JP2013234176A - Antiprotozoan composition containing caspofungin or its salt and biguanide-based compound or its salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an antiprotozoan composition useful to keratitis, especially acanthamoeba keratitis which is one of eye infection due to wearing contact lenses.SOLUTION: An antiprotozoan composition includes caspofungin (a kind of macrocyclic lipopeptide echinocandin, also named as 1-[(4R,5S)-5-[(2-aminoethyl)amino]-N-(10R,12S-10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithin]-5-[(3R)-3-hydroxy-L-ornithin]pneumocandin B) or its salt, and a biguanide-based compound or its salt. As the biguanide-based compound, polyhexanide, chlorhexidine and alexidine are preferably cited.

Description

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

  Acanthamoeba is a ubiquitous free-living protozoan that exists in two forms, nutrients or cysts. These species include A.I. polyphaga, A.M. castellani, A.M. lenticulata, A. et al. hatchetti, A.H. astronyxis, A.M. cubertsoni, A. et al. rhysodes and the like. Acanthamoeba exists as a nutrient when the growth conditions are good. This nutrient is highly sensitive to the drug due to its high membrane permeability, but when the growth conditions deteriorate, it becomes a cyst with a double wall, and this cystized Acanthamoeba (hereinafter referred to as “Acant Amoebacyst)” ")" Also showed dry resistance, heat resistance and chemical resistance, and it was very difficult to kill them.

  In recent years, Acanthamoeba keratitis has attracted attention as one of the eye infections caused by wearing contact lenses. Acanthamoeba keratitis is an intractable disease caused by Acanthamoeba corneal infection. Symptoms such as visual impairment, strong eye pain, etc. In the worst case, it may lead to blindness. Acanthamoeba keratitis is very difficult to treat because there are currently no drugs on the market that have a clear clinical effect on acanthamoebacysts. According to “Infectious keratitis clinical practice guideline”, it is considered realistic to combine methods that are considered to be effective as much as possible. 1) Curettage of corneal lesion, 2) At present, treatment by eye drops, 3) systemic administration thereof, or 4) a combination therapy of these three is performed.

  On the other hand, various contact lens care agents including a multipurpose solution for contact lens care (hereinafter also referred to as “multipurpose solution” or “MPS”) are commercially available for the purpose of sterilizing bacteria attached to the soft contact lens. ing. As an active ingredient of MPS, polyhexanide hydrochloride is mainly blended, but it is known that polyhexanide hydrochloride has a weak anti-amoeba action against acanthamoeba, particularly acanthamoebacyst.

  As a drug considered to have anti-amoeba activity, Non-Patent Document 1 describes that caspofungin has an anti-amoebic action against acanthamoeba cysts at high concentrations and exposure for 24 hours or more.

  Patent Document 1 describes that polyhexanide hydrochloride, which is a biguanide compound, has an anti-acanthamoeba activity. However, as described above, the anti-amoeba action of polyhexanide hydrochloride blended in commercially available MPS is weak.

As described above, it is known that caspofungin and biguanide compounds each show a weak anti-amoeba action, but no composition showing a strong anti-amoeba action in combination with caspofungin and biguanide compounds has been known. .
In addition, none of the prior art documents disclose any ophthalmic compositions such as a contact lens care agent and a preventive and / or therapeutic agent for keratitis that simultaneously contain caspofungin or a salt thereof and a biguanide compound. Moreover, there is no description or suggestion of its action on Acanthamoeba, especially its action on Acanthamoebacyst.
Therefore, a composition having a higher antiprotozoal action against protozoa such as Acanthamoeba cysts, particularly contact lens care agents such as MPS having such action, and Acanthamoeba keratitis caused by protozoa, particularly Acanthamoeba keratitis. The development of ophthalmic compositions useful as preventive and / or therapeutic agents is highly desired.

International Publication WO97 / 36487 Publication Pamphlet

Sabrina Bouyer et al., Journal of Antimicrobial Chemotherapy, 2007, 59, 122-124

  An object of the present invention is to provide an antiprotozoan composition exhibiting a potent antiprotozoal action against protozoa such as Acanthamoeba, particularly Acanthamoeba cysts. More specifically, the object of the present invention is to provide a new contact lens care agent such as MPS having a potent antiprotozoal action, and diseases caused by protozoa such as Acanthamoeba, such as keratitis, In particular, it is to provide an ophthalmic composition useful as a preventive and / or therapeutic agent for Acanthamoeba keratitis.

  As a result of intensive studies to improve the anti-amoeba action against protozoa such as Acanthamoeba, particularly Acanthamoeba cysts, the present inventors have found that, by combining caspofungin or a salt thereof, and a biguanide compound or a salt thereof, respectively. As compared with the case where it was used alone, the anti-amoeba action was found to be remarkably enhanced, and the present invention was completed.

