WO2021006317A1 - プロトテカ症の新規治療剤 - Google Patents
プロトテカ症の新規治療剤 Download PDFInfo
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- WO2021006317A1 WO2021006317A1 PCT/JP2020/026904 JP2020026904W WO2021006317A1 WO 2021006317 A1 WO2021006317 A1 WO 2021006317A1 JP 2020026904 W JP2020026904 W JP 2020026904W WO 2021006317 A1 WO2021006317 A1 WO 2021006317A1
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- prototheca
- disease
- composition
- treatment
- rabconazole
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
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- 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
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- 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
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- 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 novel therapeutic agent or a preventive agent for prototheca disease.
- Prototheca is a type of algae, but it does not photosynthesize because it loses chloroplasts secondarily. Therefore, since it is a heterotrophic organism that inoculates an energy source from the outside, it is vegetatively or parasitically nourished. It lives in moist environments such as soils, plant surfaces, animal digestive organs (host intestinal flora), lakes and sewage around the world, but it is also a zoonotic pathogen that infects humans and animals.
- prototheca disease The infectious disease caused by prototheca is called prototheca disease, which is a zoonotic disease that infects dogs, cats, livestock and humans.
- Prototheca infectious diseases have been attracting attention as emerging infectious diseases in recent years, and interdisciplinary and international cooperation is required for their countermeasures.
- the first human prototheca disease in Japan was reported in 1983 and has since been scattered.
- Prototheca is thought to be infected from the environment because it inhabits plant surfaces, soil, lakes and marshes, but it is also a pathogen of opportunistic infections because it is resident in the digestive tract of animals. Therefore, animal prototheca disease has been reported in dogs and cats as a mastitis-causing microorganism in dairy cattle all over the world including Japan.
- Prototheca disease in dogs and cats causes acute to chronic inflammatory pathogenicity of the skin, but it is also a fatal disease that spreads to systemic organs including the central nervous system.
- skin infection is found exclusively, and the infection route is often skin trauma.
- dogs are said to have more severe disseminated (deep) prototheca disease.
- Prototheca disease is also considered to be an opportunistic infection, and it is thought that the onset of prototheca disease is likely to increase with the onset of bacterial alternation due to the administration of antibacterial agents for diarrhea and the increasing frequency of administration of immunosuppressants and anticancer agents. In the case of immunodeficiency, there is also concern about the transition from skin infection to dissemination.
- bovine prototheca mastitis causes poor milk quality and zoonotic diseases.
- animal protecosis is regarded as a problem in industrial animals and pet animals, and there is an urgent need to establish a control method and a treatment method for the problem.
- Prototheca pathogens The most well-known species of prototheca pathogens are Prototheca wickerhamii and Prototheca zopfii.
- Prototheca wickerhamii is the most common human and small animal pathogen, and Prototheca zopfii causes sporadic prototheca disease in humans and small animals.
- Amphotericin B (AMB) and azoles which are antifungal agents, have been used for the treatment of this disease, but the clinical response in the treatment of humans and animals is generally weak. From our previous study of susceptibility to AMB, gentamicin (GM), kanamycin (KM) and itraconazole (ITZ) in vivo, these agents are effective against several strains of Prototheca wickerhamii and Prototheca zopfii. It has been shown to be untargeted (Non-Patent Document 1).
- Non-Patent Document 2 kanamycin
- GM gentamicin
- AMB amphotericin B
- ITZ itraconazole
- An object of the present invention is to provide a novel therapeutic agent or preventive agent effective against an infectious disease caused by Prototheca.
- a composition for treating or preventing prototheca disease which comprises rabconazole or a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient.
- the composition according to the above [1] which is used for the treatment or prevention of prototheca disease affecting dogs or cats.
- the composition according to the above [1] which is a pharmaceutical composition for treating or preventing prototheca disease affecting humans.
- a composition for treating or preventing prototecosis which comprises a prodrug of rabconazole (preferably fosravuconazole) or a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient.
- rabconazole preferably fosravuconazole
- a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient.
- the composition according to the above [7] which is used for treating or preventing prototheca disease affecting dogs or cats.
- composition according to the above [7] which is used for the treatment or prevention of prototheca disease (preferably prototheca bovine mastitis) affecting cattle.
- a method for treating prototheca disease which comprises administering a therapeutically effective amount of labconazole or a pharmaceutically acceptable salt, hydrate or solvate thereof to an animal suffering from prototheca disease.
- the present invention provides a composition for effective treatment or prevention of prototheca disease.
