阅读说明：本技术 抗真菌剂 (Antifungal agent ) 是由 加纳塁 尾川修 于 2020-04-06 设计创作，主要内容包括：本发明的目的在于提供一种对隐球菌病有效的抗真菌剂。根据本发明,提供一种抗真菌剂,其特征在于,是含有雷夫康唑作为有效成分的抗真菌剂,向患有隐球菌病的动物给予。根据本发明,还提供一种抗真菌剂,其特征在于,是含有雷夫康唑作为有效成分的抗真菌剂,向患有对选自氟康唑、伊曲康唑和伏立康唑中的三唑系抗菌剂具有耐药性的隐球菌的动物给予。(The object of the present invention is to provide an antifungal agent effective against cryptococcosis. According to the present invention, there is provided an antifungal agent characterized by comprising ravuconazole as an active ingredient and being administered to an animal suffering from cryptococcosis. According to the present invention, there is also provided an antifungal agent characterized by comprising ravuconazole as an active ingredient, which is administered to an animal having cryptococcus resistant to a triazole-based antibacterial agent selected from the group consisting of fluconazole, itraconazole and voriconazole.)

1. An antifungal agent characterized by comprising ravuconazole as an active ingredient and being administered to an animal suffering from cryptococcosis.

2. An antifungal agent according to claim 1, wherein the animal suffering from cryptococcosis is an animal infected with an immunodeficiency virus or a leukemia virus.

3. An antifungal agent according to claim 1 or 2, wherein the animal has Cryptococcus neoformans grubbs var.

4. The antifungal agent of claim 3, wherein the Cryptococcus neoformans variant with G-roubi is resistant to at least one selected from the group consisting of fluconazole, itraconazole, and voriconazole.

5. The antifungal agent according to claim 3, wherein the Cryptococcus neoformans variant with G-roubi is resistant to at least two selected from the group consisting of fluconazole, itraconazole and voriconazole.

6. The antifungal agent of claim 1, wherein the cryptococcosis is cryptococcosis caused by cryptococcosis that exhibit resistance to antifungal agents other than ravuconazole.

7. The antifungal agent according to claim 6, wherein the antifungal agent other than ravuconazole is at least 1 antifungal agent selected from the group consisting of fluconazole, itraconazole, and voriconazole.

8. An antifungal agent according to any one of claims 1 to 7 wherein the animal is a human.

9. An antifungal agent according to any one of claims 1 to 7 wherein the animal is a cat.

10. An antifungal agent characterized by being an antifungal agent containing a prodrug of ravuconazole as an active ingredient and being administered to an animal suffering from cryptococcosis.

11. An antifungal agent according to claim 10, wherein the animal with cryptococcosis is infected with immunodeficiency virus or leukemia virus.

12. An antifungal agent according to claim 10 or 11, wherein the animal has Cryptococcus neoformans grubbs var.

13. The antifungal agent of claim 12, wherein the cryptococcus neoformans grubbs is resistant to at least one selected from the group consisting of fluconazole, itraconazole, and voriconazole.

14. The antifungal agent of claim 12, wherein the cryptococcus neoformans grubbs is resistant to at least 2 selected from the group consisting of fluconazole, itraconazole and voriconazole.

15. An antifungal agent according to claim 10, wherein the cryptococcosis is cryptococcosis caused by cryptococcosis that exhibit resistance to antifungal agents other than ravuconazole.

16. The antifungal agent according to claim 15, wherein the antifungal agent other than ravuconazole is at least one antifungal agent selected from the group consisting of fluconazole, itraconazole, and voriconazole.

17. An antifungal agent as claimed in any one of claims 10 to 16 wherein the prodrug of ravuconazole is fosravuconazole.

18. An antifungal agent according to any one of claims 10 to 17 wherein the animal is a human.

19. An antifungal agent according to any one of claims 10 to 17 wherein the animal is a cat.

20. An antifungal agent characterized by comprising ravuconazole as an active ingredient and being administered to an animal having cryptococcus resistant to at least 2 triazole-based antibacterial agents selected from the group consisting of fluconazole, itraconazole and voriconazole.

21. The antifungal agent of claim 20, wherein said Cryptococcus is Cryptococcus neoformans grubby (Cryptococcus neoformans var. grubbii).

22. An antifungal agent characterized by being an antifungal agent containing a prodrug of ravuconazole as an active ingredient, and being administered to an animal having cryptococcus resistant to at least 2 triazole-based antibacterial agents selected from the group consisting of fluconazole, itraconazole and voriconazole.

23. The antifungal agent of claim 22, wherein said Cryptococcus is Cryptococcus neoformans grubby (Cryptococcus neoformans var. grubbii).

24. The antifungal agent of claim 22 or 23, wherein the prodrug of ravuconazole is fosravuconazole.

25. An antifungal agent according to any one of claims 20 to 24 wherein the animal is a human.

26. An antifungal agent according to any one of claims 20 to 24 wherein the animal is a cat.

27. A method for treating an animal having cryptococcosis, comprising administering to the animal a therapeutically effective amount of ravuconazole.