That is, the present invention relates to the following.
(1) An antiprotozoan composition containing caspofungin or a salt thereof, and a biguanide compound or a salt thereof.
(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 a salt thereof is caspofungin diacetate.
(4) The antiprotozoan according to any one of (1) to (3), wherein the biguanide compound or a salt thereof is at least one compound selected from the group consisting of polyhexanide, chlorhexidine, alexidine, and salts thereof. Composition.
(5) The antiprotozoan composition according to any one of (1) to (4), wherein the biguanide compound or a salt thereof is polyhexanide hydrochloride.
(6) The antiprotozoan composition according to any one of (1) to (5), wherein the protozoa is at least one protozoan selected from the group consisting of amoebida (Amoebida) and microsporidia (Microsporida) object.
(7) The antiprotozoan composition according to any one of (1) to (5), wherein the protozoan is an amoeba.
(8) The antiprotozoan composition according to any one of (1) to (5), wherein the protozoan is Acanthamoeba.
(9) The antiprotozoan composition according to any one of (1) to (8), which is a contact lens care agent.
(10) The antiprotozoan composition according to (9), wherein the contact lens care agent is a contact lens care multipurpose solution.
(11) The antiprotozoan composition according to any one of (1) to (8), which is an ophthalmic composition.
(12) The antiprotozoan composition according to (11), which is a preventive and / or therapeutic agent for keratitis.
(13) The antiprotozoan composition according to (12), wherein the keratitis is Acanthamoeba keratitis.

The present invention further relates to the following.
(14) A method for cleaning, rinsing, disinfecting and / or storing a contact lens, the method comprising contacting the contact lens with the contact lens care agent according to (9) or (10).
(15) A method for disinfecting a contact lens case or a contact lens, the method comprising the step of bringing the contact lens case or the contact lens into contact with the contact lens care agent according to (9) or (10).
(16) A method for killing a contact lens case or a protozoan attached to a contact lens, comprising the step of bringing the contact lens case or the contact lens into contact with the contact lens care agent according to (9) or (10) above Method.
(17) A method for preventing or treating ophthalmic symptoms in a patient, wherein the antiprotozoan composition according to any one of (1) to (8) is therapeutically applied to a patient's eye in need A method comprising administering in an effective amount.
(18) The method according to (17), wherein the ophthalmic symptom is keratitis.
(19) The method according to (18), wherein the keratitis is Acanthamoeba keratitis.
(20) Use of the antiprotozoan composition according to any one of (1) to (8) for a contact lens care agent.
(21) The use according to (20), wherein the contact lens care agent is a contact lens care multipurpose solution.
(22) Use of the antiprotozoan composition according to any one of (1) to (8) for cleaning, rinsing, disinfecting and / or storing contact lenses.

  INDUSTRIAL APPLICABILITY According to the present invention, an antiprotozoan composition exhibiting a potent antiprotozoal action against protozoa such as Acanthamoeba, particularly Acanthamoeba cyst, is provided. That is, by containing both caspofungin or a salt thereof and a biguanide compound or a salt thereof, protozoan such as Acanthamoeba can be killed by using it at a low concentration in a short time compared to the case where each is used alone. In addition, the adhesion of protozoa such as Acanthamoeba to contact lenses can be suppressed, so that contact lens care agents such as multipurpose solutions for contact lens care can be provided in accordance with the actual use. In addition, since caspofungin or a salt thereof, and a biguanide compound or a salt thereof have strong antiprotozoal activity compared to each of them alone, diseases caused by protozoa, particularly acanthamoeba, such as keratitis, especially acant An ophthalmic composition useful as an agent for preventing and / or treating amoeba keratitis can be provided.

In the pharmacological test 1, it is a figure which shows the result of having evaluated the anti-amoeba action with respect to an acanthamoeba cyst of caspofungin, Micafungin, Andurafungin, artesunate, artemate, quinine, and polyhexanide hydrochloride. In Pharmacological Test 2, it is a figure which shows the result of having evaluated the anti-amoeba effect | action with respect to an acanthamoeba cyst by combined use of a caspofungin, Micafungin, or Andurafungin, and polyhexanide hydrochloride. In the pharmacological test 3, it is a figure which shows the result of having evaluated the anti-amoeba action with respect to an acanthamoeba cyst by combined use with a caspofungin and polyhexanide hydrochloride in various concentration groups.

  The present invention is described in detail below.

  In the present specification, the protozoa means amoeba (Amoebida) or microsporida (Microsporida) and the like. Specific examples of amoeba include Acanthamoeba, Naegleria, Hartmannella, Vannella and the like.

  In this specification, Acanthamoeba means A. astronyxis, A.M. comandoni, A.M. divisionionsis, A.M. griffini, A.M. hatchetti, A.H. healii, A.H. jacobsi, A.M. lenticulata, A. et al. cubertsoni, A. et al. lugdenensis, A.M. mauritaniensis, A.M. palestinesis, A.P. pearcei, A .; polyphaga, A.M. pustulosa, A.M. quina, A.M. rhysodes, A.R. royreba, A.R. tericola, A.M. triangularis, A.M. tubeashi, A .; polyphaga, A.M. castellani and the like.

