the compositions were colorless and transparent.
• the pharmaceutical composition of the present invention is stable after lyophilizing the solution containing Compound (II) at pH 4.0 to 7.0 at least, preferably at pH 4.5 to 7.0.
• the pharmaceutical composition of the present invention is stable containing about 3.5 %, more particularly 3.4 % by weight or less of water.
• a composition in lyophilized form in which the cyclic polypeptide compound (I) or its pharmaceutically acceptable salt are stabilized by a stabilizer such as polysaccharide, disaccharide and sodium chloride.
• a stabilizer such as polysaccharide, disaccharide and sodium chloride.
• the cyclic polypeptide compound (I) has an antifungal activity, particularly against the following fungi. Acremonium;
• Absidia e.g., Absidia corymbifera, etc.
• Aspergillus e.g., Aspergillus clavatus, Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus terreus, Aspergillus versicolor, etc
• Blastomyces e.g., Blastomyces dermatitidis, etc
• Candida e.g., Candida albicans, Candida glabrata, Candida guilliermondii, Candida kefyr, Candida krusei, Candida parapsilosis, Candida stellatoides, Candida tropicalis, Candida utilis, etc.
• Cladospo ⁇ um e.g., Cladosporium t ⁇ choides, etc
• Coccidioides e.g., Coccidioides immitis, etc
• Cryptococcus e.g., Cryptococcus neoformans, etc
• Cunninghamella e.g., Cunninghamella elegans, etc
• Dermatophyte e.g., Dermatophyte
• Exophiala e.g., Exophiala dermatitidis, Exophiala spinifera, etc
• Epidermophyton e.g., Epidermophyton floccosum, etc
• Fonsecaea e.g., Fonsecaea pedrosoi, etc
• Fusa ⁇ um e.g., Fusa ⁇ um solani, etc
• Geot ⁇ chum e.g., Geot ⁇ chum candiddum, etc
• Histoplasma e.g., Histoplasma capsulatum var. capsulatum, etc
• Malassezia e.g., Malassezia furfur, ec
• Microsporum e.g., Microsporum canis, Microsporum gypseum, etc.
• Paracoccidioides e.g., Paracoccidioides brasiliensis, etc
• Penicillium e.g., Penicillium marneffei, etc
• Phialophora e.g., Phialophora
• Pneumocystis e.g., Pneumocystis carinii, etc
• Pseudallescheria e.g., Pseudallescheria boydii, etc
• Rhizopus e.g., Rhizopus microsporus var. rhizopodiformis, Rhizopus oryzae, etc
• Saccharomyces e.g., Saccharomyces cerevisiae, etc. Scopulariopsis;
• Sporothrix e.g., Sporothrix schenchii, etc
• Trichophyton e.g., Trichophyton mentagrophytes, Trichophyton rubrum, etc
• Trichosporon e.g., Trichosporon asahii, Trichosporon cutaneum, etc.
• the above fungi are well known to cause various infection diseases in skin, hair, nail, oral mucosa, gastrointestinal tract, bronchus, lung, endocardium, brain, meninges, urinary organ, vaginal protion, oral cavity, ophthalmus, systemic, kidney, bronchus, heart, external auditory canal, bone, nasal cavity, paranasal cavity, spleen, liver, hypodermal tissue, lymph duct, gastrointestine, articulation, muscle, tendon, interstitial plasma cell in lung, and so on.
• the cyclic polypeptide compound (I) of the present composition is useful for preventing and treating various infectious diseases, such as dermatophytosis (e.g., trichophytosis, etc), pityriasis versicolor, candidiasis, cryptococcosis, geotrichosis, trichosporosis, aspergillosis, penicilliosis, fusariosis, zygomycosis, sporotrichosis, chromomycosis, coccidioidomycosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, pseudallescheriosis, mycetoma, mycotic keratitis, otomycosis, pneumocystosis, and so on.
• infectious diseases such as dermatophytosis (e.g., trichophytosis, etc), pityriasis versicolor
• a commercial package comprising the cyclic polypeptide compound (I) of the present composition and a written matter associated therewith, wherein the written matter states that the pharmaceutical composition can or should be used for preventing or treating infections disease.

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