28. The method of claim 27, wherein the animal having cryptococcosis is an animal infected with an immunodeficiency virus or a leukemia virus.

29. The method of claim 27 or 28, wherein the animal has Cryptococcus neoformans grubbs var.

30. The method of claim 29, wherein the cryptococcus neoformans grubbs is resistant to at least 1 selected from fluconazole, itraconazole, and voriconazole.

31. The method of claim 27, wherein said cryptococcosis is cryptococcosis caused by cryptococcosis that exhibit resistance to antifungal agents other than ravuconazole.

32. The method according to claim 31, wherein the antifungal agent other than ravuconazole is at least 1 antifungal agent selected from the group consisting of fluconazole, itraconazole and voriconazole.

33. The method of any one of claims 27 to 32, wherein the animal is a human.

34. The method of any one of claims 27 to 32 wherein the animal is a cat.

35. A method for treating an animal having cryptococcosis, comprising administering to the animal a therapeutically effective amount of a prodrug of ravuconazole.

36. The method of claim 35, wherein the animal having cryptococcosis is an animal infected with an immunodeficiency virus or a leukemia virus.

37. The method of claim 35 or 36, wherein the animal has Cryptococcus neoformans grubbs var.

38. The method of claim 37, wherein the cryptococcus neoformans grubbs is resistant to at least 1 selected from fluconazole, itraconazole, and voriconazole.

39. The method of claim 35, wherein said cryptococcosis is cryptococcosis caused by cryptococcosis that exhibit resistance to antifungal agents other than ravuconazole.

40. The method according to claim 39, wherein the antifungal agent other than ravuconazole is at least 1 antifungal agent selected from the group consisting of fluconazole, itraconazole and voriconazole.

41. The method of any one of claims 35 to 40, wherein the prodrug of ravuconazole is fosravuconazole.

42. A method according to any one of claims 35 to 41 wherein the animal is a human.

43. A method according to any one of claims 35 to 41 wherein the animal is a cat.

Technical Field

The present invention relates to an antifungal agent.

Background

The present invention relates to an antifungal agent. In particular, the present invention relates to an antifungal agent effective against cryptococcosis.

Although a large number of various fungi are parasitic on the skin and body of animals including humans, there is little serious harm to animals. This is because the proliferation of such a frequently existing bacterium is suppressed by the immunity of the host. However, in the case of diseases causing immune reduction such as acquired immunodeficiency syndrome (AIDS), in the course of using an immunosuppressive agent in organ transplantation or the like, or in the case of immune reduction due to an important factor such as physical strength deterioration accompanying aging, the growth of frequently occurring bacteria having low pathogenic bacteria whose growth is suppressed by the immune system is often observed, and as a result, the diseases are sometimes caused, and the diseases are called opportunistic infections. That is, opportunistic infection refers to infection in which the balance maintained between the host and the pathogen is disrupted by a decrease in host-side resistance, resulting in host morbidity. Examples of opportunistic infections caused by fungi include candidiasis, cryptococcosis, and pneumocystis pneumonia (also referred to as pneumonia of carinii).

Cryptococcosis (cryptococcosis) is a fungal infection caused by cryptococcosis neoformans (cryptococcosis neoformans) and cryptococcosis gorgeous (cryptococcosis gattii) as fungi, and is infected by inhalation of yeast-like fungal cells. Thus, cryptococcosis usually invades the nasal cavity, respiratory tract, lungs. In addition, meningitis may also be caused by infection spreading to the brain and the spinal cord-covering tissue (cerebrospinal membrane). In addition, the drug may spread to tissues such as the skin due to invasion by trauma or the like.

This fungus is already present in the world, but cryptococcosis is relatively rare before the onset of aids epidemic. However, it is now the most common potentially lethal fungal infection among aids patients. The causative agent of cryptococcosis in AIDS patients is mostly Cryptococcus neoformans (Cryptococcus neoformans).

Cryptococcus infections cause bacteria that infect people with reduced immune system functions other than aids patients. Infection may also occur in people suffering from hodgkin lymphoma or sarcoidosis, or in people who use drugs that inhibit immune system function, such as drugs that prevent rejection after organ transplantation or corticosteroids (when used for a long period of time).

Cryptococcus neoformans (Cryptococcus neoformans) is further classified into a type a (Cryptococcus neoformans var. grubii (referred to as Cryptococcus grubii)), a type D (Cryptococcus neoformans var. neoformans (referred to as Cryptococcus deneoformans)) and a type AD from the viewpoint of serological type. In addition, Cryptococcus gattii is further classified into type B and type C. As the frequency of pathogens in cryptococcal patients other than aids patients, Cryptococcus neoformans (Cryptococcus neoformans) accounts for the majority in the western and european isothermic regions including japan. In the tropics, Cryptococcus gattii accounts for more than half. On the other hand, Cryptococcus neoformans (Cryptococcus neoformans) accounts for the vast majority of the pathogens in cryptococcal patients as aids patients, and Cryptococcus neoformans var. grubbii, which is the serotype a of Cryptococcus neoformans (Cryptococcus neoformans), reaches 99% of the total, particularly in patients other than the division. Domestic, also Cryptococcus neofomans var. grubi infection is the vast majority.