  In the present specification, microsporidia are referred to as Encephalitozoon. cuniculi, Encephalitozoon. hellem, Encephalitozoon. intestinalis, Vitaforma corneae, Anncalia algerae, Microspodium (M. ceylonensis and M. africanum), Nosema sp. (N. ocularum), Annalia konnori, Trachiplestophora hominis, and the like.

  In the present specification, the antiprotozoal action means an action of killing or removing part or all of the protozoa, or an action of suppressing the growth of the protozoa.

  In the present specification, the anti-amoebic action refers to an action of killing or removing a part or all of amoeba, or an action of suppressing the growth of amoeba. In addition, “anti-amoeba activity” includes anti-amoeba activity against acanthamoeba (also referred to as “anti-acant amoeba activity”), anti-amoeba activity against acanthamoeba cyst (also referred to as “anti-acanthamoeba cyst activity”), and acanthamoeba. This includes the killing effect on vegetatives and / or cysts, or the cyst formation inhibiting action of Acanthamoeba.

  In the present specification, the antiprotozoan composition refers to a composition capable of exerting an antiprotozoal action on a part or all of protozoa represented by Amoebida, Microsporida and the like. means.

  In this specification, the contact lens includes any of a soft contact lens, a hard contact lens, and an oxygen-permeable hard contact lens. Soft contact lenses include both ionic and non-ionic, and include both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses (soft contact lenses different from silicone hydrogel lenses).

  In this specification, the contact lens care agent refers to various compositions used for the care of contact lenses, such as contact lens mounting liquid, contact lens cleaning liquid, contact lens rinsing liquid, contact lens disinfecting liquid, contact lens preserving liquid, and contact. It means a multipurpose solution for lens care (multipurpose solution or MPS).

  In this specification, the multipurpose solution for contact lens care (multipurpose solution or MPS) is an agent for contact lens care that can perform at least two or more of cleaning, rinsing, disinfection, and storage of contact lenses in one liquid. Means.

  In this specification, the ophthalmic composition means a pharmaceutical composition for ophthalmic use, and includes, for example, eye drops (including eye drops for contact lenses), eye wash (including eye drops for contact lenses), and eye ointments. An ophthalmic composition such as an agent is meant.

  In the present specification, keratitis refers, for example, to bacterial keratitis, fungal keratitis, acanthamoeba keratitis, corneal ulcer (corneal ulcer) It means frickten (corneal phlyctenule), corneal herpes (herpetic keratitis), and the like. Acanthamoeba keratitis is keratitis caused by Acanthamoeba.

The antiprotozoan composition of the present invention is any composition containing caspofungin or a salt thereof and a biguanide compound or a salt thereof.
The antiprotozoan composition of the present invention can be a solution dissolved in various solvents, but is preferably an aqueous composition that is an aqueous solution.

Caspofungin contained in the composition of the present invention has the following formula (1):

It is a compound shown by these.
This caspofungin (CAS registration number is “162808-62-0”) is one type of macrocyclic lipopeptide echinocandin, which is caspofungin or 1-[(4R, 5S) -5-[(2 - aminoethyl) ^{amino] -N 2 - (10R, 12S} -10,12- dimethyl-1-oxotetradecyl) -4-hydroxy -L- ornithine] -5 - [(3R) -3- hydroxy -L- ornithine] also referred to as Pneumocandin _{B 0.}

In the composition of the present invention, the salt of caspofungin is not particularly limited as long as it is a pharmacologically or physiologically acceptable salt, and for example, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, boric acid and the like. A salt with 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 and pamoic acid. Preferred is acetate, propionate or lactate, and more preferred is diacetate.
These caspofungin salts may be used alone or in any combination of two or more.

  In the present invention, caspofungin or a salt thereof may be in the form of a hydrate or a solvate.

  Furthermore, when there are geometrical isomers or optical isomers in caspofungin, these isomers are also included in the scope of the present invention.

  When caspofungin has proton tautomerism, those tautomers are also included in the present invention.

  When crystalline polymorphs and crystalline polymorphic groups (crystalline polymorphic systems) exist in caspofungin or a salt thereof, or a hydrate or solvate thereof, the crystalline polymorphs and crystalline polymorphic groups (crystalline Polymorphic systems) are also within the scope of the present invention. Here, the crystal polymorphism group (crystal polymorphism system) means that the crystal form changes depending on the conditions and state of production, crystallization and storage of these crystals (including the formulated state in this state). Means the individual crystal forms at each stage and the entire crystal form of the process.

  Caspofungin or a salt thereof, or a hydrate or solvate thereof can be produced according to a usual method in the field of synthetic organic chemistry. For example, it can be produced according to the method described in US Pat. No. 5,378,804, US Pat. No. 5,552,521, US Pat. No. 5,952,300, US Pat. Also, commercially available products such as Cancidas (registered trademark) (Merck & CO., Inc.) can be used.

