WO2013154209A1 - Antiprotozoan composition containing caspofungin or its salt and biguanide compound or its salt - Google Patents

Antiprotozoan composition containing caspofungin or its salt and biguanide compound or its salt Download PDF

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Publication number
WO2013154209A1
WO2013154209A1 PCT/JP2013/061431 JP2013061431W WO2013154209A1 WO 2013154209 A1 WO2013154209 A1 WO 2013154209A1 JP 2013061431 W JP2013061431 W JP 2013061431W WO 2013154209 A1 WO2013154209 A1 WO 2013154209A1
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Prior art keywords
contact lens
salt
antiprotozoan
caspofungin
acanthamoeba
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PCT/JP2013/061431
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French (fr)
Inventor
Hajime Ibuki
Mitsushi Hikida
Kazutaka Kido
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Santen Pharmaceutical Co., Ltd.
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Publication of WO2013154209A1 publication Critical patent/WO2013154209A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L12/00—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor
    • A61L12/08—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor using chemical substances
    • A61L12/14—Organic compounds not covered by groups A61L12/10 or A61L12/12
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
    • A01N47/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=CX2 groups, e.g. isothiourea
    • A01N47/44—Guanidine; Derivatives thereof
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L12/00—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor
    • A61L12/08—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor using chemical substances
    • A61L12/14—Organic compounds not covered by groups A61L12/10 or A61L12/12
    • A61L12/141—Biguanides, e.g. chlorhexidine
    • A61L12/142—Polymeric biguanides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • 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
    • A61P33/04—Amoebicides
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to an antiprotozoan composition containing caspofungin or its salt and a biguanide compound or its salt.
  • Acanthamoeba is a ubiquitous free-living protozoan that exists dimorphically either as a trophozoite or cyst. Its species include A. polyphaga, A. castellanii, A. lenticulata, A. hatchetti, A. astronyxis, A. culbertsoni and A. rhysodes. Acanthamoeba exists as a trophozoite under favorable growth conditions.
  • the trophozoite is highly sensitive to drugs because it has high drug membrane permeability, but in deteriorating growth conditions it transforms into a cyst with a double wall, and Acanthamoeba in the cyst form (hereinafter referred to as "Acanthamoeba cyst”) exhibits dryness resistance, heat resistance and chemical resistance. Thus, it was exceedingly difficult to eradicate Acanthamoeba cyst.
  • Acanthamoeba keratitis has become noted as an ocular infection associated with contact lens wear, and Acanthamoeba keratitis is an intractable condition involving infection of the cornea by Acanthamoeba, exhibiting symptoms such as hyperemia, blurred vision, and high ophthalmalgia, and in worst cases even loss of vision. Because drugs that exhibit a clear clinical effect against Acanthamoeba cyst currently do not exist on the market, treatment of Acanthamoeba keratitis is very difficult.
  • MPS multipurpose solutions for contact lens care
  • polyhexanide hydrochloride As the active ingredient of an MPS, polyhexanide hydrochloride is generally incorporated, but polyhexanide hydrochloride is known to have a weak amebicidal effect against Acanthamoeba, and especially Acanthamoeba cyst.
  • caspofungin One drug considered to have amebicidal activity is caspofungin, described in Non-patent Document 1 as having an amebicidal effect against Acanthamoeba cyst upon exposure at high concentration for 24 hours or longer.
  • Patent Document 1 also discloses that the biguanide compound polyhexanide hydrochloride has an anti-Acanthamoeba effect.
  • the amebicidal effect of polyhexanide hydrochloride incorporated in commercially available MPS is weak, as mentioned above.
  • caspofungin and biguanide compounds are each known to have weak amebicidal effects, but no composition is known that combines caspofungin and a biguanide compound and exhibits a powerful amebicidal effect.
  • compositions with a higher antiprotozoan effect against protozoa such as Acanthamoeba cyst, and especially a contact lens care product such as an MPS having such an effect, or an ophthalmic composition useful as an agent for prevention and/or treatment of Acanthamoeba keratitis caused by protozoan and especially Acanthamoeba.
  • Patent document 1 International Patent Publication WO No. 97/36487 Pamphlet
  • Non-patent document 1 Sabrina Bouyer et al., Journal of Antimicrobial Chemotherapy, 2007, 59, 122-124
  • the invention relates to the following.
  • An antiprotozoan composition containing caspofungin or its salt and a biguanide compound or its salt.
  • the antiprotozoan composition according to (1 1) which is an agent for prevention and/or treatment of keratitis.
  • the invention further relates to the following.
  • a method of cleaning, rinsing, disinfecting and/or storing a contact lens comprising a step of contacting the contact lens with the contact lens care product according to (9) or (10).
  • a method of disinfecting a contact lens case or contact lens comprising a step of contacting the contact lens case or contact lens with the contact lens care product according to (9) or (10).
  • a method of eliminating or killing protozoa adhering to a contact lens case or contact lens comprising a step of contacting the contact lens case or contact lens with the contact lens care product according to (9) or (10).
  • a method for preventing or treating ophthalmologic conditions in a patient comprising a step of administering the antiprotozoan composition according to any of (1) to (8) onto an eye of the patient in need thereof in a therapeutically effective amount.
  • an antiprotozoan composition that exhibits a powerful antiprotozoan effect against protozoa such as Acanthamoeba, and especially Acanthamoeba cyst. That is, by including both caspofungin or its salt and a biguanide compound or its salt, their use for brief periods and at low concentration can eradicate protozoa such as Acanthamoeba and minimize adhesion of protozoa such as Acanthamoeba onto contact lenses more adequately than using either one alone, and it is thus possible to provide a contact lens care product such as a multipurpose contact lens care solution suited for the conditions of use.
  • a contact lens care product such as a multipurpose contact lens care solution suited for the conditions of use.
  • composition has powerful antiprotozoan activity compared to using either caspofungin or its salt or a biguanide compound or its salt alone, it is possible to provide an ophthalmic composition that is useful as an agent for prevention and/or treatment of diseases associated with protozoa, and especially Acanthamoeba, such as keratitis and especially Acanthamoeba keratitis.
  • FIG. 1 This shows the results of evaluating the amebicidal effects of caspofungin, micafungin, anidulafungin, artesunate, artemether, quinine and polyhexanide hydrochloride on Acanthamoeba cyst, in Pharmacological Test 1.
  • FIG. 2 This shows the results of evaluating the amebicidal effects on Acanthamoeba cyst by combining caspofungin, micafungin or anidulafungin with polyhexanide hydrochloride, in Pharmacological Test 2.
  • FIG. 3 This shows the results of evaluating the amebicidal effect on Acanthamoeba cyst by combining caspofungin with polyhexanide hydrochloride in different concentration groups, in Pharmacological Test 3.
  • protozoan refers to a member of Amoebida or
  • Amoebida include Acanthamoeba, Naegleria, Hartmannella and Vannella.
  • Acanthamoeba refers to A. astronyxis, A.
  • polyphaga A. pustulosa, A. quina, A. rhysodes, A. royreba, A. terricola, A. triangularis, A. tubiashi, A. polyphaga, A. castellani and the like.
  • Microsporida refers to Encephalitozoon cuniculi, Encephalitozoon. hellem, Encephalitozoon. intestinalis, Vittaforma corneae, Anncaliia algerae, Microsporidium (M. ceylonensis and M. africanum), Nosema sp. (N. ocularum), Anncaliia connori, Trachipleistophora hominis, and the like.
  • antiprotozoan effect means an effect of totally or partially eradicating or eliminating a protozoan, or inhibiting growth of a protozoan.
  • amebicidal effect means an effect of totally or partially eradicating or eliminating an amoeba, or inhibiting growth of an amoeba.
  • amebicidal effect includes an amebicidal effect against Acanthamoeba (also referred to as “anti-Acanthamoeba effect”), an amebicidal effect against Acanthamoeba cyst (also referred to as “anti-Acanthamoeba cyst effect”), an eradicating effect against Acanthamoeba trophozoites and/or cysts, and an inhibiting effect on cyst formation of Acanthamoeba.
  • antiprotozoan composition refers to a
  • composition that can exhibit an antiprotozoan effect against a total or partial protozoa, typically Amoebida and Microsporida.
  • contact lens includes soft contact lenses, hard contact lenses and oxygen-permeable hard contact lenses.
  • soft contact lens includes both ionic and nonionic types, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses (soft contact lenses that differ from silicone hydrogel lenses).
  • contact lens care product means any composition that is used for care of contact lenses, such as a contact lens inserting solution, contact lens cleaning solution, contact lens rinsing solution, contact lens antiseptic solution, contact lens storage solution or multipurpose contact lens care solution(multipurpose solution or MPS).
  • MPS multipurpose solution or MPS refers to a contact lens care product that can accomplish two or more operations from among cleaning, rinsing, disinfection or storage of contact lenses, with a single solution.
  • ophthalmic composition refers to a medical composition for ophthalmic use, such as an ophthalmic composition which may be eye drops (including eye drops for contact lenses), an eye wash (including an eye wash for contact lenses), or an eye ointment.
  • keratitis refers to, for example, bacterial keratitis, fungal keratitis, Acanthamoeba keratitis, corneal ulcer, corneal phlyctenule or herpetic keratitis.
  • Acanthamoeba keratitis is keratitis caused by Acanthamoeba.
  • the antiprotozoan composition of the invention is any composition that contains caspofungin or its salt and a biguanide compound or its salt.