The incidence of this cryptococcosis in the general population is reported to be 0.209 per 10 million people per year. However, the incidence of AIDS is 2-4 of 1000 per year, and is very high.

Animals other than humans may also develop cryptococcosis. In particular cats are known to suffer from cryptococcosis. Spontaneous onset of healthy cats is also occasionally seen, particularly in cats with reduced immunity due to feline immunodeficiency virus infection, feline leukemia virus infection, and the like. Cryptococcosis in felines is typically a pathogenic bacterium of Cryptococcus neofomans var. Cryptococcosis in animals other than humans is considered to be an opportunistic infection in most cases. Animals such as mammals, birds, reptiles, etc. suffering from cryptococcosis sometimes exhibit cold-like symptoms, pneumonia, encephalitis, abortion, endometritis, dermatitis, mastitis, etc. Birds are carriers of Cryptococcus neoformans (Cryptococcus neoformans) pathogens, and since the excrements of birds (especially pigeons) are a source of nutrition, fungi are common in the soil contaminated by them.

On the other hand, the prevalence of fungal infections has increased dramatically over the past few decades. Most of these fungi have resistance to first-line antifungals such as azoles and polyenes, thus preventing appropriate treatment and/or prevention of disease. The increase in fungal infections and resistance to past therapeutic agents are globally important public health threats.

Antifungal agents such as Fluconazole (FLCZ) are used as azole antifungal agents for the treatment of cryptococcosis. However, FLCZ resistant strains have been reported to be isolated from human cryptococcosis patients. In addition, isolated strains of the FLCZ resistant Cryptococcus neoformans strain from cats with cryptococcosis were reported. Further, it was reported that when a FLCZ drug-resistant strain was cultured in a medium containing Voriconazole (VRCZ) as an azole antifungal agent having a stronger antibacterial activity than FLCZ, a multi-drug-resistant strain against the azole antifungal agent was easily isolated. The emergence of multidrug-resistant bacteria in azole antifungal drugs used as first-line antifungal drugs is a major problem.

Ravuconazole is the same azole antifungal agent as fluconazole and voriconazole, and shows effective activity against various fungi. In particular, it has been reported that the compound shows excellent activity against Candida albicans (Candida albicans) and a novel Cryptococcus neoformans var. neoformans (Cryptococcus neoformans), respectively (non-patent document 1: Yamaguchi, Med. Mycol. J., vol.57E, E73-E110,2016). Ravuconazole is a triazole-based antibacterial agent similar to fluconazole, but is not currently used as a pharmaceutical.

Documents of the prior art

Non-patent document

Non-patent document 1: yamaguchi, Med. Mycol. J., vol.57E, E73-E110,2016

Disclosure of Invention

The object of the present invention is to provide an antifungal agent effective against cryptococcosis.

The present inventors have conducted intensive studies to solve the above problems, and as a result, have found that ravuconazole exhibits an antifungal effect against a serotype a bacterium (Cryptococcus neofomans var. grubiii) of a Cryptococcus neofomans, which is one of causative bacteria of cryptococcosis, and also exhibits an antifungal effect against a Cryptococcus neofomans having multi-drug resistance, and have completed the present invention. The present invention includes the following aspects.

[1] An antifungal agent characterized by comprising ravuconazole as an active ingredient and being administered to an animal suffering from cryptococcosis.

[2] The antifungal agent according to the above [1], wherein the animal suffering from cryptococcosis is an animal infected with immunodeficiency virus or leukemia virus.

[3] The antifungal agent according to the above [1] or [2], wherein the above animal has Cryptococcus neoformans var. grubbii.

[4] The antifungal agent according to the above [3], wherein the Cryptococcus neoformans variant with a Grinbergia is resistant to at least one selected from the group consisting of fluconazole, itraconazole and voriconazole.

[5] The antifungal agent according to the above [3], wherein the above Cryptococcus neoformans variant with a Grinbergia is resistant to at least two selected from the group consisting of fluconazole, itraconazole and voriconazole.

[6] The antifungal agent according to the above [1], wherein the cryptococcosis is cryptococcosis caused by cryptococcosis that shows resistance to antifungal agents other than ravuconazole.

[7] The antifungal agent according to the above [6], wherein the antifungal agent other than ravuconazole is at least 1 antifungal agent selected from the group consisting of fluconazole, itraconazole and voriconazole.

[8] The antifungal agent according to any one of the above [1] to [7], wherein the animal is a human.