  In the composition of the present invention, the content ratio of caspofungin or a salt thereof is not particularly limited as long as it is a concentration sufficient to exert a desired antiprotozoal action, but the type thereof, the type of biguanide compound or salt thereof used together, It is appropriately set according to the formulation form of the composition. As an example, in the case of an aqueous composition, in particular, in the case of eye drops, the content ratio of caspofungin or a salt thereof with respect to the total amount of the aqueous composition is usually a concentration as a total amount, converted to the concentration of caspofungin itself, 0.01 to 10% (w / v), preferably 0.05 to 10% (w / v), more preferably 0.1 to 5% (w / v). In the case of MPS, the content ratio of caspofungin or a salt thereof is usually 0.000005 to 0.1% (w / v), preferably 0.00005, as a total concentration with respect to the total amount of the aqueous composition. It is -0.05% (w / v), More preferably, it is 0.0001-0.01% (w / v).

  The biguanide compound or a salt thereof contained in the composition of the present invention is an arbitrary compound having at least one biguanide group [—NHC (═NH) NHC (═NH) NH—].

  In the composition of the present invention, the biguanide compound or a salt thereof is not particularly limited as long as it is pharmacologically or physiologically acceptable. Examples of the biguanide compound or a salt thereof include polyhexanide or a salt thereof (hereinafter also referred to as “polyhexamethylene biguanide” or “PHMB”), chlorhexidine or a salt thereof, or alexidine or a salt thereof, and preferably a polyhexanide. Or its salt, More preferably, polyhexanide hydrochloride is mentioned.

Polyhexanide has the following general formula (2):

It is a compound shown by these. In formula, n is a number which shows the repetition of the unit in (), is an integer of 1-500, Preferably, it is an integer of 2-200, More preferably, it is an integer of 4-100, More preferably, it is 4-20 Is an integer.

  In the composition of the present invention, the salt of polyhexanide is not particularly limited as long as it is a pharmacologically or physiologically acceptable salt. For example, the salt of polyhexanide with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, boric acid, etc. Salt: A salt with an organic acid such as acetic acid, gluconic acid, maleic acid, ascorbic acid, stearic acid, tartaric acid, citric acid, preferably an inorganic acid salt, more preferably a hydrochloride. These polyhexanide salts may be used alone or in any combination of two or more.

Chlorhexidine has the following formula (3):

It is a compound shown by these.

  In the composition of the present invention, the salt of chlorhexidine is not particularly limited as long as it is a pharmacologically or physiologically acceptable salt. For example, the salt of chlorhexidine with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, boric acid or the like is not limited. Salt: Acetic acid, gluconic acid, maleic acid, ascorbic acid, stearic acid, tartaric acid, citrate, and other organic acids, preferably hydrochloride, acetate or gluconate, more preferably gluconate . These chlorhexidine salts may be used alone or in any combination of two or more.

Alexidine has the following formula (4):

It is a compound shown by these.

  In the composition of the present invention, the salt of alexidine is not particularly limited as long as it is a pharmacologically or physiologically acceptable salt. For example, the salt of alexidine with hydrochloric acid, hydrobromic acid, sulfuric acid, boric acid or the like Salt; salt with organic acid such as acetic acid, gluconic acid, maleic acid, ascorbic acid, stearic acid, tartaric acid, citric acid, preferably hydrochloride, acetate or gluconate, more preferably hydrochloride, still more preferably Is the dihydrochloride salt. Further, these alexidine salts may be used alone or in any combination of two or more.

  In the composition of the present invention, the biguanide compound or a salt thereof may be in the form of a hydrate or a solvate.

  When a biguanide compound has geometric isomers or optical isomers, these isomers are also included in the scope of the present invention.

  When biguanide compounds have proton tautomerism, such tautomers are also included in the present invention.

  In the case where a crystal polymorph and a crystal polymorph group (crystal polymorph system) exist in a biguanide compound or a salt thereof, or a hydrate or solvate thereof, the crystal polymorph and crystal polymorph group thereof (Crystal polymorphic system) is also included in the scope of the present invention. Here, the crystal polymorphism group (crystal polymorphism system) means that the crystal form changes depending on the conditions and state of production, crystallization and storage of these crystals (including the formulated state in this state). Means the individual crystal forms at each stage and the entire crystal form of the process.

  In the composition of the present invention, the biguanide compounds or salts thereof may be used alone or in any combination of two or more.

  The biguanide compound can be produced according to a conventional method in the field of synthetic organic chemistry. Moreover, the biguanide compound can use what is marketed as follows.

  As the polyhexanide hydrochloride, for example, those commercially available under the trade name of Proxel (registered trademark) IB from Zeneca Co., Ltd. and under the trade name of Lonzabac (registered trademark) BG from Lonza Japan Co., Ltd. can be used.