  • the antiprotozoan composition of the invention may be a solution dissolved in a particular solvent, and preferably it is an aqueous composition, as a water-soluble solution.
  • the caspofungin in the composition of the invention is the compound represented by the following formula (1).
  • Caspofungin (CAS Accession No. 162808-62-0) is a kind of macrocyclic lipopeptide echinocandin, and it is also referred to as either caspofungin or 1-[(4R, 5S)-5-[(2-aminoethyl)amino]-N 2 -( 10R, 12S- 10, 12-dimethyl- l-oxotetradecyl)-4-hydroxy -L-omithine]-5-[(3R)-3-hydroxy-L-ornithine]pneumocandin B 0 .
  • a salt of caspofungin is not particularly restricted so long as it is a pharmacologically or physiologically acceptable salt, and for example, it may be a salt of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or boric acid; or a salt of an organic acid such as acetic acid, citric acid, tartaric acid, propionic acid, succinic acid, oxalic acid, malic acid, maleic acid, lactic acid, glutamic acid or pamoic acid.
  • caspofungin salts may be used alone or they may be used in any combinations of two or more kinds.
  • caspofungin or its salt may also be in the form of a hydrate or solvate.
  • a polymorphic crystal group is the individual crystalline form at each stage, in cases where the crystalline form changes, and the overall crystalline form during that process, depending on the conditions and state (including the state of formulation) of production, crystallization and storage of the crystals.
  • Caspofungin or its salt, or a hydrate or solvate thereof can be produced by a common method in the field of synthetic organic chemistry. For example, it can be produced by the method described in US5378804, US5552521, US5952300 or
  • the content ratio of caspofungin or its salt in the composition of the invention is not particularly restricted so long as it is a sufficient concentration for exhibiting the desired antiprotozoan effect, and it may be appropriately set according to its kind, the kind of biguanide compound or its salt used in combination with it, and the kind of pharmaceutical preparation of the composition.
  • the content ratio of caspofungin or its salt with respect to the total aqueous composition will usually be 0.01 to 10% (w/v), preferably 0.05 to 10% (w/v) and more preferably 0.1 to 5% (w/v), as the total concentration in terms of the concentration of caspofungin itself.
  • the content ratio of caspofungin or its salt with respect to the total aqueous composition will usually be 0.000005 to 0.1% (w/v), preferably 0.00005 to 0.05% (w/v) and more preferably 0.0001 to 0.01% (w/v), as the total concentration.
  • the biguanide compound or its salt in the composition of the invention is not particularly restricted so long as it is a pharmacologically or physiologically acceptable compound.
  • biguanide compounds and their salts include polyhexanide and its salts (hereinafter also referred to as "polyhexamethylene biguanide” or "PHMB”), chlorhexidine and its salts or alexidine and its salts, with polyhexanide and its salts being preferred and polyhexanide hydrochloride being more preferred.
  • Polyhexanide is a compound represented by the following formula (2).
  • n is a numeral representing the number of repeating units in parentheses, which may be an integer of 1 to 500, preferably an integer of 2 to 200, more preferably an integer of 4 to 100 and even more preferably an integer of 4 to 20.
  • a salt of polyhexanide is not particularly restricted so long as it is a pharmacologically or physiologically acceptable salt, and for example, it may be a salt of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or boric acid; or a salt of an organic acid such as acetic acid, gluconic acid, maleic acid, ascorbic acid, stearic acid, tartaric acid or citric acid, and preferably an inorganic acid salt, with hydrochloride being more preferred.
  • these polyhexanide salts may be used alone or they may be used in any combinations of two or more kinds.
  • Chlorhexidine is the compound represented by the following formula (3). [Chemical Formula 3
  • a salt of chlorhexidine is not particularly restricted so long as it is a pharmacologically or physiologically acceptable salt, and for example, it may be a salt of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or boric acid; or a salt of an organic acid such as acetic acid, gluconic acid, maleic acid, ascorbic acid, stearic acid, tartaric acid or citric acid, and preferably a hydrochloride, acetate or gluconate, with gluconates being more preferred.
  • These chlorhexidine salts may be used alone or they may be used in any combinations of two or more kinds.
  • Alexidine is the compound represented by the following formula (4). [Chemical Formula 4]
  • a salt of alexidine is not particularly restricted so long as it is a pharmacologically or physiologically acceptable salt, and for example, it may be a salt of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or boric acid; or a salt of an organic acid such as acetic acid, gluconic acid, maleic acid, ascorbic acid, stearic acid, tartaric acid or citric acid, and preferably a hydrochloride, acetate, or gluconate, with hydrochlorides being preferred and dihydrochlorides being even more preferred.
  • These alexidine salts may be used alone or they may be used in any combinations of two or more kinds.
  • the biguanide compound or its salt in the composition of the invention may also be in the form of a hydrate or solvate.
  • a polymorphic crystal group is the individual crystalline form at each stage, in cases where the crystalline form changes, and the overall crystalline form during that process, depending on the conditions and state (including the state of pharmaceutical preparation) of production, crystallization and storage of the crystals.
  • the biguanide compound or its salt in the composition of the invention may be used alone, or in any combinations of two or more kinds.
  • the biguanide compound can be produced by a common method in the field of synthetic organic chemistry.
  • a biguanide compound used may also be any of the following commercially available products.
  • polyhexanide hydrochloride compounds those which are commercially available under the trade names Proxel (registered trademark) IB from Zeneca, or Lonzabac (registered trademark) BG from Lonza, Japan may be used.
  • chlorhexidine gluconate compounds those which are commercially available under the trade name Hibitane (registered trademark) from Dainippon
  • alexidine dihydrochloride compounds those which are commercially available from Sigma-Aldrich Japan, KK., for example, may be used.
  • the content ratio of a biguanide compound or its salt in the composition of the invention is not particularly restricted so long as it is a sufficient concentration for exhibiting the desired antiprotozoan effect, and it may be appropriately set according to the kind of biguanide compound or its salt, the kind of caspofungin or its salt used in combination with it, and the kind of pharmaceutical preparation of the composition.
  • the content ratio of the biguanide compound or its salt with respect to the total aqueous composition will usually be 0.001 to 1% (w/v), preferably 0.005 to 0.5% (w/v) and more preferably 0.01 to 0.2% (w/v), as the total concentration in terms of the concentration of the biguanide compound itself.
  • the content ratio of the biguanide compound or its salt with respect to the total aqueous composition will usually be 0.000005 to 0.01% (w/v), preferably 0.00001 to 0.005% (w/v) and more preferably 0.00005 to 0.001% (w/v), as the total concentration.
  • the proportion of the biguanide compound or its salt with respect to caspofungin or its salt in the composition of the invention is not particularly restricted so long as it is an amount sufficient to exhibit the desired antiprotozoan effect.
  • the total amount of biguanide compound or its salt to 1 part by weight as the total of caspofungin or its salt will usually be 0.0005 to 50 parts by weight, preferably 0.001 to 10 parts by weight and more preferably 0.002 to 5 parts by weight.
  • the total amount of biguanide compound or its salt to 1 part by weight as the total of caspoiungin or its salt will usually be 0.00005 to 100 parts by weight, preferably 0.0001 to 50 parts by weight and more preferably 0.005 to 10 parts by weight.
  • Polidronium chloride (CAS Accession No. 75345-27-6) may be used instead of a biguanide compound or its salt in the composition of the invention.
  • additives may be included in the composition of the invention as necessary, examples including additives such as buffering agents, surfactants, tonicity agents, antiseptic agents, pH regulators, thickening agents, chelating agents, stabilizers, protein removing agents and the like, for an aqueous composition.
  • Buffering agents are not particularly restricted so long as they are
  • pharmacologically or physiologically acceptable examples include at least one kind selected from phosphoric acid, phosphoric acid salts such as sodium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate, potassium phosphate, potassium dihydrogenphosphate and dipotassium hydrogenphosphate; boric acid, borax, boric acid salts such as sodium borate and potassium borate; citric acid salts such as sodium citrate and disodium citrate; acetic acid salts such as sodium acetate and potassium acetate; carbonic acid salts such as sodium carbonate and sodium hydrogencarbonate; or ⁇ -aminocaproic acid and trometamol, among which there are preferred at least one kind selected from phosphoric acid, sodium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate, potassium phosphate, potassium dihydrogenphosphate and dipotassium hydrogenphosphate, with sodium dihydrogenphosphate and disodium hydrogenphosphate being more preferred.
  • the content ratio of the buffering agent is appropriately set according to the kind of buffering agent, the kinds of other compounding ingredients and their content ratios, and the form of pharmaceutical preparation of the aqueous composition.
  • the content ratio of a buffering agent in the composition of the invention will usually be 0.001 to 5% (w/v), preferably 0.003 to 3% (w/v) and more preferably 0.03 to 2% (w/v), as the total concentration.