[9] The antifungal agent according to any one of the above [1] to [7], wherein the animal is a cat.

[10] An antifungal agent characterized by being an antifungal agent containing a prodrug of ravuconazole as an active ingredient and being administered to an animal suffering from cryptococcosis.

[11] The antifungal agent according to the above [10], wherein the animal having cryptococcosis is infected with immunodeficiency virus or leukemia virus.

[12] The antifungal agent according to the above [10] or [11], wherein the above animal has Cryptococcus neoformans var. grubbii.

[13] The antifungal agent according to the above [12], wherein the Cryptococcus neoformans variant with a Grinbergia is resistant to at least one selected from the group consisting of fluconazole, itraconazole and voriconazole.

[14] The antifungal agent according to the above [12], wherein the above Cryptococcus neoformans variant with a Grinbergia is resistant to at least two selected from the group consisting of fluconazole, itraconazole and voriconazole.

[15] The antifungal agent according to the above [10], wherein the cryptococcosis is cryptococcosis caused by cryptococcosis that shows resistance to antifungal agents other than ravuconazole.

[16] The antifungal agent according to the above [15], wherein the antifungal agent other than ravuconazole is at least one antifungal agent selected from the group consisting of fluconazole, itraconazole and voriconazole.

[17] The antifungal agent according to any one of the above [10] to [16], wherein the prodrug of ravuconazole is Fosravuconazole (Fosravuconazole).

[18] The antifungal agent according to any one of the above [10] to [17], wherein the animal is a human.

[19] The antifungal agent according to any one of the above [10] to [17], wherein the animal is a cat.

[20] An antifungal agent characterized by comprising ravuconazole as an active ingredient and being administered to an animal having cryptococcus resistant to at least 2 triazole-based antibacterial agents selected from the group consisting of fluconazole, itraconazole and voriconazole.

[21] The antifungal agent according to the above [20], wherein the Cryptococcus is Cryptococcus neoformans grubby (Cryptococcus neoformans var. grubbii).

[22] An antifungal agent characterized by being an antifungal agent containing a prodrug of ravuconazole as an active ingredient, and being administered to an animal having cryptococcus resistant to at least 2 triazole-based antibacterial agents selected from the group consisting of fluconazole, itraconazole and voriconazole.

[23] The antifungal agent according to the above [22], wherein the Cryptococcus is Cryptococcus neoformans grubby (Cryptococcus neoformans var. grubbii).

[24] The antifungal agent according to the above [22] or [23], wherein the prodrug of ravuconazole is fosravuconazole.

[25] The antifungal agent according to any one of the above [20] to [24], wherein the animal is a human.

[26] The antifungal agent according to any one of the above [20] to [24], wherein the animal is a cat.

[27] A method for treating an animal having cryptococcosis, comprising administering to the animal a therapeutically effective amount of ravuconazole.

[28] The method according to [27], wherein the animal having cryptococcosis is an animal infected with immunodeficiency virus or leukemia virus.

[29] The method according to the above [27] or [28], wherein the animal has Cryptococcus neoformans var. grubbii.

[30] The method according to [29], wherein the cryptococcus neoformans grubbs is resistant to at least 1 selected from the group consisting of fluconazole, itraconazole and voriconazole.

[31] The method according to [27] above, wherein the cryptococcosis is cryptococcosis caused by cryptococcosis that exhibits resistance to antifungal agents other than ravuconazole.

[32] The method according to the above [31], wherein the above antifungal agent other than ravuconazole is at least 1 antifungal agent selected from the group consisting of fluconazole, itraconazole and voriconazole.

[33] The method according to any one of the above [27] to [32], wherein the animal is a human.

[34] The method according to any one of the above [27] to [32], wherein the animal is a cat.

[35] A method for treating an animal having cryptococcosis, comprising administering to the animal a therapeutically effective amount of a prodrug of ravuconazole.

[36] The method according to [35], wherein the animal having cryptococcosis is an animal infected with immunodeficiency virus or leukemia virus.

[37] The method according to the above [35] or [36], wherein the animal has Cryptococcus neoformans var. grubbii.

[38] The method according to [37], wherein the cryptococcus neoformans grubbs is resistant to at least 1 selected from the group consisting of fluconazole, itraconazole and voriconazole.

[39] The method according to [35] above, wherein the cryptococcosis is cryptococcosis caused by cryptococcosis that exhibits resistance to antifungal agents other than ravuconazole.

[40] The method according to the above [39], wherein the above antifungal agent other than ravuconazole is at least 1 antifungal agent selected from the group consisting of fluconazole, itraconazole and voriconazole.

[41] The method according to any one of [35] to [40], wherein the prodrug of ravuconazole is fosravuconazole.

[42] The method according to any one of [35] to [41], wherein the animal is a human.

[43] The method according to any one of [35] to [41], wherein the animal is a cat.

According to the present invention, an antifungal agent effective against cryptococcosis is provided.