- X to Y when used as a lower limit to include Y with X as the upper limit, or as an upper limit to include Y with X as the lower limit.
- the term "labconazole” as used in the context of a therapeutic or prophylactic composition, or a therapeutic or prophylactic method refers to labconazole, a pharmaceutically acceptable salt, hydrate and solvate thereof. It is used in the meaning of including all.
- the term “fosravuconazole” is used to include all of fosravuconazole, its pharmaceutically acceptable salts, hydrates and solvates.
- compositions preferably a pharmaceutical composition
- rabconazole as an active ingredient
- Another aspect of the present invention is a composition (preferably a pharmaceutical composition) containing rabconazole as an active ingredient, which is intended to be used in an animal suffering from prototheca disease caused by Prototheca wickerhamii.
- compositions preferably a pharmaceutical composition
- rabconazole as an active ingredient intended for use in animals suffering from prototheca zopfii caused by prototheca zopfii.
- compositions preferably a pharmaceutical composition
- a prodrug of rabconazole preferably fosravuconazole
- Another aspect of the invention is a composition comprising a prodrug of rabconazole, preferably fosravuconazole, as an active ingredient, intended for use in animals suffering from prototheca disease caused by Prototheca wickerhamii (preferably pharmaceuticals).
- Composition preferably a pharmaceutical composition
- compositions comprising a prodrug of rabconazole, preferably fosravuconazole, as an active ingredient, intended for use in animals suffering from prototheca zopfii caused by prototheca zopfii.
- a prodrug of rabconazole preferably fosravuconazole
- Pharmaceutical composition
- Labconazole has been reported as a compound showing antibacterial activity against various fungal pathogens including Candida, Aspergillus, and Cryptococcus.
- Labconazole is an azole antifungal compound having the following structural formula (I).
- a method for producing rabconazole is disclosed in, for example, Organic Process Research & Development 2009, 13, 716-728, and can be produced with reference to such disclosure. Such disclosure is hereby incorporated by reference. In the production, those skilled in the art can appropriately use the technology known in the technical field without limitation.
- Fosravuconazole is a compound having the following structural formula (II) in which the hydroxyl group of rabconazole is replaced with a phosphomonooxymethyl ester.
- Fosravuconazole is a prodrug of rabconazole that is rapidly converted to rabconazole when administered to animals such as humans.
- the L-lysine ethanol adduct of fosravuconazole is currently marketed as a drug for tinea unguium.
- Fosravuconazole can also be synthesized by appropriately using a technique known in the art.
- the labconazole contained in the composition of the present invention may be a pharmaceutically acceptable salt.
- “Pharmaceutically acceptable salt” refers to any non-toxic salt formed from a compound of formula (I) above. Suitable salts include, for example, but not limited to, hydrochlorides, hydrobromates, hydroiodates, phosphates, hydrogen phosphates, inorganic acid salts such as sulfates, acetates, birds.
- Salts of acidic groups such as, lower alkylamines such as methylamine, ethylamine, cyclohexylamine, substitutions with organic bases such as diethanolamine, triethanolamine and other lower alkylamines, glycine salts, lysine salts, arginine salts, ornithine salts. , Glutamate, asparaginate and other amino acid salts can be mentioned.
- the labconazole contained in the composition of the present invention may also be a hydrous product such as a hydrate formed from the compound represented by the above formula (I) or a solvate.
- hydrate means a compound or salt thereof that further comprises a stoichiometric or non-stoichiometric amount of water bound by a non-covalent intermolecular force.
- solvate means a compound or salt thereof, further comprising a stoichiometric or non-stoichiometric amount of the solvent bound by a non-covalent intermolecular force. ..
- Preferred solvents are those that are acceptable for administration to volatile, non-toxic and / or trace amounts of animals, preferably humans. For example, but not limited to, water, ethanol, and the like.
- the fosravuconazole contained in the composition of the present invention may be a pharmaceutically acceptable salt.
- “Pharmaceutically acceptable salt” refers to any non-toxic salt formed from a compound of formula (II) above. Specifically, the above-mentioned salts described in relation to labconazole can be mentioned.
- the fosravuconazole contained in the composition of the present invention may be a hydrous product such as a hydrate formed from the compound represented by the above formula (II) or a solvate. Hydrate and solvate have the same meaning as above.
- Preferred solvents are those that are acceptable for administration to volatile, non-toxic and / or trace amounts of animals, preferably humans, such as, but not limited to, water, ethanol and the like.