  As the chlorhexidine gluconate, for example, one commercially available from Dainippon Sumitomo Pharma Co., Ltd. under the trade name Hibiten (registered trademark) can be used.

  As the alexidine dihydrochloride, for example, those commercially available from Sigma-Aldrich Corporation can be used.

  In the composition of the present invention, the content ratio of the biguanide compound or a salt thereof is not particularly limited as long as it is a concentration sufficient to exert a desired antiprotozoal action, but the type of biguanide compound or a salt thereof, caspofungin used together Or it sets suitably according to the kind of the salt, the formulation form of a composition, etc. As an example, in the case of an aqueous composition, in particular, in the case of eye drops, the content ratio of the biguanide compound or a salt thereof relative to the total amount of the aqueous composition is the concentration as the total amount, and the concentration of the biguanide compound itself. In terms of conversion, it is usually 0.001 to 1% (w / v), preferably 0.005 to 0.5% (w / v), more preferably 0.01 to 0.2% (w / v). is there. In particular, in the case of MPS, the content ratio of the biguanide compound or a salt thereof is usually 0.000005 to 0.01% (w / v) in terms of the total amount with respect to the total amount of the aqueous composition. Preferably it is 0.00001-0.005% (w / v), More preferably, it is 0.00005-0.001% (w / v).

  In the composition of the present invention, the ratio of the biguanide compound or salt thereof to caspofungin or a salt thereof is not particularly limited as long as it is an amount sufficient to exert a desired antiprotozoal action. As an example, in the case of an aqueous composition, particularly in the case of eye drops, the total amount of biguanide compound or salt thereof is usually 0.0005 to 50 parts by weight, preferably 0.005 parts per 1 part by weight of the total amount of caspofungin or a salt thereof. 001 to 10 parts by weight, more preferably 0.002 to 5 parts by weight. In particular, in the case of MPS, the total amount of the biguanide compound or a salt thereof is usually 0.00005 to 100 parts by weight, preferably 0.0001 to 50 parts by weight per 1 part by weight of the total amount of caspofungin or a salt thereof. Preferably it is 0.005-10 weight part.

  In the composition of the present invention, polydronium chloride (CAS registration number is “75345-27-6”) may be used instead of the biguanide compound or a salt thereof.

  In addition to the above, the composition of the present invention may contain various additives as necessary. For example, in the case of an aqueous composition, a buffer, a surfactant, an isotonic agent, a preservative, and a pH adjustment. Additives such as an agent, a thickener, a chelating agent, a stabilizer, and a protein removing agent can be contained.

  The buffer is not particularly limited as long as it is pharmacologically or physiologically acceptable. For example, phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, phosphoric acid Phosphates such as potassium dihydrogen and dipotassium hydrogen phosphate; borates such as boric acid, borax, sodium borate and potassium borate; citrates such as sodium citrate and disodium citrate; sodium acetate And acetates such as potassium acetate; carbonates such as sodium carbonate and sodium bicarbonate; and at least one selected from ε-aminocaproic acid and trometamol, preferably phosphoric acid, sodium phosphate, phosphoric acid Sodium dihydrogen, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate and At least one selected from a hydrogen phosphate dipotassium, more preferable examples thereof include sodium dihydrogen phosphate and disodium hydrogen phosphate.

  When a buffering agent is blended in the aqueous composition, the content of the buffering agent can be appropriately set according to the type of the buffering agent, the type and content of other blending components, the formulation form of the aqueous composition, and the like. In the composition of the present invention, the content of the buffering agent is generally 0.001 to 5% (w / v), preferably 0.003 to 3% (w / v), as the total concentration. Preferably it is 0.03 to 2% (w / v).

  The surfactant is not particularly limited as long as it is pharmacologically or physiologically acceptable. For example, monolauric acid POE (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polysorbate 40) POE sorbitan fatty acid esters such as monostearic acid POE (20) sorbitan (polysorbate 60), tristearic acid POE (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80); POE / POP block copolymers such as poloxamer 235, poloxamer 188, poloxamer 403, poloxamer 237, poloxamer 124; POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil) POE hydrogenated castor oil such as 60); POE alkyl ethers such as POE (9) lauryl ether; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether; POE (10) nonylphenyl ether and the like Nonionic surfactants such as POE alkylphenyl ethers of POE (POE is polyoxyethylene, POP is polyoxypropylene, and the number in parentheses indicates the number of moles added); alkyldiaminoethylglycine or a salt thereof (for example, Amphoteric surfactants such as hydrochlorides; anionic surfactants such as alkylbenzene sulfonates, alkyl sulfates, polyoxyethylene alkyl sulfates, aliphatic α-sulfomethyl esters, α-olefin sulfonic acids; Benzalkonium, benzethonium chloride, etc. At least one selected from the group of cationic surfactants, preferably nonionic surfactants, more preferably selected from POE sorbitan fatty acid esters, POE hydrogenated castor oil, or POE • POP block copolymers And at least one selected from polysorbate 80, polyoxyethylene hydrogenated castor oil 60 and poloxamer 407.