Detailed Description

The present invention will be described below with reference to exemplary embodiments as examples, but the present invention is not limited to the embodiments described below, along with preferred methods and materials that can be used in the practice of the present invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any materials and methods equivalent or similar to those described in the present specification can be used in the practice of the present invention. All publications and patents cited in the present specification in connection with the invention described in the present specification constitute a part of the present specification as contents indicating methods, materials, and the like that can be used in the present invention.

In the present specification, when the expression "X to Y" is used, the meaning including X as a lower limit and Y as an upper limit or the meaning including X as an upper limit and Y as a lower limit is used.

In the present specification, when referred to as "ravuconazole" in the context of antifungal agents or methods of treatment, it is used in its full meaning including ravuconazole, pharmaceutically acceptable salts, hydrates and solvates thereof. In the present specification, when "fosrafaconazole" is referred to in the context of an antifungal agent or a therapeutic method, it is used in its entire meaning including fosrafaconazole, a pharmaceutically acceptable salt, a hydrate and a solvate thereof.

One embodiment of the present invention is an antifungal agent comprising ravuconazole as an active ingredient for the purpose of being used for animals suffering from cryptococcosis.

Another embodiment of the present invention is an antifungal agent comprising ravuconazole as an active ingredient for the purpose of being used in an animal suffering from cryptococcus having multi-resistance to azole antifungal agents.

Another embodiment of the present invention is an antifungal agent comprising ravuconazole as an active ingredient for the purpose of use in animals infected with immunodeficiency virus or leukemia virus and further animals suffering from cryptococcosis.

Another embodiment of the present invention is an antifungal agent comprising a prodrug of ravuconazole, preferably fosravuconazole, as an active ingredient for the purpose of being used in animals suffering from cryptococcosis.

Another embodiment of the present invention is an antifungal agent containing a prodrug of ravuconazole, preferably fosravuconazole, as an active ingredient for the purpose of being used in animals suffering from cryptococcus having multi-resistance to azole antifungals.

Another embodiment of the present invention is an antifungal agent containing a prodrug of ravuconazole, preferably fosravuconazole, as an active ingredient for the purpose of use in animals infected with immunodeficiency virus or leukemia virus and further animals suffering from cryptococcosis.

Another embodiment of the invention is a method for treating an animal with cryptococcosis by administering to the animal a therapeutically effective amount of ravuconazole.

Another embodiment of the invention is a method for treating an animal having cryptococcus having multi-resistance to azole antifungal agents, comprising administering to the animal a therapeutically effective amount of ravuconazole.

Another embodiment of the invention is a method for treating an animal infected with an immunodeficiency virus or a leukemia virus, and further having cryptococcosis, administering to the animal a therapeutically effective amount of ravuconazole.

Another embodiment of the present invention is a method for treating an animal with cryptococcosis by administering to the animal a therapeutically effective amount of a prodrug of ravuconazole, preferably fosrapedazole.

Another embodiment of the invention is a method for treating an animal having cryptococcus having multi-resistance to azole antifungals, comprising administering to the animal a therapeutically effective amount of a prodrug of ravuconazole, preferably fosraponazole.

Another embodiment of the invention is a method for treating an animal infected with an immunodeficiency virus or a leukemia virus and further suffering from cryptococcosis, by administering to the animal a therapeutically effective amount of a prodrug of ravuconazole, preferably fosrapaconazole.

Ravuconazole is reported to be a compound that exhibits antibacterial activity against various fungal pathogens including candida, aspergillus, and cryptococcus. Ravuconazole is an azole antifungal compound having the following structural formula (I), having a chemical structure similar to fluconazole.

The production method of ravuconazole is disclosed in, for example, Organic Process Research & Development 2009,13,716-728, and can be produced by referring to the above disclosure. The above disclosure is incorporated by reference as part of this specification. In manufacturing, a person skilled in the art can appropriately use techniques known in the art without limitation.

Fosrafaconazole is a compound having the following structural formula (II) in which the hydroxyl group of raviconazole is substituted with monomethoxymethyl phosphate (phospho methyl ester).

Fosfluconazole is a prodrug of raviconazole and is rapidly converted to raviconazole upon administration to humans. The L-lysine ethanol adduct of fosfluconazole is now marketed as a medicament for the treatment of onychomycosis. Fosfluconazole can also be suitably synthesized using techniques well known in the art.

The ravuconazole comprised by the antifungal agent of the present invention may also be a pharmaceutically acceptable salt. "pharmaceutically acceptable salts" refers to all non-toxic salts formed by the compounds represented by formula (I) above. Examples of suitable salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, hydrogenphosphate and sulfate, acetate, trifluoroacetate, malate, succinate, tartrate, lactate, citrate, maleate, fumarate, sorbate, ascorbate, salicylate, phthalate and methanesulfonate, organic acid salts such as trifluoromethanesulfonate and benzenesulfonate, inorganic salts such as ammonium salts, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts of acidic groups such as carboxylate, salts with organic bases such as lower alkylamines such as methylamine, ethylamine and cyclohexylamine, substituted lower alkylamines such as diethanolamine and triethanolamine, and amino acid salts such as glycinate, lysine salt, arginine salt, ornithine salt, glutamate and aspartate, but the present invention is not limited thereto.