  • pharmacologically or physiologically acceptable one examples include at least one kind selected from nonionic surfactants, including POE sorbitan fatty acid esters such as POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monopalmitate (polysorbate 40), POE (20) sorbitan monostearate (polysorbate 60), POE (20) sorbitan tristearate (polysorbate 65) and POE (20) sorbitan monooleate (polysorbate 80); POE- POP block copolymers such as Poloxamer 407, Poloxamer 235, Poloxamer 188,
  • Poloxamer 403, Poloxamer 237 and Poloxamer 124 POE hydrogenated castor oils such as POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); POE alkyl ethers such as POE (9) lauryl ether; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether; and POE alkylphenyl ethers such as POE (10) nonylphenyl ether (where POE is polyoxyethylene and POP is polyoxypropylene, and the numbers in parentheses are the addition mole numbers); amphoteric surfactants including
  • alkyldiaminoethylglycine and its salts such as hydrochlorides
  • anionic surfactants including alkylbenzenesulfonic acid salts, alkylsulfuric acid salts,
  • a-olefinsulfonic acids such as benzalkonium chloride and benzethonium chloride, and preferably at least one kind selected from nonionic surfactants, and more preferably POE sorbitan fatty acid esters, POE hydrogenated castor oils and POE- POP block copolymers, and even more preferably at least one kind selected from polysorbate 80, polyoxyethylene hydrogenated castor oil 60 and
  • the content ratio is appropriately set according to the kind of surfactant, the kinds of other compounding ingredients and their content ratios, and the form of pharmaceutical preparation of the aqueous composition.
  • the content ratio of a surfactant in the composition of the invention will usually be 0.001 to 10% (w/v), preferably 0.005 to 5% (w/v) and more preferably 0.005 to 3% (w/v), as the total concentration.
  • Tonicity agents are not particularly restricted so long as they are
  • pharmacologically or physiologically acceptable examples include at least one selected from disodium hydrogenphosphate, sodium dihydrogenphosphate, potassium dihydrogenphosphate, sodium hydrogensulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium hydrogencarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin and propylene glycol.
  • the content ratio of the tonicity agent may be appropriately set according to the kind of tonicity agent, the kinds and concentrations of other compounding ingredients, and the form of pharmaceutical preparation of the antiprotozoan composition.
  • the osmotic pressure will usually be 200 to 450 milliosmoles (mOSm) and preferably 250 to 370 milliosmoles (mOSm).
  • pH regulators there are no particular restrictions on pH regulators so long as they are pharmacologically or physiologically acceptable, and examples include at least one selected from hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide and ammonium hydroxide.
  • the content ratio of the pH regulator may be appropriately set according to the kind of pH regulator, the kinds and amounts of other compounding ingredients, and the form of preparation of the antiprotozoan composition.
  • the pH is not particularly restricted so long as it is within a pharmacologically or physiologically acceptable range, but it will usually be 4.0 to 9.5, preferably 5.0 to 9.0, more preferably 5.0 to 8.5 and even more preferably 5.0 to 7.5.
  • thickening agents there are no particular restrictions on thickening agents so long as they are pharmacologically or physiologically acceptable, and examples include at least one selected from among hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose and carboxymethyl cellulose.
  • the content ratio of the thickening agent is appropriately set according to the kind of thickening agent, the kinds of other compounding ingredients and their content ratios, and the form of pharmaceutical preparation of the aqueous composition.
  • the thickening agent concentration will usually be 0.01 to 10% (w/v) and preferably 0.05 to 3% (w/v), as the total concentration.
  • Chelating agents are not particularly restricted so long as they are
  • pharmacologically or physiologically acceptable examples include at least one selected from sodium edetate, sodium citrate and condensed sodium phosphate.
  • the content ratio of the chelating agent may be appropriately set according to the kind of chelating agent, the kinds of other compounding ingredients and their content ratios, and the form of pharmaceutical preparation of the aqueous composition.
  • the content ratio of the chelating agent will usually be 0.002 to 0.5% (w/v) and preferably 0.005 to 0.1% (w/v), as the total concentration.
  • a proteolytic enzyme may also be incorporated suitably in an appropriate amount.
  • the composition of the invention may contain water at usually 20% or greater, preferably 50% or greater, more preferably 80% or greater arid even more preferably 90% or greater, with respect to the total amount of the composition.
  • the water used is preferably distilled water, purified water or sterilized purified water. .
  • Examples of form of the pharmaceutical preparation of the composition of the invention include ophthalmic compositions such as eye drops (including contact lens eye drops), eye washes (including contact lens eye washes) and eye ointment; and contact lens care products such as contact lens inserting solutions, contact lens cleaning solutions, contact lens rinsing solutions, contact lens antiseptic solutions, contact lens storage solutions and multipurpose solutions for contact lens care (multipurpose solutions or MPS).
  • Ophthalmic compositions and contact lens care products are preferred, eye drops and contact lens care products are more preferred, and eye drops, contact lens cleaning solutions, contact lens rinsing solutions, contact lens antiseptic solutions, contact lens storage solutions and multipurpose solutions for contact lens care (multipurpose solutions or MPS) are even more preferred.
  • the antiprotozoan composition of the invention may also be in the form of a freeze-dried formulation that is reconstituted with water immediately prior to use.
  • the antiprotozoan composition of the invention may be prepared as any form of the pharmaceutical preparations as mentioned above.
  • an aqueous composition as one example, it may be produced by dissolving the caspofungin or its salt and the biguanide compound or its salt, and if necessary the additives such as a buffering agent, surfactant, tonicity agent, antiseptic agent, pH regulator, thickening agent, chelating agent, stabilizer and protein removing agent, in a solvent such as water.
  • composition of the invention when the composition of the invention is a contact lens care product, it may be used as any of various types of contact lens care products for soft contact lenses, hard contact lenses and oxygen-permeable hard contact lenses, and it is preferably used for soft contact lenses.
  • the invention also relates to a method of cleaning, rinsing, disinfecting and/or storing a contact lens.
  • the method of the invention comprises a step of contacting the contact lens with the contact lens care product of the invention.
  • the treatment time for contacting a contact lens with the contact lens care product according to the present invention is not particularly restricted, but usually between 5 minutes and 24 hours, and preferably between 1 and 12 hours.
  • the way of contacting the contact lens with the contact lens care product of the invention is not particularly restricted.
  • the contact lens care product of the invention is dropped by several drops on a contact lens removed from an eye, then the contact lens is rubbed for several seconds to several tens of seconds while the contact lens being sandwiched between thumb and forefinger, or being kept on a palm.
  • the contact lens is rinsed with several milliliters of the contact lens care product of the invention.
  • the contact lens is immersed in the contact lens case filled with the contact lens care product of the invention.
  • the invention also relates to a method of disinfecting a contact lens case or contact lens.
  • the method of the invention comprises a step of contacting the contact lens case or contact lens with the contact lens care product of the invention.
  • the treatment time for contacting the contact lens case or contact lens with the contact lens care product of the invention is not particularly restricted, but usually between 5 minutes and 24 hours, and preferably between 1 and 12 hours.
  • the way of contacting the contact lens case or contact lens with the contact lens care product of the invention is not particularly restricted.
  • the contact lens is immersed in the contact lens case filled with the contact lens care product of the invention.
  • the invention further relates to a method of eliminating or killing protozoa adhering to a contact lens case or contact lens.
  • the method of the invention comprises a step of contacting the contact lens case or contact lens with the contact lens care product of the invention.
  • the treatment time for contacting the contact lens case or contact lens with the contact lens care product of the invention is not particularly restricted, but usually between 5 minutes and 24 hours, and preferably between 1 and 12 hours.
  • the way of contacting the contact lens case or contact lens with the contact lens care product of the invention is not particularly restricted.
  • the contact lens is immersed in the contact lens case filled with the contact lens care product of the invention.
  • composition of the invention when it is an ophthalmic composition, it may be used as an agent for prevention and/or treatment of keratitis, preferably an agent for prevention and/or treatment of bacterial keratitis, fungal keratitis, Acanthamoeba keratitis, corneal ulcer, corneal phlyctenule or herpetic keratitis, and more preferably an agent for prevention and/or treatment of Acanthamoeba keratitis.
  • the invention also relates to a method for preventing or treating
  • the method of the invention comprises a step of administering the antiprotozoan composition of the invention onto an eye of the patient in need thereof in a therapeutically effective amount.
  • the administrating amount and frequency of the antiprotozoan composition of the invention can be appropriately selected depending on the dosage form, symptom and age of the patient to be administered, and the like.
  • the dosage form is eye drops
  • the eye drops may be instilled once to several times (for example, 1 to 6 times) a day in an amount of one to several drops at a time.
  • the ophthalmologic conditions are preferably keratitis, and more preferably Acanthamoeba keratitis.
  • Micafungin sodium hereinafter, also referred to as "MCFG”; Funguard (registered trademark), for drip infusion, product of Astellas Pharma, Inc.), caspofungin diacetate (hereinafter, also referred to as "CPFG”; Cancidas (registered trademark), Merck & Co.
  • ADFG anidulafungin
  • Pfizer Inc. artemether
  • artemether Tokyo Kasei Kogyo Co., Ltd.
  • quinine Koreano Kagaku Co., Ltd.
  • polyhexanide hydrochloride hereinafter, also referred to as "PHMB”
  • Artesunate was dissolved using phosphate buffer at pH 7.0, and prepared as a test solution to a final concentration of 500 ⁇ g/ml.
  • the Acanthamoeba used was Acanthamoeba castellani ATCC30324
  • A. castellani (hereinafter, also referred to as "A. castellani”). After culturing A. castellani in PYG liquid medium at 25°C for 1 week, the medium was exchanged with cyst-formed medium and culturing was continued for 2 weeks. The A. castellani cysts were recovered, and a 1.7 x 10 6 /ml suspension was prepared with 1/4 Ringer's solution.