- the fosravuconazole contained in the composition of the present invention as an active ingredient is preferably an L-lysine ethanol adduct of fosravuconazole.
- composition of the present invention may contain a prodrug of rabconazole as an active ingredient.
- the "prodrug” of rabconazole includes both “prodrug ester” and “prodrug ether”.
- prodrug ester the hydroxyl of the compound represented by the above formula (I) is reacted with either an alkyl, an alkoxy, or an aryl-substituted acylating agent or a phosphorifying agent by a method known to those skilled in the art.
- prodrug ether includes both phosphate acetals and glucosides of the compounds represented by the above formulas, which are produced using methods known to those of skill in the art.
- a prodrug refers to a compound that is converted to the parent compound represented by the above formula (I) in vivo, for example, by hydrolysis in blood.
- the prodrug of rabconazole contained in the composition of the present invention may be a pharmaceutically acceptable salt.
- the prodrug of rabconazole contained in the composition of the present invention may also be a hydrous product such as a hydrate or a solvate.
- the prodrug contained in the composition of the present invention is preferably fosravuconazole, more preferably fosravuconazole-L-lysine ethanol adduct.
- composition of the present invention may include, in addition to any compound of rabconazole or a prodrug of rabconazole, one or more pharmaceutically acceptable carriers and, as appropriate, other agents, such as antifungal agents.
- the term "pharmaceutically acceptable carrier” is used in any and all solvents, dispersion media, coatings, antioxidants, chelating agents, as is known to those skilled in the art.
- Preservatives eg, antibacterial agents
- surfactants eg, antibacterial agents
- buffers e.g., osmotic pressure regulators
- absorption retarders e.g., sodium bicarbonate
- salts e.g., sodium bicarbonate
- drug stabilizers e.g., sodium bicarbonate
- excipients e.g., sodium bicarbonate
- diluents binders
- disintegrants e.g., sodium bicarbonate
- sweeteners e.g., sodium bicarbonate
- fragrances e.g., sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate
- the term "therapeutically effective amount” refers to an amount of rabconazole or a prodrug of rabconazole (preferably fosravu) that, when administered to an animal in need of treatment, produces a therapeutic effect. Conazole).
- the therapeutically effective amount depends on the target animal and the disease symptoms to be treated, the weight and age of the target animal, the severity of the disease symptoms, the administration method, etc., and is easily determined by those skilled in the art. Can be done.
- the term animal of interest is an animal in need of treatment, typically a mammal.
- it refers to primates (eg, humans), cats, dogs, cows, sheep, goats, horses, rabbits, rats, mice, koalas, and the like.
- the animal of interest is preferably a human, cat, dog or cow.
- the subject to which the composition of the present invention is administered is an animal suffering from prototheca disease.
- it is an animal suffering from prototheca disease caused by Prototheca wickerhamii or Prototheca zopfii.
- compositions of the invention comprising either rabconazole (formula (I) above) or a prodrug of rabconazole (eg, fosravuconazole (formula (II) above)) are known, for example, for the formulation of pharmaceutical compositions. It can be prescribed according to the method of.
- Representative pharmaceutical compositions may include the pharmaceutically acceptable carriers described above. The use of these carriers is well known in the art. Further, a method for preparing a pharmaceutical composition containing an active ingredient is well known in the art.
- composition of the present invention can be formulated to suit a specific route of administration according to the purpose of use.
- the route of administration is not limited to this, and includes, for example, oral, parenteral, intravenous, intradermal, subcutaneous, transdermal, inhalation, topical, transmucosal, rectal, or eye drop administration.
- the compositions of the present invention can be formulated in solid or liquid form. Fixed forms include, but are not limited to, tablets, capsules, pills, granules, powders, suppositories, patches, ointments, creams, gels.
- Liquid forms include, but are not limited to, solutions, suspensions, emulsions, lotions, sprays, for example.
- Administration of the compositions of the present invention is usually limited to, but is not limited to, oral administration, intravenous administration, intramuscular administration, or transdermal administration.
- compositions of the present invention prepared for oral administration may be either a liquid composition or a solid composition.
- compositions can be prepared using liquid carriers such as water, glycols, oils, alcohols and the like.
- Solid formulations such as tablets and capsules generally contain binders such as calcium stearate as well as binders, disintegrants and the like, starch, sugar, kaolin, ethyl cellulose, calcium carbonate and sodium, calcium phosphate, talc. , Lactose and other solid carriers can be used to prepare the composition. Tablets and capsules are the most advantageous oral dosage forms because they are easy to administer. For ease of administration and dosage uniformity, it is particularly advantageous to formulate the composition in unit dosage form.