The ravuconazole contained in the antifungal agent of the present invention may be an aqueous product such as a hydrate formed from the compound represented by the above formula (I), a solvate thereof, or the like. The term "hydrate" as used herein refers to a compound or salt thereof that further comprises a stoichiometric or non-stoichiometric amount of water, bonded using non-covalent intermolecular forces. The term "solvate" as used herein refers to a compound or salt thereof bonded by non-covalent intermolecular forces further comprising a stoichiometric or non-stoichiometric amount of a solvent. Preferred solvents are volatile, non-toxic, and/or trace amounts of solvents that are acceptable for administration to humans. Examples of the solvent include, but are not limited to, water and ethanol.

The antifungal agent of the present invention may contain fosrafaconazole as a pharmaceutically acceptable salt. "pharmaceutically acceptable salts" refers to all non-toxic salts formed by the compounds represented by formula (II) above. Specifically, the salts described in the related contents of ravuconazole are mentioned.

The fosrafaconazole contained in the antifungal agent of the present invention may also be an aqueous product such as a hydrate formed from the compound represented by the above formula (II), a solvate thereof, or the like. Hydrates and solvates are as defined above. Preferred solvents are volatile, non-toxic, and/or trace amounts of solvents that are acceptable for administration to humans. Examples of the solvent include, but are not limited to, water and ethanol.

The fosfluconazole contained as the active ingredient in the antifungal agent of the present invention is preferably an L-lysine ethanol adduct of fosfluconazole.

The antifungal agent of the present invention may contain a prodrug of ravuconazole as an active ingredient. The "prodrug" of ravuconazole encompasses both the "prodrug ester" and the "prodrug ether". "prodrug ester" includes esters and carbonates formed by reacting the hydroxyl group of the compound represented by the above formula (I) with any of alkyl-, alkoxy-, or aryl-substituted acylating or phosphorylating agents using methods well known to those skilled in the art to form an acetate, pivalate, methyl carbonate, benzoate, amino acid ester, phosphate ester, half-acid ester (e.g., malonate, succinate, or glutarate), and the like. The term "prodrug ether" as used herein encompasses both phosphate acetals and O-glucosides of the compounds represented by the above formulae which are manufactured using methods well known to those skilled in the art.

A prodrug is a compound that is converted to the parent compound represented by the above formula (I) by hydrolysis in vivo, for example, in blood.

The prodrug of ravuconazole contained in the antifungal agent of the present invention may also be a pharmaceutically acceptable salt. The prodrug of ravuconazole contained in the antifungal agent of the present invention may be an aqueous product such as a hydrate, a solvate, or the like.

The prodrug contained in the antifungal agent of the present invention is preferably fosfluconazole, and more preferably fosfluconazole-L-lysine ethanol adduct.

The antifungal agent of the present invention may contain 1 or more pharmaceutically acceptable carriers and other suitable antifungal agents in addition to any of the compounds of ravuconazole or prodrugs of ravuconazole.

The term "pharmaceutically acceptable carrier" as used in this specification encompasses any and all solvents, dispersion media, coatings, antioxidants, chelating agents, preservatives (e.g., antimicrobials), surfactants, buffers, osmotic pressure regulators, absorption retarders, salts, drug stabilizers, excipients, diluents, binders, disintegrants, sweeteners, fragrances, lubricants, dyes, and the like, and combinations thereof, known to those skilled in the art. Except for the case where any carrier is incompatible with the active ingredient of the present invention, it may be used in the antifungal agent (hereinafter, sometimes referred to as composition) or the treatment method of the present invention.

The term "therapeutically effective amount" as used herein refers to an amount of ravuconazole or a prodrug of ravuconazole (preferably fosravuconazole) that is sufficient to produce a therapeutic effect when administered to a mammal in need of treatment. The therapeutically effective amount will vary depending on the subject and the disease condition being treated, the weight and age of the subject, the severity of the disease condition, the method of administration, and the like, and can be readily determined by one skilled in the art.

The term "subject" as used herein refers to an animal in need of treatment, including mammals, birds, fish. Typically, the animal is a mammal. For example, primate (e.g., human), cat, dog, cow, sheep, goat, horse, rabbit, rat, mouse, coral, and the like. In one embodiment, the subject animal is preferably a human, cat or dog, more preferably a human or cat.

The subjects to which the antifungal agent of the present invention is administered are animals suffering from cryptococcosis. Preferably, the animal is an animal that has a cryptococcosis disease resulting from a reduction in the function of the immune system due to infection with an immunodeficiency virus or a leukemia virus, or for other reasons. More preferably an animal having Cryptococcus neoformans grubby (Cryptococcus neoformans var. grubbii) as a causative bacterium of cryptococcosis.