  • A. castellani suspension final cyst count: 1.7 x 10 4 /ml
  • test solution which was the exposed test solution, was recovered, the A. castellani cysts were centrifuged and the test solution was removed. To the centrifuged A. castellani cysts was then added 2 ml of 1/4 Ringer's solution to form a suspension which was again centrifuged, and the supernatant was removed before suspension in 1 ml of PYG liquid medium. Solutions diluted 10, 10 2 , 10 3 , 10 4 and 10 5 fold with PYG liquid medium were also prepared.
  • the Log reduction was calculated from these results.
  • the Log reduction is the value representing the logarithm for the degree of reduction in the cell count from the initial inoculated count. For example, a Log reduction of 1 means that the Acanthamoeba count has decreased to 1/10, while a Log reduction of 2 means that the amoeba count has decreased to 1/100.
  • amebicidal effect on Acanthamoeba cyst by combining caspofungin, micafungin or anidulafungin (all candin-based antifungal drugs) with polyhexanide hydrochloride was evaluated. It was investigated whether or not an amebicidal effect against Acanthamoeba cyst is exhibited by each drug with 6 hours of exposure, considering the conditions of use of a contact lens care product such as a multipurpose contact lens care solution.
  • a test solution was prepared according to Pharmacological Test 1.
  • amebicidal effect on Acanthamoeba cyst by combining caspofungin with polyhexanide hydrochloride was evaluated with different concentration groups. It was also investigated whether or not an amebicidal effect against Acanthamoeba cystis exhibited by a caspofungin and polyhexanide hydrochloride combination group with 6 hours of exposure, considering the conditions of use of a contact lens care product such as a multipurpose contact lens care solution.
  • Test solution preparation method A test solution was prepared according to Pharmacological Test 1.
  • antiprotozoan composition of the invention will now be described in greater detail by preparation examples.
  • Tonicity agent q. s. pH regulator q. s.
  • This multipurpose contact lens care solution can be prepared by adding caspofungin diacetate and/or another salt thereof and other additives to sterilized purified water, and thoroughly mixing them.
  • a composition containing caspofungin diacetate, or caspofungin diacetate and other constituent components, may be used by dissolving it in sterilized purified water or dissolving it in sterilized purified water containing all or a portion of the constituent components other than caspofungin diacetate, immediately before use.
  • This eye drop formulation can be prepared by adding caspofungin diacetate and/or another salt thereof and other additives to sterilized purified water, and thoroughly mixing them.
  • a composition containing caspofungin diacetate, or caspofungin diacetate and other constituent components, may be used by dissolving it in sterilized purified water or dissolving it in sterilized purified water containing all or a portion of the constituent components other than caspofungin diacetate, immediately before use.

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Abstract

The present invention relates to an antiprotozoan composition containing caspofungin or its salt and a biguanide compound or its salt.

Description

DESCRIPTION
ANTIPROTOZOAN COMPOSITION CONTAINING CASPOFUNGIN OR ITS SALT AND BIGUANIDE COMPOUND OR ITS SALT
TECHNICAL FIELD
[0001]
The present invention relates to an antiprotozoan composition containing caspofungin or its salt and a biguanide compound or its salt.
BACKGROUND ART
[0002]
Acanthamoeba is a ubiquitous free-living protozoan that exists dimorphically either as a trophozoite or cyst. Its species include A. polyphaga, A. castellanii, A. lenticulata, A. hatchetti, A. astronyxis, A. culbertsoni and A. rhysodes. Acanthamoeba exists as a trophozoite under favorable growth conditions. The trophozoite is highly sensitive to drugs because it has high drug membrane permeability, but in deteriorating growth conditions it transforms into a cyst with a double wall, and Acanthamoeba in the cyst form (hereinafter referred to as "Acanthamoeba cyst") exhibits dryness resistance, heat resistance and chemical resistance. Thus, it was exceedingly difficult to eradicate Acanthamoeba cyst.
[0003]
In recent years, Acanthamoeba keratitis has become noted as an ocular infection associated with contact lens wear, and Acanthamoeba keratitis is an intractable condition involving infection of the cornea by Acanthamoeba, exhibiting symptoms such as hyperemia, blurred vision, and high ophthalmalgia, and in worst cases even loss of vision. Because drugs that exhibit a clear clinical effect against Acanthamoeba cyst currently do not exist on the market, treatment of Acanthamoeba keratitis is very difficult. According to the "Guidelines for Treatment of Infectious Keratitis", a combined use of the methods believed to be even moderately effective is considered to be realistic, and 1) curettage of the corneal lesion, 2) eyedrop administration of putatively effective drugs, 3) systemic administration of the same, and 4) combination therapy involving all three of the above are used for treatment of Acanthamoeba keratitis under present circumstances.
[0004]
Various types of contact lens care products are available on the market for sterilization of bacteria that adhere to soft contact lenses, including multipurpose solutions for contact lens care (hereinafter also referred to as "multipurpose solutions" or "MPS"). As the active ingredient of an MPS, polyhexanide hydrochloride is generally incorporated, but polyhexanide hydrochloride is known to have a weak amebicidal effect against Acanthamoeba, and especially Acanthamoeba cyst.
[0005]
One drug considered to have amebicidal activity is caspofungin, described in Non-patent Document 1 as having an amebicidal effect against Acanthamoeba cyst upon exposure at high concentration for 24 hours or longer.
[0006]
Patent Document 1 also discloses that the biguanide compound polyhexanide hydrochloride has an anti-Acanthamoeba effect. However, the amebicidal effect of polyhexanide hydrochloride incorporated in commercially available MPS is weak, as mentioned above.
[0007]
As described above, caspofungin and biguanide compounds are each known to have weak amebicidal effects, but no composition is known that combines caspofungin and a biguanide compound and exhibits a powerful amebicidal effect.
In addition, none of the prior art documents disclose a contact lens care product that includes both caspofungin or its salt and a biguanide compound, or an ophthalmic composition for prevention and/or treatment of keratitis, nor do they describe or suggest an effect against Acanthamoeba and particularly Acanthamoeba cyst.
Thus, a strong demand exists for the development of a composition with a higher antiprotozoan effect against protozoa such as Acanthamoeba cyst, and especially a contact lens care product such as an MPS having such an effect, or an ophthalmic composition useful as an agent for prevention and/or treatment of Acanthamoeba keratitis caused by protozoan and especially Acanthamoeba.
PRIOR ART DOCUMENTS
Patent document
[0008]
[Patent document 1] International Patent Publication WO No. 97/36487 Pamphlet
Non-patent document
[0009]
[Non-patent document 1] Sabrina Bouyer et al., Journal of Antimicrobial Chemotherapy, 2007, 59, 122-124
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0010]
It is an object of the present invention to provide an antiprotozoan composition that exhibits a powerful antiprotozoan effect against protozoa such as Acanthamoeba, and especially Acanthamoeba cyst. More specifically, it is an object of the invention to provide a novel contact lens care product, such as an MPS, having a powerful antiprotozoan effect, and an ophthalmic composition that is useful as an agent for prevention and/or treatment of diseases associated with protozoa such as Acanthamoeba, including keratitis, and especially Acanthamoeba keratitis.
Means for Solving the Problems
[0011]
As a result of intensive research on improving amebicidal effects against protozoa such as Acanthamoeba, and especially Acanthamoeba cyst, the present inventors have found that using caspofungin or its salt and a biguanide compound or its salt in combination markedly augments the amebicidal effect compared to the use of either alone, and have completed this invention.
[0012]
Specifically, the invention relates to the following.
(1) An antiprotozoan composition containing caspofungin or its salt and a biguanide compound or its salt.
(2) The antiprotozoan composition according to (1), which is an aqueous
composition.
(3) The antiprotozoan composition according to (1) or (2), wherein the caspofungin or its salt is caspofungin diacetate.
(4) The antiprotozoan composition according to any of (1) to (3), wherein the biguanide compound or its salt is at least one compound selected from the group consisting of polyhexanide, chlorhexidine, alexidine, and their salts.
(5) The antiprotozoan composition according to any of (1) to (4), wherein the biguanide compound or its salt is polyhexanide hydrochloride.
(6) The antiprotozoan composition according to any of (1) to (5), wherein the protozoan is at least one protozoan selected from the group consisting of Amoebida and Microsporida. (7) The antiprotozoan composition according to any of (1) to (5), wherein the protozoan is an Amoebida.
(8) The antiprotozoan composition according to any of (1) to (5), wherein the protozoan is an Acanthamoeba.
(9) The antiprotozoan composition according to any of (1) to (8), which is a contact lens care product.
(10) The antiprotozoan composition according to (9), wherein the contact lens care product is a multipurpose contact lens care solution.
(1 1) The antiprotozoan composition according to any of (1) to (8), which is an ophthalmic composition.
(12) The antiprotozoan composition according to (1 1), which is an agent for prevention and/or treatment of keratitis.
(13) The antiprotozoan composition according to (12), wherein the keratitis is
Acanthamoeba keratitis.
[0013]
The invention further relates to the following.
(14) A method of cleaning, rinsing, disinfecting and/or storing a contact lens, the method comprising a step of contacting the contact lens with the contact lens care product according to (9) or (10).
(15) A method of disinfecting a contact lens case or contact lens, the method comprising a step of contacting the contact lens case or contact lens with the contact lens care product according to (9) or (10).