  When a surfactant is blended in the aqueous composition, the content ratio can be appropriately set according to the type of the surfactant, the type and content ratio of other blended components, the formulation form of the aqueous composition, and the like. In the composition of the present invention, the content of the surfactant is usually 0.001 to 10% (w / v), preferably 0.005 to 5% (w / v), as the total concentration. Preferably it is 0.005-3% (w / v).

  The isotonic agent is not particularly limited as long as it is pharmacologically or physiologically acceptable, for example, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfite, Examples include at least one selected from sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, and propylene glycol. it can.

  When an isotonic agent is added to the aqueous composition, the content of the tonicity agent depends on the type of tonicity agent, the type and concentration of other ingredients, the formulation of the antiprotozoan composition, etc. It can be set appropriately. In the case of an aqueous composition, the osmotic pressure is usually 200 to 450 milliosmol (mOSm), preferably 250 to 370 milliosmol (mOSm).

  The pH adjuster is not particularly limited as long as it is pharmacologically or physiologically acceptable. For example, at least one selected from hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide, ammonium hydroxide and the like is used. Can be mentioned. When a pH adjuster is added to the aqueous composition, the content of the pH adjuster is appropriately set according to the type of pH adjuster, the type and amount of other compounding components, the formulation of the antiprotozoan composition, and the like. be able to.

  The pH when the composition of the present invention is an aqueous composition is not particularly limited as long as it is within a pharmacologically or physiologically acceptable range, but is usually 4.0 to 9.5, Preferably it is 5.0-9.0, More preferably, it is 5.0-8.5, More preferably, it is 5.0-7.5.

  The thickener is not particularly limited as long as it is pharmacologically or physiologically acceptable. For example, at least one selected from hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and the like is used. Can be mentioned.

  When a thickener is blended in the aqueous composition, the content of the thickener is appropriately determined according to the type of the thickener, the type and content of other blending components, the formulation form of the aqueous composition, and the like. Can be set. The concentration of the thickener is usually 0.01 to 10% (w / v), preferably 0.05 to 3% (w / v) as the total concentration.

  The chelating agent is not particularly limited as long as it is pharmacologically or physiologically acceptable, and examples thereof include at least one selected from sodium edetate, sodium citrate, condensed sodium phosphate and the like. .

  When a chelating agent is blended in an aqueous composition, the content of the chelating agent should be set appropriately according to the type of chelating agent, the type and content of other blending components, the formulation form of the aqueous composition, etc. Can do. The content rate of a chelating agent is 0.002-0.5% (w / v) normally as a density | concentration of the total amount, Preferably it is 0.005-0.1% (w / v).

  The stabilizer is not particularly limited as long as it is pharmacologically or physiologically acceptable, and an appropriate amount of the above-mentioned buffering agent, chelating agent and the like can be appropriately mixed.

  As the protein removing agent, an appropriate amount of a proteolytic enzyme can be appropriately blended.

  When the composition of the present invention is an aqueous composition, the composition is usually 20% or more, preferably 50% or more, more preferably 80% or more, and still more preferably 90% water relative to the total amount of the composition. It contains in the ratio of% or more. The water to be used is preferably distilled water, purified water or sterilized purified water.

  Examples of the dosage form of the composition of the present invention include ophthalmic compositions such as eye drops (including eye drops for contact lenses), eye wash (including eye drops for contact lenses), eye ointments; And contact lens care agents such as contact lens cleaning solution, contact lens rinsing solution, contact lens disinfecting solution, contact lens preserving solution, and contact lens care multipurpose solution (multipurpose solution or MPS). Preferably ophthalmic compositions and contact lens care agents, more preferably eye drops and contact lens care agents, more preferably eye drops, contact lens cleaning solutions, contact lens rinsing solutions, contact lens disinfecting solutions, contact lens preserving solutions and Mention may be made of a multipurpose solution for contact lens care (multipurpose solution or MPS).

  The antiprotozoan composition of the present invention may be a freeze-dried preparation that is reconstituted with water or the like immediately before use.

  The antiprotozoan composition of the present invention can be in various forms as described above. As an example, in the case of an aqueous composition, caspofungin or a salt thereof, and a biguanide compound or a salt thereof, and if necessary, the above-described buffer, surfactant, tonicity agent, preservative, pH adjuster, thickener, It can be produced by dissolving additives such as chelating agents, stabilizers, and protein removing agents in a solvent such as water.

  When the composition of the present invention is a contact lens care agent, it can be used as a care agent for any contact lens such as a soft contact lens, a hard contact lens, and an oxygen-permeable hard contact lens, preferably a soft contact lens. Can be used for lenses.