- the composition in unit dosage form constitutes one aspect of the invention.
- the composition of the present invention can be prepared, for example, as a patch, an ointment, or a cream for transdermal administration.
- the patch may be either a tape agent or a happing agent, and is not limited to this.
- an acrylic pressure-sensitive adhesive, a rubber-based pressure-sensitive adhesive, or a silicone-based pressure-sensitive adhesive is used as a base material, and a labconazole or a prodrug of labconazole is used.
- an additive used in a patch can be added for stabilizing the active ingredient, controlling the elution property, and controlling the adhesiveness.
- composition of the present invention can be used in any dosage form such as a gel agent, a liquid agent, a suspension agent, a spray agent, etc., and preparation into these dosage forms is a material used in the art. And methods can be used.
- composition of the present invention can also be used as an eye drop, for example, for eye drop administration.
- the eye drops may be any of aqueous eye drops, suspension eye drops, oil-based eye drops, eye ointments, and time-dissolving eye drops, and preparation into these dosage forms is used in the art. It can be done using the materials and methods used.
- compositions of the present invention can be prepared for injection and take the form of suspensions, solutions or emulsions in oily or aqueous vehicles such as 0.85% sodium chloride or 5% dextrose in water. Can be done. It can also contain preparations such as suspending agents, stabilizers and / or dispersants. Buffers and additives (such as saline or glucose) can be added to make the solution isotonic. The compound can also be dissolved in alcohol / propylene glycol or polyethylene glycol for intravenous drip infusion. These compositions can also be provided in unit dosage forms, preferably in ampoules or in multi-dose containers, with preservatives added. Alternatively, the active ingredient can be in powder form so as to reconstitute with a suitable vehicle prior to administration.
- oily or aqueous vehicles such as 0.85% sodium chloride or 5% dextrose in water. Can be done. It can also contain preparations such as suspending agents, stabilizers and / or dispersants. Buffers and additive
- 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 administration target, the age, the administration method, and the like.
- administration to humans for example, but not limited to this, in the case of oral preparations, usually 10 to 5000 mg, preferably 20 to 2000 mg, more preferably 50 to 500 mg, still more preferably 100 to 200 mg per day is 1 It may be administered once or twice daily, for days to weeks, and in some cases for months to a year, continuously or intermittently.
- administration to cats for example, but not limited to this, usually 2 to 1000 mg, preferably 10 to 100 mg, more preferably 20 to 40 mg per day, once or twice a day, from several days to several days.
- administration to dogs for example, but not limited to this, usually 2 to 1000 mg, preferably 10 to 500 mg, more preferably 20 to 100 mg per day, once or twice a day for several days to several weeks. In some cases, it may be administered continuously or intermittently for several months to one year.
- administration for the treatment of bovine prototheca mastitis for example, but not limited to, usually 10 to 10000 mg, preferably 20 to 5000 mg, more preferably 50 to 1000 mg per day, once to 2 times per day. It may be administered continuously or intermittently for several days to several weeks, and in some cases months to one year.
- composition of the present invention may also contain other antifungal agents in addition to labconazole or fosravuconazole.
- Other antifungal agents include, but are not limited to, natamycin, limocidin, nystatin, amphotericin B, candicine, hamycin, perimycin, myconazole, ketoconazole, clotrimazole, econazole, omoconazole, bihonazole, butconazole, fenticonazole, isoconazole.
- the composition of the present invention contains, in addition to rabconazole or a prodrug of rabconazole (preferably fosravuconazole), a combination (combination) of two or more active ingredients including other antifungal agents.
- compositions of the present invention can also be administered in combination with other agents for concomitant therapy.
- Concomitant administration includes sequential, simultaneous or parallel administration of the two drugs.
- Other agents that can be administered in combination include the antifungal agents described above.
- the present invention also comprises administering a therapeutically effective amount of labconazole or a prodrug of labconazole (preferably fosravuconazole) to an animal with prototheca disease, preferably a dog, cat, bovine, or human.
- a therapeutically effective amount of labconazole or a prodrug of labconazole preferably fosravuconazole
- the present invention also includes methods (combination) for the treatment of prototheca disease, including administration to a patient in combination with other known agents.
- Other agents may include the antifungal agents mentioned above.