(16) A method of eliminating or killing protozoa adhering to a contact lens case or contact lens, the method comprising a step of contacting the contact lens case or contact lens with the contact lens care product according to (9) or (10).
(17) A method for preventing or treating ophthalmologic conditions in a patient, the method comprising a step of administering the antiprotozoan composition according to any of (1) to (8) onto an eye of the patient in need thereof in a therapeutically effective amount.
(18) The method according to (17), wherein the ophthalmologic condition is keratitis.
( 19) The method according to ( 18), wherein the keratitis is Acanthamoeba keratitis.
(20) Use of the antiprotozoan composition according to any of (1) to (8) for a contact lens care product.
(21) The use according to (20), wherein the contact lens care product is a multipurpose contact lens care solution.
(22) Use of the antiprotozoan composition according to any one of (1) to (8) for cleaning, rinsing, disinfecting and/or storing a contact lens.
Effect of the Invention
[0014]
According to the invention there is provided an antiprotozoan composition that exhibits a powerful antiprotozoan effect against protozoa such as Acanthamoeba, and especially Acanthamoeba cyst. That is, by including both caspofungin or its salt and a biguanide compound or its salt, their use for brief periods and at low concentration can eradicate protozoa such as Acanthamoeba and minimize adhesion of protozoa such as Acanthamoeba onto contact lenses more adequately than using either one alone, and it is thus possible to provide a contact lens care product such as a multipurpose contact lens care solution suited for the conditions of use. In addition, because the
composition has powerful antiprotozoan activity compared to using either caspofungin or its salt or a biguanide compound or its salt alone, it is possible to provide an ophthalmic composition that is useful as an agent for prevention and/or treatment of diseases associated with protozoa, and especially Acanthamoeba, such as keratitis and especially Acanthamoeba keratitis.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015]
[Fig. 1] This shows the results of evaluating the amebicidal effects of caspofungin, micafungin, anidulafungin, artesunate, artemether, quinine and polyhexanide hydrochloride on Acanthamoeba cyst, in Pharmacological Test 1.
[Fig. 2] This shows the results of evaluating the amebicidal effects on Acanthamoeba cyst by combining caspofungin, micafungin or anidulafungin with polyhexanide hydrochloride, in Pharmacological Test 2.
[Fig. 3] This shows the results of evaluating the amebicidal effect on Acanthamoeba cyst by combining caspofungin with polyhexanide hydrochloride in different concentration groups, in Pharmacological Test 3.
MODE FOR CARRYING OUT THE INVENTION
[0016]
The invention will now be explained below in detail.
[0017]
In the present specification, "protozoan" refers to a member of Amoebida or
Microsporida. Specific examples of Amoebida include Acanthamoeba, Naegleria, Hartmannella and Vannella.
[0018]
In the present specification, "Acanthamoeba" refers to A. astronyxis, A.
comandoni, A. divionensis, A. griffini, A. hatchetti, A. healyi, A. jacobsi, A. lenticulata, A. culbertsoni, A. lugdunensis, A. mauritaniensis, A, palestinensis, A. pearcei, A.
polyphaga, A. pustulosa, A. quina, A. rhysodes, A. royreba, A. terricola, A. triangularis, A. tubiashi, A. polyphaga, A. castellani and the like.
[0019]
In the present specification, " Microsporida" refers to Encephalitozoon cuniculi, Encephalitozoon. hellem, Encephalitozoon. intestinalis, Vittaforma corneae, Anncaliia algerae, Microsporidium (M. ceylonensis and M. africanum), Nosema sp. (N. ocularum), Anncaliia connori, Trachipleistophora hominis, and the like.
[0020]
In the present specification, "antiprotozoan effect" means an effect of totally or partially eradicating or eliminating a protozoan, or inhibiting growth of a protozoan.
[0021]
In the present specification, "amebicidal effect" means an effect of totally or partially eradicating or eliminating an amoeba, or inhibiting growth of an amoeba.
The term "amebicidal effect" includes an amebicidal effect against Acanthamoeba (also referred to as "anti-Acanthamoeba effect"), an amebicidal effect against Acanthamoeba cyst (also referred to as "anti-Acanthamoeba cyst effect"), an eradicating effect against Acanthamoeba trophozoites and/or cysts, and an inhibiting effect on cyst formation of Acanthamoeba.
[0022]
In the present specification, "antiprotozoan composition" refers to a
composition that can exhibit an antiprotozoan effect against a total or partial protozoa, typically Amoebida and Microsporida.
[0023]
In the present specification, "contact lens" includes soft contact lenses, hard contact lenses and oxygen-permeable hard contact lenses. The term "soft contact lens" includes both ionic and nonionic types, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses (soft contact lenses that differ from silicone hydrogel lenses).
[0024]
In the present specification, "contact lens care product" means any composition that is used for care of contact lenses, such as a contact lens inserting solution, contact lens cleaning solution, contact lens rinsing solution, contact lens antiseptic solution, contact lens storage solution or multipurpose contact lens care solution(multipurpose solution or MPS).
[0025]
In the present specification, a "multipurpose contact lens care solution"
(multipurpose solution or MPS) refers to a contact lens care product that can accomplish two or more operations from among cleaning, rinsing, disinfection or storage of contact lenses, with a single solution.
[0026]
In the present specification, "ophthalmic composition" refers to a medical composition for ophthalmic use, such as an ophthalmic composition which may be eye drops (including eye drops for contact lenses), an eye wash (including an eye wash for contact lenses), or an eye ointment.
[0027]
In the present specification, keratitis refers to, for example, bacterial keratitis, fungal keratitis, Acanthamoeba keratitis, corneal ulcer, corneal phlyctenule or herpetic keratitis. Acanthamoeba keratitis is keratitis caused by Acanthamoeba.
[0028]
The antiprotozoan composition of the invention is any composition that contains caspofungin or its salt and a biguanide compound or its salt.
The antiprotozoan composition of the invention may be a solution dissolved in a particular solvent, and preferably it is an aqueous composition, as a water-soluble solution.
[0029]
The caspofungin in the composition of the invention is the compound represented by the following formula (1).
[Chemical Formula 1]
Figure imgf000009_0001
Caspofungin (CAS Accession No. 162808-62-0) is a kind of macrocyclic lipopeptide echinocandin, and it is also referred to as either caspofungin or 1-[(4R, 5S)-5-[(2-aminoethyl)amino]-N2-( 10R, 12S- 10, 12-dimethyl- l-oxotetradecyl)-4-hydroxy -L-omithine]-5-[(3R)-3-hydroxy-L-ornithine]pneumocandin B0.
[0030]
In the composition of the invention, a salt of caspofungin is not particularly restricted so long as it is a pharmacologically or physiologically acceptable salt, and for example, it may be a salt of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or boric acid; or a salt of an organic acid such as acetic acid, citric acid, tartaric acid, propionic acid, succinic acid, oxalic acid, malic acid, maleic acid, lactic acid, glutamic acid or pamoic acid. Preferred are acetic acid salts, propionic acid salts and lactic acid salts, with diacetic acid salts being more preferred.
These caspofungin salts may be used alone or they may be used in any combinations of two or more kinds.
[0031]
According to the invention, caspofungin or its salt may also be in the form of a hydrate or solvate.
[0032]
Furthermore, when geometric isomers or optical isomers of caspofungin exist, these isomers are also within the scope of the invention.
[0033]
When proton tautomers of caspofungin exist, these tautomers are also included in the invention.
[0034] When caspofungin or its salt, or a hydrates or solvate thereof, exists as polymorphic crystals or a polymorphic crystal group (a polymorphic crystal system), such polymorphic crystals and polymorphic crystal groups (polymorphic crystal systems) are also included within the scope of the invention. A polymorphic crystal group (polymorphic crystal system) is the individual crystalline form at each stage, in cases where the crystalline form changes, and the overall crystalline form during that process, depending on the conditions and state (including the state of formulation) of production, crystallization and storage of the crystals.
[0035]
Caspofungin or its salt, or a hydrate or solvate thereof, can be produced by a common method in the field of synthetic organic chemistry. For example, it can be produced by the method described in US5378804, US5552521, US5952300 or
US6136783. There may also be used a product commercially available under a trade name such as Cancidas (Registered trademark) (Merck & Co., Inc.).
[0036]
The content ratio of caspofungin or its salt in the composition of the invention is not particularly restricted so long as it is a sufficient concentration for exhibiting the desired antiprotozoan effect, and it may be appropriately set according to its kind, the kind of biguanide compound or its salt used in combination with it, and the kind of pharmaceutical preparation of the composition. As an example in the case of an aqueous composition, and particularly for eye drops, the content ratio of caspofungin or its salt with respect to the total aqueous composition will usually be 0.01 to 10% (w/v), preferably 0.05 to 10% (w/v) and more preferably 0.1 to 5% (w/v), as the total concentration in terms of the concentration of caspofungin itself. For an MPS, the content ratio of caspofungin or its salt with respect to the total aqueous composition will usually be 0.000005 to 0.1% (w/v), preferably 0.00005 to 0.05% (w/v) and more preferably 0.0001 to 0.01% (w/v), as the total concentration.
[0037]
The biguanide compound or its salt in the composition of the invention is any compound having at least one biguanide group [-NHC(=NH)NHC(=NH)NH-].