  The invention also relates to a method for cleaning, rinsing, disinfecting and / or storing contact lenses. The method of the present invention includes the step of contacting a contact lens with the contact lens care agent of the present invention. In this case, the treatment time for bringing the contact lens into contact with the contact lens care agent of the present invention is not particularly limited, but is usually 5 minutes to 24 hours, and preferably 1 to 12 hours. The method for bringing the contact lens into contact with the contact lens care agent of the present invention is not particularly limited, and can be carried out, for example, by the following method. When washing, drop a few drops of the contact lens care agent of the present invention onto the contact lens removed from the eye and hold the contact lens between the thumb and forefinger or on the palm of the hand for several seconds to several times. Rub for 10 seconds. In the case of rinsing, the contact lens is rinsed with several ml of the contact lens care agent of the present invention. When storing and disinfecting, the contact lens is immersed in a contact lens case filled with the contact lens care agent of the present invention.

  The present invention also relates to a method for disinfecting a contact lens case or contact lens. The method of the present invention includes the step of contacting a contact lens case or contact lens with the contact lens care agent of the present invention. In this case, the treatment time for contacting the contact lens case or contact lens with the contact lens care agent of the present invention is not particularly limited, but is usually 5 minutes to 24 hours, preferably 1 to 12 hours. . The contact lens case or the method of bringing the contact lens into contact with the contact lens care agent of the present invention is not particularly limited. For example, the contact lens is immersed in a contact lens case filled with the contact lens care agent of the present invention.

  The present invention further relates to a method for killing protozoa attached to a contact lens case or contact lens. The method of the present invention includes the step of contacting a contact lens case or contact lens with the contact lens care agent of the present invention. In this case, the treatment time for contacting the contact lens case or contact lens with the contact lens care agent of the present invention is not particularly limited, but is usually 5 minutes to 24 hours, preferably 1 to 12 hours. . The contact lens case or the method of bringing the contact lens into contact with the contact lens care agent of the present invention is not particularly limited. For example, the contact lens is immersed in a contact lens case filled with the contact lens care agent of the present invention.

  When the composition of the present invention is an ophthalmic composition, a preventive and / or therapeutic agent for keratitis, preferably bacterial keratitis, fungal keratitis, acanthamoeba keratitis Prophylactic and / or therapeutic agent for (acanthamoeba keratitis), corneal ulcer, corneal phlyctenule, corneal herpes (herpetic keratitis), and more preferably as a prophylactic and / or therapeutic agent for acanthamoeba keratitis be able to.

  The invention also relates to a method for preventing or treating ophthalmic conditions in a patient. The method of the invention comprises administering the antiprotozoal composition of the invention in a therapeutically effective amount to the eye of a patient in need thereof. The dose and frequency of administration of the antiprotozoan composition of the present invention are appropriately selected depending on the dosage form, the symptoms of the patient to be administered, the age, etc. For example, in the case of an eye drop dosage form, 1 to several per dose. Drops can be instilled 1 to several times per day (eg 1 to 6 times). The ophthalmic symptom is preferably keratitis, more preferably Acanthamoeba keratitis.

  Although the result of a pharmacological test and the example of a formulation are shown below, these illustrations are for understanding this invention better, and do not limit the scope of the present invention.

[Pharmacological test 1]
The anti-amoeba action of caspofungin, Micafungin, Andurafungin (above, candin antifungal), artesunate, artemeta, quinine (above, antimalarial) and polyhexanide hydrochloride against acanthamoebacyst was evaluated.

(Test solution preparation method)
Micafungin sodium (hereinafter also referred to as “MCFG”; for Fanguard (registered trademark) infusion, Astellas Pharma Inc.), caspofungin diacetate (hereinafter also referred to as “CPFG”; Cancidas (registered trademark), Merck & Co. Inc.), Andurafungin (hereinafter also referred to as “ADFG”; Eraxis (registered trademark), Pfizer Inc.), Artemeta (Tokyo Chemical Industry Co., Ltd.), Quinine (Kanto Chemical Co., Inc.), Polyhexanide hydrochloride ( (Hereinafter also referred to as “PHMB”) is dissolved in a 1/4 Ringer solution (Wako Pure Chemical Industries, Ltd.), and artemeta is prepared to a final concentration of 100 μg / ml, and otherwise, 500 μg / ml. This was used as a test solution. Artesunate (Tokyo Kasei Kogyo Co., Ltd.) was dissolved in a pH 7.0 phosphate buffer solution and prepared to a final concentration of 500 μg / ml to prepare a test solution.