- Prototheca wickerhamii Prototheca zopfii
- Prototheca blaskeae Clinical and environmental isolates of Prototheca wickerhamii, Prototheca zopfii, and Prototheca blaskeae were used to test their susceptibility to labconazole.
- Example 1 Preparation of isolates For Prototheca wickerhamii, isolates (1 cat and 2 dogs) were obtained from dogs and cats suffering from prototheca disease.
- prototheca zopfii prototheca bovine mastitis isolates (Genotype 2, 10 strains) and environmental isolates (Genotype 1, 10 strains) were obtained.
- Prototheca blaskeae a prototheca mastitis isolate (1 strain) was obtained.
- Genotype 1 established strains SAG20063 T
- Genotype 2 established strains SAG2021 T
- Isolates were maintained on Yeast Extract-Peptone-Dextrose agar (YPD: 1% yeast extract, 2% peptone, 2% dextrose, 2% agar) and tested for antifungal susceptibility.
- YPD 1% yeast extract, 2% peptone, 2% dextrose, 2% agar
- the susceptibility of isolates to the antifungal agents itraconazole (ITZ, Merck KGA) and labconazole (RVZ, selenium pharma) was performed using the broth microdilution assay and according to the CLSI M27-A3 guidelines.
- MIC minimum inhibitory concentration
- Candida parapsilosis ATCC 22019 obtained from ATCC was used, and the MIC assay of the CLSI M27-A3 test was performed.
- the table below shows the MIC results of each isolate in the CLSI M27-A3 test.
- the MICs of the three clinical isolates of Prototheca wickerhamii were 4 to> 32 mg / L for itraconazole versus 0.03 mg / L for labconazole.
- the MIC of 11 isolates of Genotype 1 of Prototheca zopfii was 0.25 to> 32 mg / L for itraconazole and 0.03 mg / L for rabconazole.
- the MIC of 11 isolates of Genotype 2 of Prototheca zopfii was 4 to> 32 mg / L for itraconazole and 0.03 to 0.25 mg / L for rabconazole.
- the MIC of one isolate of Prototheca blaskeae was 32 mg / L for itraconazole versus 0.03 mg / L for rabconazole.
- the MIC of the azole drug for the control (reference) strain Candida parapsilosis ATCC 22019 is 0.125 for itraconazole and 0.03 mg / L for rabconazole, the recommendations described in the CLSI M27-A3 assay appendix. It was within the range.
- Rabconazole also has a stronger activity than the known results on the effects of kanamycin (KM), gentamicin (GM), amphotericin B (AMB) and itraconazole (ITZ) on the prototheca prototheca wickerhamii, Prototheca zopfii and Prototheca blaskeae. Indicated. These results indicate that labconazole may be a potential first-line drug in the treatment of human and animal protothecosis.
- composition containing labconazole provided by the present invention is useful as a therapeutic agent for prototheca disease.