[0038]
The biguanide compound or its salt in the composition of the invention is not particularly restricted so long as it is a pharmacologically or physiologically acceptable compound. Examples of biguanide compounds and their salts include polyhexanide and its salts (hereinafter also referred to as "polyhexamethylene biguanide" or "PHMB"), chlorhexidine and its salts or alexidine and its salts, with polyhexanide and its salts being preferred and polyhexanide hydrochloride being more preferred.
[0039]
Polyhexanide is a compound represented by the following formula (2).
[ emical Formula 2]
Figure imgf000011_0001
In the formula, n is a numeral representing the number of repeating units in parentheses, which may be an integer of 1 to 500, preferably an integer of 2 to 200, more preferably an integer of 4 to 100 and even more preferably an integer of 4 to 20.
[0040]
In the composition of the invention, a salt of polyhexanide is not particularly restricted so long as it is a pharmacologically or physiologically acceptable salt, and for example, it may be a salt of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or boric acid; or a salt of an organic acid such as acetic acid, gluconic acid, maleic acid, ascorbic acid, stearic acid, tartaric acid or citric acid, and preferably an inorganic acid salt, with hydrochloride being more preferred. These polyhexanide salts may be used alone or they may be used in any combinations of two or more kinds.
[0041]
Chlorhexidine is the compound represented by the following formula (3). [Chemical Formula 3
Figure imgf000011_0002
[0042]
In the composition of the invention, a salt of chlorhexidine is not particularly restricted so long as it is a pharmacologically or physiologically acceptable salt, and for example, it may be a salt of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or boric acid; or a salt of an organic acid such as acetic acid, gluconic acid, maleic acid, ascorbic acid, stearic acid, tartaric acid or citric acid, and preferably a hydrochloride, acetate or gluconate, with gluconates being more preferred. These chlorhexidine salts may be used alone or they may be used in any combinations of two or more kinds.
[0043]
Alexidine is the compound represented by the following formula (4). [Chemical Formula 4]
Figure imgf000012_0001
[0044]
In the composition of the invention, a salt of alexidine is not particularly restricted so long as it is a pharmacologically or physiologically acceptable salt, and for example, it may be a salt of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or boric acid; or a salt of an organic acid such as acetic acid, gluconic acid, maleic acid, ascorbic acid, stearic acid, tartaric acid or citric acid, and preferably a hydrochloride, acetate, or gluconate, with hydrochlorides being preferred and dihydrochlorides being even more preferred. These alexidine salts may be used alone or they may be used in any combinations of two or more kinds.
[0045]
The biguanide compound or its salt in the composition of the invention may also be in the form of a hydrate or solvate.
When geometric isomers or optical isomers of a biguanide compound exist, these isomers are also within the scope of the invention.
[0047]
When proton tautomers of a biguanide compound exist, these tautomers are also included in the invention.
[0048]
When a biguanide compound or its salt, or hydrates or solvates thereof, exist as polymorphic crystals or a polymorphic crystal group (a polymorphic crystal system), such polymorphic crystals and polymorphic crystal groups (polymorphic crystal systems) are also included within the scope of the invention. A polymorphic crystal group (polymorphic crystal system) is the individual crystalline form at each stage, in cases where the crystalline form changes, and the overall crystalline form during that process, depending on the conditions and state (including the state of pharmaceutical preparation) of production, crystallization and storage of the crystals.
[0049]
The biguanide compound or its salt in the composition of the invention may be used alone, or in any combinations of two or more kinds.
[0050] The biguanide compound can be produced by a common method in the field of synthetic organic chemistry. A biguanide compound used may also be any of the following commercially available products.
[0051]
As polyhexanide hydrochloride compounds, those which are commercially available under the trade names Proxel (registered trademark) IB from Zeneca, or Lonzabac (registered trademark) BG from Lonza, Japan may be used.
[0052]
As chlorhexidine gluconate compounds, those which are commercially available under the trade name Hibitane (registered trademark) from Dainippon
Sumitomo Pharma Co., Ltd. may be used.
[0053]
As alexidine dihydrochloride compounds, those which are commercially available from Sigma-Aldrich Japan, KK., for example, may be used.
[0054]
The content ratio of a biguanide compound or its salt in the composition of the invention is not particularly restricted so long as it is a sufficient concentration for exhibiting the desired antiprotozoan effect, and it may be appropriately set according to the kind of biguanide compound or its salt, the kind of caspofungin or its salt used in combination with it, and the kind of pharmaceutical preparation of the composition. As an example in the case of an aqueous composition, and particularly for eye drops, the content ratio of the biguanide compound or its salt with respect to the total aqueous composition will usually be 0.001 to 1% (w/v), preferably 0.005 to 0.5% (w/v) and more preferably 0.01 to 0.2% (w/v), as the total concentration in terms of the concentration of the biguanide compound itself. For an MPS, in particular, the content ratio of the biguanide compound or its salt with respect to the total aqueous composition will usually be 0.000005 to 0.01% (w/v), preferably 0.00001 to 0.005% (w/v) and more preferably 0.00005 to 0.001% (w/v), as the total concentration.
[0055]
The proportion of the biguanide compound or its salt with respect to caspofungin or its salt in the composition of the invention is not particularly restricted so long as it is an amount sufficient to exhibit the desired antiprotozoan effect. As an example for an aqueous composition, and especially for eye drops, the total amount of biguanide compound or its salt to 1 part by weight as the total of caspofungin or its salt will usually be 0.0005 to 50 parts by weight, preferably 0.001 to 10 parts by weight and more preferably 0.002 to 5 parts by weight. For an MPS, in particular, the total amount of biguanide compound or its salt to 1 part by weight as the total of caspoiungin or its salt will usually be 0.00005 to 100 parts by weight, preferably 0.0001 to 50 parts by weight and more preferably 0.005 to 10 parts by weight.
[0056]
Polidronium chloride (CAS Accession No. 75345-27-6) may be used instead of a biguanide compound or its salt in the composition of the invention.
[0057]
Other additives may be included in the composition of the invention as necessary, examples including additives such as buffering agents, surfactants, tonicity agents, antiseptic agents, pH regulators, thickening agents, chelating agents, stabilizers, protein removing agents and the like, for an aqueous composition.
[0058]
Buffering agents are not particularly restricted so long as they are
pharmacologically or physiologically acceptable, and examples include at least one kind selected from phosphoric acid, phosphoric acid salts such as sodium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate, potassium phosphate, potassium dihydrogenphosphate and dipotassium hydrogenphosphate; boric acid, borax, boric acid salts such as sodium borate and potassium borate; citric acid salts such as sodium citrate and disodium citrate; acetic acid salts such as sodium acetate and potassium acetate; carbonic acid salts such as sodium carbonate and sodium hydrogencarbonate; or ε-aminocaproic acid and trometamol, among which there are preferred at least one kind selected from phosphoric acid, sodium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate, potassium phosphate, potassium dihydrogenphosphate and dipotassium hydrogenphosphate, with sodium dihydrogenphosphate and disodium hydrogenphosphate being more preferred.
[0059]
When a buffering agent is to be added to an aqueous composition, the content ratio of the buffering agent is appropriately set according to the kind of buffering agent, the kinds of other compounding ingredients and their content ratios, and the form of pharmaceutical preparation of the aqueous composition. The content ratio of a buffering agent in the composition of the invention will usually be 0.001 to 5% (w/v), preferably 0.003 to 3% (w/v) and more preferably 0.03 to 2% (w/v), as the total concentration.
[0060]
There are no particular restrictions on a surfactant so long as it is a
pharmacologically or physiologically acceptable one, and examples include at least one kind selected from nonionic surfactants, including POE sorbitan fatty acid esters such as POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monopalmitate (polysorbate 40), POE (20) sorbitan monostearate (polysorbate 60), POE (20) sorbitan tristearate (polysorbate 65) and POE (20) sorbitan monooleate (polysorbate 80); POE- POP block copolymers such as Poloxamer 407, Poloxamer 235, Poloxamer 188,
Poloxamer 403, Poloxamer 237 and Poloxamer 124; POE hydrogenated castor oils such as POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60); POE alkyl ethers such as POE (9) lauryl ether; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether; and POE alkylphenyl ethers such as POE (10) nonylphenyl ether (where POE is polyoxyethylene and POP is polyoxypropylene, and the numbers in parentheses are the addition mole numbers); amphoteric surfactants including
alkyldiaminoethylglycine and its salts (such as hydrochlorides); anionic surfactants including alkylbenzenesulfonic acid salts, alkylsulfuric acid salts,
polyoxyethylenealkylsulfuric acid salts, aliphatic a-sulfomethyl esters and
a-olefinsulfonic acids; and cationic surfactants such as benzalkonium chloride and benzethonium chloride, and preferably at least one kind selected from nonionic surfactants, and more preferably POE sorbitan fatty acid esters, POE hydrogenated castor oils and POE- POP block copolymers, and even more preferably at least one kind selected from polysorbate 80, polyoxyethylene hydrogenated castor oil 60 and
Poloxamer 407.
[0061]
When a surfactant is to be added to an aqueous composition, the content ratio is appropriately set according to the kind of surfactant, the kinds of other compounding ingredients and their content ratios, and the form of pharmaceutical preparation of the aqueous composition. The content ratio of a surfactant in the composition of the invention will usually be 0.001 to 10% (w/v), preferably 0.005 to 5% (w/v) and more preferably 0.005 to 3% (w/v), as the total concentration.