The antifungal agent of the present invention containing any one of ravuconazole (formula (I) above) or a prodrug of ravuconazole (for example, fosravuconazole (formula (II) above)) can be formulated in a known manner for the formulation of pharmaceutical compositions. Representative pharmaceutical compositions may comprise a pharmaceutically acceptable carrier as described above. The use of such vectors is well known in the art. In addition, methods for preparing pharmaceutical compositions containing active ingredients are well known in the art.

The compositions of the present invention may be formulated in a manner suitable for the particular route of administration corresponding to the purpose of use. Examples of routes of administration include, but are not limited to, oral, parenteral, intravenous, intradermal, subcutaneous, transdermal, inhalation, topical, transmucosal, or rectal administration. The composition of the present invention may be formulated in a solid form or a liquid form. Examples of the fixed form include, but are not limited to, tablets, capsules, pills, granules, powders, and suppositories. The liquid form includes, but is not limited to, a solution, a suspension, or an emulsion. The compositions of the present invention are preferably administered orally.

The composition of the present invention formulated for oral administration may be either a liquid or solid component. Liquid formulations the compositions may be prepared using water, glycols, oils, alcohols, and liquid carriers like those described above. For solid preparations such as tablets and capsules, a composition can be generally prepared by containing a binder, a disintegrant and auxiliary materials similar thereto together with a lubricant such as calcium stearate and using a solid carrier such as starch, sugar, kaolin, ethyl cellulose, calcium carbonate and sodium carbonate, calcium phosphate, talc, lactose and the like. Tablets and capsules are the most advantageous oral dosage forms because of their ease of administration. In order to achieve ease of administration and uniformity of the amount administered, it is particularly advantageous to blend the composition in unit dosage form. The composition in unit dosage form forms an embodiment of the invention.

The composition can be prepared into injection, and can be in the form of suspension, solution or emulsion in oily or aqueous carrier such as 0.85% sodium chloride or 5% glucose in water. In addition, a blending agent such as a suspending agent, a stabilizer and/or a dispersant may be contained. The solution can be made isotonic by the addition of buffers and additives (saline or dextrose, etc.). For intravenous drip administration, the compounds may also be dissolved in alcohol/propylene glycol or polyethylene glycol. These compositions may also be provided in unit dosage form in ampoules or in multi-dose containers, preferably with an added preservative. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle before administration.

Administration of the compositions of the present invention is generally oral or intravenous. When the composition of the present invention is used for the treatment of cryptococcosis, preferably for the direct treatment of lung and bronchi, the inhalation method is preferred in the case where there is no central nervous system infection such as meningitis. For administration by inhalation, the compounds of the invention are delivered in the form of aerosol particles using, for example, a nebulizer. A preferred delivery system for inhalation is a Metered Dose Inhaler (MDI) aerosol. In the case of a central nervous system infection such as meningitis or the possibility thereof, oral administration including liquid preparation or intravenous administration is considered. A liquid formulation is preferably used in the administration of the composition of the invention in the treatment of cryptococcosis.

The dose of the above compound in the composition of the present invention is appropriately selected depending on the type of disease, the symptom of the subject to be administered, the age, the administration method, and the like. When administered to a human, for example, in the case of an oral preparation, the administration is usually carried out 1 to 2 times per 1 day for several weeks to several months at 10 to 5000mg, preferably 20 to 2000mg, more preferably 50 to 500mg, and further preferably 100 to 200mg every 1 day, and the administration may be continuously or intermittently carried out from half a year to 1 year as the case may be, but is not limited thereto. In addition, when administered to a cat, for example, 2 to 1000mg, preferably 10 to 100mg, more preferably 20 to 40mg per 1 day is administered 1 to 2 times for 1 day for several weeks to several months, and in some cases, may be administered continuously or intermittently from half a year to 1 year, but is not limited thereto.

The compositions of the invention may also contain other antifungal agents in addition to ravuconazole or fosravuconazole. Examples of other antifungal agents include natamycin, rimycin, nystatin, amphotericin B, candixin, hamycin, epimycin, miconazole, ketoconazole, clotrimazole, econazole, omoconazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, fluconazole, fosfluconazole, itraconazole, isaconazole, posaconazole, voriconazole, terconazole, abaconazole, abafungin, terbinafine, netilmine, butenafine, amorolfine, anidulafungin, caspofungin, micafungin, ciclopirox, tolnaftate, and flucytosine, but are not limited thereto. Therefore, the composition of the present invention comprises a combination (compounding agent) of 2 or more active ingredients containing other antifungal agents in addition to ravuconazole or a prodrug of ravuconazole (preferably, fosravuconazole).

The compositions of the present invention may additionally be administered in combination with other antifungal agents for combination therapy. Co-administration includes sequential, simultaneous or parallel administration of the two agents. Other antifungal agents that can be administered in combination may be used without limitation.