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Abstract
Description
[1]ラブコナゾール、あるいはその薬学的に許容できる塩、水和物又は溶媒和物を有効成分として含む、プロトテカ症に対する治療又は予防のための組成物。
[2]イヌ又はネコが罹患したプロトテカ症の治療又は予防のために使用する上記[1]に記載の組成物。
[3]ウシが罹患したプロトテカ症(好ましくは、プロトテカ性ウシ乳房炎)の治療又は予防のために使用する上記[1]に記載の組成物。
[4]ヒトが罹患したプロトテカ症の治療又は予防のための医薬組成物である上記[1]に記載の組成物。
[5]前記プロトテカ症が、Prototheca wickerhamiiにより引き起こされるプロトテカ症である上記[1]~[4]のいずれか一つに記載の組成物。
[6]前記プロトテカ症が、Prototheca zopfiiにより引き起こされるプロトテカ症である上記[1]~[4]のいずれか一つに記載の組成物。
[7]ラブコナゾールのプロドラッグ(好ましくは、ホスラブコナゾール)、あるいはその薬学的に許容できる塩、水和物又は溶媒和物を有効成分として含む、プロトテカ症に対する治療又は予防のための組成物。
[8]イヌ又はネコが罹患したプロトテカ症の治療又は予防のために使用される上記[7]に記載の組成物。
[9]ウシが罹患したプロトテカ症(好ましくは、プロトテカ性ウシ乳房炎)の治療又は予防のために使用される上記[7]に記載の組成物。
[10]ヒトが罹患したプロトテカ症に対する治療又は予防のための医薬組成物である上記[7]に記載の組成物。
[11]前記プロトテカ症が、Prototheca wickerhamiiにより引き起こされるプロトテカ症である上記[7]~[10]のいずれか一つに記載の組成物。
[12]前記プロトテカ症が、Prototheca zopfiiにより引き起こされるプロトテカ症である上記[7]~[10]のいずれか一つに記載の組成物。
[14]前記動物がイヌ又はネコである上記[13]に記載の治療方法。
[15]前記動物がウシである上記[13]に記載の治療方法。
[16]前記動物がヒトである上記[13]に記載の治療方法。
[17]前記プロトテカ症が、Prototheca wickerhamiiにより引き起こされるプロトテカ症である上記[13]~[16]のいずれか一つに記載の治療方法。
[18]前記プロトテカ症が、Prototheca zopfiiにより引き起こされるプロトテカ症である上記[13]~[16]のいずれか一つに記載の治療方法。
[19]プロトテカ症を罹患した動物に対して、治療有効量のラブコナゾールのプロドラッグ(好ましくは、ホスラブコナゾール)、あるいはその薬学的に許容できる塩、水和物又は溶媒和物を投与することを含む、プロトテカ症の治療方法。
[20]前記動物がイヌ又はネコである上記[19]に記載の治療方法。
[21]前記動物がウシである上記[19]に記載の治療方法。
[22]前記動物がヒトである上記[19]に記載の治療方法。
[23]前記プロトテカ症が、Prototheca wickerhamiiにより引き起こされるプロトテカ症である上記[19]~[22]のいずれか一つに記載の治療方法。
[24]前記プロトテカ症が、Prototheca zopfiiにより引き起こされるプロトテカ症である上記[19]~[22]のいずれか一つに記載の治療方法。
本明細書において、治療又は予防のための組成物、あるいは治療方法又は予防方法との関連で「ラブコナゾール」という場合は、ラブコナゾール、その薬学的に許容される塩、水和物及び溶媒和物の全てを含む意味で用いられる。同様に、本明細書において、「ホスラブコナゾール」という場合は、ホスラブコナゾール、その薬学的に許容される塩、水和物及び溶媒和物の全てを含む意味で用いられる。
本発明の別の一つの態様は、Prototheca wickerhamiiにより引き起こされるプロトテカ症に罹患した動物に使用することを目的としたラブコナゾールを有効成分として含む組成物(好ましくは医薬組成物)である。
本発明の別の一つの態様は、Prototheca zopfiiにより引き起こされるプロトテカ症に罹患した動物に使用することを目的としたラブコナゾールを有効成分として含む組成物(好ましくは、医薬組成物)である。
本発明の一つの態様は、プロトテカ症に罹患した動物に使用することを目的としたラブコナゾールのプロドラッグ、好ましくはホスラブコナゾールを有効成分として含む組成物(好ましくは医薬組成物)である。
本発明の別の一つの態様は、Prototheca wickerhamiiにより引き起こされるプロトテカ症に罹患した動物に使用することを目的としたラブコナゾールのプロドラッグ、好ましくはホスラブコナゾールを有効成分として含む組成物(好ましくは医薬組成物)である。
本発明の別の一つの態様は、Prototheca zopfiiにより引き起こされるプロトテカ症に罹患した動物に使用することを目的としたラブコナゾールのプロドラッグ、好ましくはホスラブコナゾールを有効成分として含む組成物(好ましくは、医薬組成物)である。
本発明の組成物が含有するホスラブコナゾールは、上記式(II)で表される化合物から形成される水和物のような含水生成物又は溶媒和物などでもよい。水和物及び溶媒和物は上記と同様の意味である。好ましい溶媒は、揮発性の、無毒の、及び/又は微量の、動物、好ましくはヒトに投与するのに許容されるものであり、これに限定されないが、水、エタノールなどである。
本発明の組成物が有効成分として含有するホスラブコナゾールは、好ましくは、ホスラブコナゾールのL-リシンエタノール付加物である。
プロドラッグは、インビボで、例えば血中での加水分解により、上記式(I)で表される親化合物に変換される化合物をいう。
本発明の組成物が含有するプロドラッグは、好ましくはホスラブコナゾール、より好ましくはホスラブコナゾール-L-リシンエタノール付加物である。