[0062]
Tonicity agents are not particularly restricted so long as they are
pharmacologically or physiologically acceptable, and examples include at least one selected from disodium hydrogenphosphate, sodium dihydrogenphosphate, potassium dihydrogenphosphate, sodium hydrogensulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium hydrogencarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin and propylene glycol.
[0063] When a tonicity agent is to be incorporated into an aqueous composition, the content ratio of the tonicity agent may be appropriately set according to the kind of tonicity agent, the kinds and concentrations of other compounding ingredients, and the form of pharmaceutical preparation of the antiprotozoan composition. For an aqueous composition, the osmotic pressure will usually be 200 to 450 milliosmoles (mOSm) and preferably 250 to 370 milliosmoles (mOSm).
[0064]
There are no particular restrictions on pH regulators so long as they are pharmacologically or physiologically acceptable, and examples include at least one selected from hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide and ammonium hydroxide. When a pH regulator is to be added to an aqueous composition, the content ratio of the pH regulator may be appropriately set according to the kind of pH regulator, the kinds and amounts of other compounding ingredients, and the form of preparation of the antiprotozoan composition.
[0065]
When the composition of the invention is an aqueous composition, the pH is not particularly restricted so long as it is within a pharmacologically or physiologically acceptable range, but it will usually be 4.0 to 9.5, preferably 5.0 to 9.0, more preferably 5.0 to 8.5 and even more preferably 5.0 to 7.5.
[0066]
There are no particular restrictions on thickening agents so long as they are pharmacologically or physiologically acceptable, and examples include at least one selected from among hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose and carboxymethyl cellulose.
[0067]
When a thickening agent is to be added to an aqueous composition, the content ratio of the thickening agent is appropriately set according to the kind of thickening agent, the kinds of other compounding ingredients and their content ratios, and the form of pharmaceutical preparation of the aqueous composition. The thickening agent concentration will usually be 0.01 to 10% (w/v) and preferably 0.05 to 3% (w/v), as the total concentration.
[0068]
Chelating agents are not particularly restricted so long as they are
pharmacologically or physiologically acceptable, and examples include at least one selected from sodium edetate, sodium citrate and condensed sodium phosphate.
[0069] When a chelating agent is to be added to an aqueous composition, the content ratio of the chelating agent may be appropriately set according to the kind of chelating agent, the kinds of other compounding ingredients and their content ratios, and the form of pharmaceutical preparation of the aqueous composition. The content ratio of the chelating agent will usually be 0.002 to 0.5% (w/v) and preferably 0.005 to 0.1% (w/v), as the total concentration.
[0070]
There are no particular restrictions on stabilizers so long as they are pharmacologically or physiologically acceptable, and the aforementioned buffering agents or chelating agents can be incorporated suitably in appropriate amounts.
[0071]
As a protein removing agent, a proteolytic enzyme may also be incorporated suitably in an appropriate amount.
[0072]
When the composition of the invention is an aqueous composition, the composition may contain water at usually 20% or greater, preferably 50% or greater, more preferably 80% or greater arid even more preferably 90% or greater, with respect to the total amount of the composition. The water used is preferably distilled water, purified water or sterilized purified water. .
[0073]
Examples of form of the pharmaceutical preparation of the composition of the invention include ophthalmic compositions such as eye drops (including contact lens eye drops), eye washes (including contact lens eye washes) and eye ointment; and contact lens care products such as contact lens inserting solutions, contact lens cleaning solutions, contact lens rinsing solutions, contact lens antiseptic solutions, contact lens storage solutions and multipurpose solutions for contact lens care (multipurpose solutions or MPS). Ophthalmic compositions and contact lens care products are preferred, eye drops and contact lens care products are more preferred, and eye drops, contact lens cleaning solutions, contact lens rinsing solutions, contact lens antiseptic solutions, contact lens storage solutions and multipurpose solutions for contact lens care (multipurpose solutions or MPS) are even more preferred.
[0074]
The antiprotozoan composition of the invention may also be in the form of a freeze-dried formulation that is reconstituted with water immediately prior to use.
[0075]
The antiprotozoan composition of the invention may be prepared as any form of the pharmaceutical preparations as mentioned above. For an aqueous composition as one example, it may be produced by dissolving the caspofungin or its salt and the biguanide compound or its salt, and if necessary the additives such as a buffering agent, surfactant, tonicity agent, antiseptic agent, pH regulator, thickening agent, chelating agent, stabilizer and protein removing agent, in a solvent such as water.
[0076]
When the composition of the invention is a contact lens care product, it may be used as any of various types of contact lens care products for soft contact lenses, hard contact lenses and oxygen-permeable hard contact lenses, and it is preferably used for soft contact lenses.
[0077]
The invention also relates to a method of cleaning, rinsing, disinfecting and/or storing a contact lens. The method of the invention comprises a step of contacting the contact lens with the contact lens care product of the invention. Here, the treatment time for contacting a contact lens with the contact lens care product according to the present invention is not particularly restricted, but usually between 5 minutes and 24 hours, and preferably between 1 and 12 hours. The way of contacting the contact lens with the contact lens care product of the invention is not particularly restricted. For example, it may be performed by the following ways: In the case of cleaning, the contact lens care product of the invention is dropped by several drops on a contact lens removed from an eye, then the contact lens is rubbed for several seconds to several tens of seconds while the contact lens being sandwiched between thumb and forefinger, or being kept on a palm. In the case of rinsing, the contact lens is rinsed with several milliliters of the contact lens care product of the invention. In the case of disinfecting and storing, the contact lens is immersed in the contact lens case filled with the contact lens care product of the invention.
[0078]
The invention also relates to a method of disinfecting a contact lens case or contact lens. The method of the invention comprises a step of contacting the contact lens case or contact lens with the contact lens care product of the invention. Here, the treatment time for contacting the contact lens case or contact lens with the contact lens care product of the invention is not particularly restricted, but usually between 5 minutes and 24 hours, and preferably between 1 and 12 hours. The way of contacting the contact lens case or contact lens with the contact lens care product of the invention is not particularly restricted. For example, the contact lens is immersed in the contact lens case filled with the contact lens care product of the invention. [0079]
The invention further relates to a method of eliminating or killing protozoa adhering to a contact lens case or contact lens. The method of the invention comprises a step of contacting the contact lens case or contact lens with the contact lens care product of the invention. Here, the treatment time for contacting the contact lens case or contact lens with the contact lens care product of the invention is not particularly restricted, but usually between 5 minutes and 24 hours, and preferably between 1 and 12 hours. The way of contacting the contact lens case or contact lens with the contact lens care product of the invention is not particularly restricted. For example, the contact lens is immersed in the contact lens case filled with the contact lens care product of the invention.
[0080]
When the composition of the invention is an ophthalmic composition, it may be used as an agent for prevention and/or treatment of keratitis, preferably an agent for prevention and/or treatment of bacterial keratitis, fungal keratitis, Acanthamoeba keratitis, corneal ulcer, corneal phlyctenule or herpetic keratitis, and more preferably an agent for prevention and/or treatment of Acanthamoeba keratitis.
[0081] .
The invention also relates to a method for preventing or treating
ophthalmologic conditions in a patient. The method of the invention comprises a step of administering the antiprotozoan composition of the invention onto an eye of the patient in need thereof in a therapeutically effective amount. The administrating amount and frequency of the antiprotozoan composition of the invention can be appropriately selected depending on the dosage form, symptom and age of the patient to be administered, and the like. When the dosage form is eye drops, for example, the eye drops may be instilled once to several times (for example, 1 to 6 times) a day in an amount of one to several drops at a time. The ophthalmologic conditions are preferably keratitis, and more preferably Acanthamoeba keratitis. EXAMPLES 1
[0082]
Pharmacological test results and preparation examples are provided below. They are provided for understanding well the present invention, and are not intended to restrict the scope of the invention.
[0083]
[Pharmacological Test 1] The amebicidal effects of caspofungin, micafungin, anidulafungin
(candin-based antifungal drugs), artesunate, artemether, quinine (antimalarial drugs) and polyhexanide hydrochloride on Acanthamoeba cyst were evaluated.
[0084]
(Test solution preparation method)
Micafungin sodium (hereinafter, also referred to as "MCFG"; Funguard (registered trademark), for drip infusion, product of Astellas Pharma, Inc.), caspofungin diacetate (hereinafter, also referred to as "CPFG"; Cancidas (registered trademark), Merck & Co. Inc.), anidulafungin (hereinafter, also referred to as "ADFG"; Eraxis (registered trademark), Pfizer Inc.), artemether (Tokyo Kasei Kogyo Co., Ltd.), quinine (Kanto Kagaku Co., Ltd.) and polyhexanide hydrochloride (hereinafter, also referred to as "PHMB") were each dissolved in 1/4 Ringer's solution (Wako Pure Chemical Industries, Ltd.), prepared as test solutions with artemether at a final concentration of 100 μg/ml, and the other agents at 500 μg/ml. Artesunate (Tokyo Kasei Kogyo Co., Ltd.) was dissolved using phosphate buffer at pH 7.0, and prepared as a test solution to a final concentration of 500 μg/ml.
[0085]
(Test method)
A test method was conducted according to the method indicated in the
December 16, 2009 Report by the independent regulatory body, National Consumer Affairs Center of Japan, under "Disinfecting functions of soft contact lens disinfectants against Acanthamoeba - based on the investigation on the condition of use"
(http://www.kokusen.go.jp/test/data/s_test/n-20091216 1.html).