The invention further comprises a method for treating cryptococcosis comprising administering to a patient a therapeutically effective amount of ravuconazole or a prodrug of ravuconazole, preferably fosfomonazole. The invention additionally encompasses methods (combinations) for treating cryptococcosis comprising administering to a patient in combination with other known antifungal agents. Examples of the antifungal agents include those exemplified for the compounding agents.

Examples

The present invention will be specifically described below with reference to examples, but the present invention is not limited to the following examples.

Clinical isolates of Cryptococcus neoformans (Cryptococcus neoformans) and multidrug resistant strains isolated from Fluconazole (FLCZ) resistant strains were used to test their susceptibility to ravuconazole.

Example 1 isolation of isolation Strain and isolation of drug-resistant Strain

For the cryptococcus isolates, 6 strains were obtained from skin-infected cats and 5 strains were obtained from systemic-infected cats, totaling 11 strains. 1 strain of cryptococcus catus and 1 strain of cryptococcus catarrhalis are fluconazole resistant strains.

Isolated strains of 3 strains of cryptococcus were obtained from skin-infected persons.

The isolated strains obtained above were all Cryptococcus neoformans grubbs strain (Cryptococcus neoformans var. grubbii strain (type a)).

In addition, 3 multidrug-resistant strains showing resistance to Fluconazole (FLCZ) and Voriconazole (VRCZ) as azole antifungal agents were obtained as follows.

2.3X 10 times of clinically isolated Fluconazole (FLCZ) resistant Cryptococcus neoformans (Cryptococcus neoformans) cells⁵Each of the cells was inoculated on a Sabouraud's dextrose agar medium containing 3. mu.g/ml as Voriconazole (VRCZ) and cultured at room temperature for 7 days. Thereafter, 12 colonies generated on the plate were inoculated into each of the agar media containing 5. mu.g/ml of Sabouraud's glucose as VRCZ. The strains were cultured at room temperature for 10 days, and the obtained colonies were further subcultured, respectively, to thereby obtain 3 azole-based drug multi-resistant strains.

Example 2 sensitivity to various azole drugs

The strain obtained in example 1 was maintained on a Sabouraud dextrose agar medium until tested for sensitivity to antifungal compounds.

Sensitivity to Ravoconazole (RVCZ) was performed using the broth dilution method (broth micro dilution assay) and following the CLSI M27-A3 guidelines. The Minimum Inhibitory Concentration (MIC) was determined after 72 hours of incubation at 35 ℃. MIC was defined as the minimum concentration that induced significant growth inhibition (about 50% inhibition or more).

Sensitivity to Fluconazole (FLCZ), Itraconazole (ITCZ) and Voriconazole (VRCZ) was evaluated using E-test. E-test was performed according to E-test Technical Guide 10(AB Biodisk, Sweden) using RPMI-1640 agar medium placed in a 90mm petri dish. E-test gradient strips were purchased from AB BIODISK. The MICs for FLCZ, ITCZ and VRCZ were determined after 72 hours incubation at 35 ℃. Each isolate was tested 2 times at different times and each test was tested 2 times.

The results of the test are shown in table 1.

[ Table 1]

^aMICs were analyzed by E-test

^bMICs were analyzed using CLSI M27-A3

^cFLCZ drug-resistant strain

FLCZ: fluconazole, TTCZ: itraconazole, VRCZ: voriconazole, RVCZ: levoconazole

The average MICs of 14 isolates (Nos. 1-14) were as follows: the fluconazole is 17.313mg/L (range: < 0.016-128mg/L), the itraconazole is 0.235mg/L (range: < 0.002-0.75mg/L), the voriconazole is 0.036mg/L (range: < 0.002-0.125mg/L), and the ravuconazole is 0.0376mg/L (range: < 0.003125-0.25 mg/L). Compared with other azole antifungal compounds, ravuconazole showed significant results.

On the other hand, MIC of azole-based drug-resistant strains (No.15-17) is as follows: fluconazole is more than 256mg/L, itraconazole is more than 32mg/L, voriconazole is 6-12mg/L, raviconazole is 0.25-0.5mg/L, and raviconazole shows remarkable effect.

As controls, MIC analyses of CLSI M27-A3 test and E-test were carried out using Candida parapsilosis (Candida parapsilosis) ATCC 22019 and Candida krusei (Candida krusei) ATCC 6258 obtained from ATCC. As a result, a high correlation was observed between the results of MIC of the azole drugs obtained in CLSI M27-A3 test and E-test, and the results were compared.

The above detailed description is only for the purpose of illustrating the present invention and is not intended to limit the scope of the claims appended hereto. Various modifications and alterations to the described embodiments will be apparent to those skilled in the art in light of the teachings set forth herein without departing from the scope of the appended claims.

Industrial applicability

The antifungal agent comprising ravuconazole provided by the present invention is useful as a therapeutic agent for cryptococcosis.