(実施例1)分離株の調製
Prototheca wickerhamii について、プロトテカ症に罹患したイヌ、ネコより分離株(ネコ 1株、イヌ 2株)を得た。Prototheca zopfii について、プロトテカ性ウシ乳房炎分離株(Genotype 2、10株)及び環境分離株(Genotype 1、10株)を得た。Prototheca blaskeae について、プロトテカ性乳房炎分離株(1株)を得た。Prototheca zopfii については、Genotype 1の樹立株(SAG20063T)及びGenotype 2の樹立株(SAG2021T)についても薬剤感受性をテストした。
分離株は、Yeast Extract-Peptone-Dextrose 寒天培地(YPD:1% yeast extract、2% peptone、2% dextrose、2% agar)で維持し、抗真菌感受性テストを行った。抗真菌剤イトラコナゾール(ITZ、Merck KGA)及びラブコナゾール(RVZ、セレンファーマ)に対する分離株の感受性は、微量液体希釈法(broth microdilution assay)を用い、CLSI M27-A3ガイドラインに従って行った。最少発育阻止濃度(MIC)は、32度で72時間培養した後に測定した。MICは、成長の顕著な阻害(約50%以上の阻害)を誘導する最少の濃度と定義した。コントロールとして、ATCCから入手したCandida parapsilosis ATCC 22019 を用い、CLSI M27-A3テストのMICアッセイを行った。CLSI M27-A3テストの各分離株のMICの結果を以下の表に示す。
コントロール(参照)株であるCandida parapsilosis ATCC 22019 に対するアゾール系薬剤のMICは、イトラコナゾールでは0.125であり、ラブコナゾールでは0.03mg/Lであり、CLSI M27-A3アッセイの添付書に記載の推奨の範囲内に収まった。
これらの結果は、ラブコナゾールがプロトテカ種の菌に対しイトラコナゾールよりも有効である(言い換えれば、防藻効果が高い)ことを示している。また、プロトテカであるPrototheca wickerhamii、Prototheca zopfii 、Prototheca blaskeae に対するカナマイシン(KM)、ゲンタマイシン(GM)、アムホテリシンB(AMB)、イトラコナゾール(ITZ)の効果についての公知の結果と比べてもラブコナゾールは強い活性を示した。
これらの結果は、ラブコナゾールが、ヒト及び動物のプロトテカ症の治療における第一選択薬剤となりうる可能性を示している。
Claims (24)
- ラブコナゾール、あるいはその薬学的に許容できる塩、水和物又は溶媒和物を有効成分として含む、プロトテカ症に対する治療又は予防のための組成物。
- イヌ又はネコが罹患したプロトテカ症の治療又は予防のために使用する請求項1に記載の組成物。
- ウシが罹患したプロトテカ症の治療又は予防のために使用する請求項1に記載の組成物。
- ヒトが罹患したプロトテカ症の治療又は予防のための医薬組成物である請求項1に記載の組成物。
- 前記プロトテカ症が、Prototheca wickerhamiiにより引き起こされるプロトテカ症である請求項1~4のいずれか一つに記載の組成物。
- 前記プロトテカ症が、Prototheca zopfiiにより引き起こされるプロトテカ症である請求項1~4のいずれか一つに記載の組成物。
- ラブコナゾールのプロドラッグ、あるいはその薬学的に許容できる塩、水和物又は溶媒和物を有効成分として含む、プロトテカ症に対する治療又は予防のための組成物。
- 前記ラブコナゾールのプロドラッグがホスラブコナゾールである請求項7に記載の組成物。
- イヌ又はネコが罹患したプロトテカ症の治療又は予防のために使用される請求項7又は8に記載の組成物。
- ウシが罹患したプロトテカ症の治療又は予防のために使用される請求項7又は8に記載の組成物。
- ヒトが罹患したプロトテカ症に対する治療又は予防のための医薬組成物である請求項7又は8に記載の組成物。
- 前記プロトテカ症が、Prototheca wickerhamiiにより引き起こされるプロトテカ症である請求項7~11のいずれか一つに記載の組成物。
- 前記プロトテカ症が、Prototheca zopfiiにより引き起こされるプロトテカ症である請求項7~11のいずれか一つに記載の組成物。
- プロトテカ症に罹患した動物(ヒトを除く)に対して、治療有効量のラブコナゾール、あるいはその薬学的に許容できる塩、水和物又は溶媒和物を投与することを含む、プロトテカ症の治療方法。
- 前記動物がイヌ又はネコである請求項14に記載の治療方法。
- 前記動物がウシである請求項14に記載の治療方法。
- 前記プロトテカ症が、Prototheca wickerhamiiにより引き起こされるプロトテカ症である請求項14~16のいずれか一つに記載の治療方法。
- 前記プロトテカ症が、Prototheca zopfiiにより引き起こされるプロトテカ症である請求項14~16のいずれか一つに記載の治療方法。
- プロトテカ症を罹患した動物(ヒトを除く)に対して、治療有効量のラブコナゾールのプロドラッグ、あるいはその薬学的に許容できる塩、水和物又は溶媒和物を投与することを含む、プロトテカ症の治療方法。
- 前記ラブコナゾールのプロドラッグがホスラブコナゾールである請求項19に記載の治療方法。
- 前記動物がイヌ又はネコである請求項19又は20に記載の治療方法。
- 前記動物がウシである請求項19又は20に記載の治療方法。
- 前記プロトテカ症が、Prototheca wickerhamiiにより引き起こされるプロトテカ症である請求項19~22のいずれか一つに記載の治療方法。
- 前記プロトテカ症が、Prototheca zopfiiにより引き起こされるプロトテカ症である請求項19~22のいずれか一つに記載の治療方法。