The Acanthamoeba used was Acanthamoeba castellani ATCC30324
(hereinafter, also referred to as "A. castellani"). After culturing A. castellani in PYG liquid medium at 25°C for 1 week, the medium was exchanged with cyst-formed medium and culturing was continued for 2 weeks. The A. castellani cysts were recovered, and a 1.7 x 106/ml suspension was prepared with 1/4 Ringer's solution.
To 9.9 ml of test solution was added 0.1 ml of A. castellani suspension (final cyst count: 1.7 x 104/ml), for exposure for a fixed period of time (n = 3). As a control group there was used 1/4 Ringer's solution and phosphate buffer at pH 7.0 instead of the test solution.
A 1 ml portion of test solution, which was the exposed test solution, was recovered, the A. castellani cysts were centrifuged and the test solution was removed. To the centrifuged A. castellani cysts was then added 2 ml of 1/4 Ringer's solution to form a suspension which was again centrifuged, and the supernatant was removed before suspension in 1 ml of PYG liquid medium. Solutions diluted 10, 102, 103, 104 and 105 fold with PYG liquid medium were also prepared.
Each diluted solution was dispensed at 200 μΐ each into 4 wells of a 96-well plate, and cultured at 25°C for 2 weeks. The presence of any growth was observed under a microscope, and the survival rate of Acanthamoeba was calculated by the Spearman-Karbar formula.
The Log reduction was calculated from these results. The Log reduction is the value representing the logarithm for the degree of reduction in the cell count from the initial inoculated count. For example, a Log reduction of 1 means that the Acanthamoeba count has decreased to 1/10, while a Log reduction of 2 means that the amoeba count has decreased to 1/100. The Spearman-Karbar formula is as follows. Spearman-Karber formula: logi0 (mean survival) = x0-d/2+d x∑(rj/ni)
x0: logio (Inverse of minimum dilution stage in which growth was seen in all of the wells)
d: log10 (Dilution factor), (wherein d = 1)
η: Number of wells in which growth was observed at each dilution stage. The minimum dilution stage at which growth was observed in all of the wells is defined as i = 0.
nj: Total number of wells at each dilution stage, (wherein ¾ = 4).
[0086]
(Test results)
The results are shown in Fig. 1.
The Log reduction for polyhexanide hydrochloride, as a component of commercially available multipurpose contact lens care solutions, was approximately 1 after 24 hours of exposure, and the Acanthamoeba count was reduced to approximately 1/10.
On the other hand, the Log reduction after 24 hours of exposure to caspofungin was approximately 2.8 and the Acanthamoeba count was reduced to approximately 1/630, and therefore a clear amebicidal effect was observed. On the other hand, virtually no such effect was observed with micafungin and anidulafungin which are candin-based antifungal drugs, of which caspofungin is a member, or artesunate, artemether or quinine, which are antimalarial drugs.
[0087]
[Pharmacological Test 2]
The amebicidal effect on Acanthamoeba cyst by combining caspofungin, micafungin or anidulafungin (all candin-based antifungal drugs) with polyhexanide hydrochloride was evaluated. It was investigated whether or not an amebicidal effect against Acanthamoeba cyst is exhibited by each drug with 6 hours of exposure, considering the conditions of use of a contact lens care product such as a multipurpose contact lens care solution.
[0088]
(Test solution preparation method)
A test solution was prepared according to Pharmacological Test 1.
[0089]
(Test method)
According to the Pharmacological Test 1, a test was carried out with the drug exposure time of 6 hours.
[0090]
(Test results)
The results are shown in Fig. 2.
An augmented amebicidal effect against Acanthamoeba cyst was observed with the combined use of caspofungin (30 μg/ml) and polyhexanide hydrochloride (1 μg/ml). The caspofungin and polyhexanide hydrochloride combination group also exhibited this effect with 6 hours of exposure. In other words, the caspofungin and polyhexanide hydrochloride combination group did not require 24 hours or longer exposure, but exhibited the effect with an exposure time suited for the conditions of use of a contact lens care products such as a multipurpose contact lens care solution.
On the other hand, almost no augmenting of the amebicidal effect against Acanthamoeba cyst was observed with combined use of either micafungin or anidulafungin with polyhexanide hydrochloride. This indicates that the antiprotozoan effect is specifically augmented by the combined use of caspofungin or its salt and a biguanide compound or its salt.
[0091]
[Pharmacological Test 3]
The amebicidal effect on Acanthamoeba cyst by combining caspofungin with polyhexanide hydrochloride was evaluated with different concentration groups. It was also investigated whether or not an amebicidal effect against Acanthamoeba cystis exhibited by a caspofungin and polyhexanide hydrochloride combination group with 6 hours of exposure, considering the conditions of use of a contact lens care product such as a multipurpose contact lens care solution.
[0092]
(Test solution preparation method) A test solution was prepared according to Pharmacological Test 1.
[0093]
(Test method)
According to the Pharmacological Test 1 , a test was carried out with the drug exposure time of 6 hours.
[0094]
(Test results)
The results are shown in Fig. 3.
An augmented amebicidal effect against Acanthamoeba cyst was observed with the combined use of caspofungin (10 μg/ml or 30 μg/ml) and polyhexanide hydrochloride (1 μg/ml). Similar to Pharmacological Test 2, the caspofungin and polyhexanide hydrochloride combination group did not require 24 hours or longer exposure, but exhibited the effect with an exposure time suited for the conditions of use of a contact lens care product such as a multipurpose contact lens care solution.
The results of Pharmacological Tests 1 to 3 confirmed that virtually no antiprotozoan effect is observed 1) when micafungin or anidulafungin, which are candin-based antifungal drugs of which caspofungin and its salts are members, or the antimalarial drugs artesunate, artemether and quinine are each used alone, 2) when micafungin is used in combination with a biguanide compound such as polyhexanide hydrochloride or 3) when anidulafungin is used in combination with a biguanide compound such as polyhexanide hydrochloride, but that it is specifically observed when caspofungin or its salt is used in combination with a biguanide compound such as polyhexanide hydrochloride.
[0095]
[Preparation Examples]
The antiprotozoan composition of the invention will now be described in greater detail by preparation examples.
[0096]
Formulation Example 1 : Multipurpose contact lens care solution (in 100 ml)
Caspofungin diacetate 3 mg
Polyhexanide hydrochloride 0.1 mg
Disodium edetate 50 mg
Boric acid 500 mg
Surfactant 500 mg
Tonicity agent q. s. pH regulator q. s.
Sterilized purified water q. s.
[0097]
This multipurpose contact lens care solution can be prepared by adding caspofungin diacetate and/or another salt thereof and other additives to sterilized purified water, and thoroughly mixing them. A composition containing caspofungin diacetate, or caspofungin diacetate and other constituent components, may be used by dissolving it in sterilized purified water or dissolving it in sterilized purified water containing all or a portion of the constituent components other than caspofungin diacetate, immediately before use.
[0098]
Formulation Example 2: Eye drops (in 5 ml)
Caspofungin diacetate 25 mg
Polyhexanide hydrochloride 1 mg
Sodium chloride 45 mg
Benzalkonium chloride 0.5 mg
Sodium hydroxide q. s.
Hydrochloric acid q. s.
Sterilized purified water q. s.
[0099]
This eye drop formulation can be prepared by adding caspofungin diacetate and/or another salt thereof and other additives to sterilized purified water, and thoroughly mixing them. A composition containing caspofungin diacetate, or caspofungin diacetate and other constituent components, may be used by dissolving it in sterilized purified water or dissolving it in sterilized purified water containing all or a portion of the constituent components other than caspofungin diacetate, immediately before use.

Claims

WO 2013/154209 " Δ ' PCT/JP2013/061431 CLAIMS
1. An antiprotozoan composition containing caspofungin or its salt and a biguanide compound or its salt.
2. The antiprotozoan composition according to claim 1, which is an aqueous composition.
3. The antiprotozoan composition according to claim 1 or 2, wherein the caspofungin or its salt is caspofungin diacetate.
4. The antiprotozoan composition according to any one of claims 1 to 3, wherein the biguanide compound or its salt is at least one compound selected from the group consisting of polyhexanide, chlorhexidine, alexidine, and their salts.
5. The antiprotozoan composition according to any one of claims 1 to 4, wherein the biguanide compound or its salt is polyhexanide hydrochloride.
6. The antiprotozoan composition according to any one of claims 1 to 5, wherein the protozoan is at least one selected from the group consisting of Amoebida and
Microsporida.
7. The antiprotozoan composition according to any one of claims 1 to 5, wherein the protozoan is an Amoebida.
8. The antiprotozoan composition according to any one of claims 1 to 5, wherein the protozoan is an Acanthamoeba.
9. The antiprotozoan composition according to any one of claims 1 to 8, which is a contact lens care product.
10. The antiprotozoan composition according to claim 9, wherein the contact lens care product is a multipurpose contact lens care solution.
11. The antiprotozoan composition according to any one of claims 1 to 8, which is an ophthalmic composition.
12. The antiprotozoan composition according to claim 11, which is an agent for prevention and/or treatment of keratitis.
13. The antiprotozoan composition according to claim 12, wherein the keratitis is Acanthamoeba keratitis.
PCT/JP2013/061431 2012-04-12 2013-04-11 Antiprotozoan composition containing caspofungin or its salt and biguanide compound or its salt WO2013154209A1 (en)

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