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US17/625,982 US20220378752A1 (en) | 2019-07-11 | 2020-07-09 | Novel therapeutic agent for prototheca disease |
KR1020227004292A KR20220034832A (ko) | 2019-07-11 | 2020-07-09 | 프로토테카증의 신규 치료제 |
JP2021530729A JPWO2021006317A1 (ja) | 2019-07-11 | 2020-07-09 | |
EP20837817.4A EP3998109A4 (en) | 2019-07-11 | 2020-07-09 | NEW THERAPEUTIC AGENT AGAINST A DISEASE CAUSED BY PROTOTHECA |
CN202080050437.XA CN114126609B (zh) | 2019-07-11 | 2020-07-09 | 原藻病的新型治疗剂 |
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Non-Patent Citations (10)
Title |
---|
CLEMONS. K. V., MARTINEZ M., CALDERON L., STEVENS D. A.: "Efficacy of Ravuconazole in Treatment of Systemic Murine Histoplasmosis", ANTIMICROB. AGENTS CHEMOTHER., vol. 46, no. 3, 2002, pages 922 - 924, XP055783310, DOI: 10.1128/AAC.46.3.922-924.2002 * |
INOUE MAKI, MIYASHITA AZUSA, NOGUCHI HIROMITSU, HIROSE NORIYUKI, NISHIMURA KAZUKO, MASUDA MICHIAKI, IHN HIRONOBU: "Case report of cutaneous protothecosis caused by Prototheca wickerhamii designated as genotype 2 and current status of human protothecosis in Japan", JOURNAL OF DERMATOLOGY, vol. 45, no. 1, 2018, pages 67 - 71, XP055783306, DOI: 10.1111/1346-8138.14010 * |
KANO, RUI: "Bovine prototheca mastitis", THE JOURNAL OF FARM ANIMAL IN INFECTIOUS DISEASE, vol. 5, no. 4, 30 November 2015 (2015-11-30), Japan, pages 139 - 144, XP009533636, ISSN: 2186-7208 * |
MIURA AYUMI ET AL.: "In vitro algaecid effect of itraconazole and ravuconazole on Prototheca species", MEDICAL MYCOLOGY, vol. 58, no. 6, 27 November 2019 (2019-11-27), pages 845 - 847, XP055783322, DOI: 10.1093/mmy/myz119 * |
ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 13, 2009, pages 716 - 728 |
RUI KANOU ET AL., THE JOURNAL OF FARM ANIMAL IN INFECTIOUS DISEASE, vol. 5, no. 4, 2016, pages 139 - 143 |
See also references of EP3998109A4 |
SOBUKAWA H. ET AL.: "In vitro susceptibility of Ptototheca zofii genotypes 1 and 2", MED. MYCOL., vol. 49, 2011, pages 222 - 224 |
WATANABE, SHINICHI: "A new dawn of treatment for tinea unguium", KANSENSHOGAKU ZASSHI = JOURNAL OF THE JAPANESE ASSOCIATION FOR INFECTIOUS DISEASES, vol. 93, no. Suppl., 1 March 2019 (2019-03-01), JP , pages 436, XP009533633, ISSN: 0387-5911 * |
YAMAGUCHI, HIDEYO: "Pharmacology and pharmacokinetics of fosravuconazole, a new oral drug for tinea unguium", JOURNAL OF THE JAPAN ORGANIZATION OF CLINICAL DERMATOLOGISTS, vol. 35, no. 5, 2018, pages 753 - 755, XP009533638, ISSN: 1349-7758 * |
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CN114126609A (zh) | 2022-03-01 |
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