(Test method)
The test method was in accordance with the method shown in the press release on December 16, 2009 "National Life Center, Japan", "Disinfection Function of Soft Contact Lens Disinfectant for Acanthamoeba-Based on Usage Survey" : //www.kokusen.go.jp/test/data/s_test/n-20091216_1.html).
As Acanthamoeba, Acanthamoeba castellani ATCC 30324 strain (hereinafter also referred to as “A. castellani”) was used. A. castellani was cultured in a PYG liquid medium at 25 ° C. for 1 week, then replaced with a cystized medium and cultured for 2 weeks. A. castellani cysts were collected and a suspension of 1.7 × 10 ⁶ / ml was prepared with a 1/4 Ringer solution.
0.1 ml of A. castellani suspension was added to 9.9 ml of the test solution (final cyst amount 1.7 × 10 ⁴ / ml) and exposed for a certain time (n = 3). Further, as a control group, a 1/4 Ringer solution and a pH 7.0 phosphate buffer solution were used instead of the test solution.
1 ml of the test solution after exposure to the test solution was collected, and the test solution was removed by centrifuging A. castellani cysts. Next, 2 ml of 1/4 Ringer's solution was added to and suspended in the centrifuged A. castellani cyst, and then centrifuged again to remove the supernatant and suspended in 1 ml of PYG liquid medium. Further, 10, 10 ² , 10 ³ , 10 ⁴ and 10 ⁵ times dilutions were prepared in a PYG liquid medium.
200 μl of each diluted solution was dispensed into 4 wells of a 96-well plate and cultured at 25 ° C. for 2 weeks. The presence or absence of proliferation was observed under a microscope, and the number of surviving Acanthamoeba was calculated by the Spearman-Karbar equation.
From this result, Log reduction was determined. “Log reduction” refers to a value in logarithm indicating how much the number of bacteria has decreased from the initial number of inoculated bacteria. For example, a Log reduction value of 1 means that the number of account amoeba has become 1/10, and a Log reduction value of 2 means that the number of amoeba has become 1/100. The Spearman-Karbar equation is as follows.
Spearman-Karber formula: log ₁₀ (average survival number) = x ₀ −d / 2 + d × Σ (r _i / n _i )
x ₀ : log ₁₀ (reciprocal of the lowest dilution step at which growth was observed in all wells)
d: log ₁₀ (dilution factor); here d = 1
r _i : Number of holes in which growth was observed at each dilution step. Let i = 0 be the lowest dilution step at which growth was observed in all wells.
n _i : total number of wells for each dilution step; here n _i = 4

(Test results)
The results are shown in FIG.
The log reduction of polyhexanide hydrochloride, which is a component of a commercially available multipurpose solution for contact lens care, under a 24-hour exposure condition was about 1, and the number of Acanthamoeba decreased to about 1/10.
On the other hand, Log reduction under the 24-hour exposure condition of caspofungin was about 2.8, the number of Acanthamoeba decreased to about 1/630, and the anti-amoeba action was clearly recognized. On the other hand, Micafungin and Andurafungin, which are candinic antifungals to which Caspofungin belongs, and Artesunate, Artemate, or Quinine, which are antimalarial drugs, were hardly observed.

[Pharmacological test 2]
The anti-amoeba action against acanthamoebacyst by the combined use of caspofungin, Micafungin or Andurafungin (above, Candine antifungal agent) and polyhexanide hydrochloride was evaluated. In addition, it was examined whether each drug exhibits an anti-amoeba action against acanthamoebacyst under the 6-hour exposure conditions considering the actual use of contact lens care agents such as a contact lens care multipurpose solution.

(Test solution preparation method)
Prepared according to Pharmacological Test 1.

(Test method)
According to Pharmacological Test 1, the drug exposure time was 6 hours.

(Test results)
The results are shown in FIG.
The combined use of caspofungin (30 μg / ml) and polyhexanide hydrochloride (1 μg / ml) enhanced the anti-amoeba action against acanthamoebacysts. In addition, the combination group of caspofungin and polyhexanide hydrochloride showed the effect after 6 hours of exposure. In other words, the combination group of caspofungin and polyhexanide hydrochloride does not require long-term exposure for 24 hours or more, and the exposure time according to the actual use of contact lens care agents such as a multipurpose solution for contact lens care is effective. Indicated.
On the other hand, even when Micafungin or Andurafungin was used in combination with polyhexanide hydrochloride, almost no enhancement of the anti-amoeba action against acanthamoebacyst was observed. This indicates that the antiprotozoal action is specifically enhanced by the combined use of caspofungin or a salt thereof and a biguanide compound or a salt thereof.

[Pharmacological test 3]
The anti-amoeba action against acanthamoebacyst by combined use of caspofungin and polyhexanide hydrochloride was evaluated in various concentration groups. Whether or not the combination group of caspofungin and polyhexanide has anti-amoeba activity against acanthamoebacyst under 6-hour exposure conditions considering the actual use of contact lens care agents such as multipurpose solutions for contact lens care It was investigated.

(Test solution preparation method)
Prepared according to Pharmacological Test 1.

(Test method)
According to Pharmacological Test 1, the drug exposure time was 6 hours.

(Test results)
The results are shown in FIG.
The combined use of caspofungin (10 μg / ml or 30 μg / ml) and polyhexanide hydrochloride (1 μg / ml) enhanced the anti-amoeba action against acanthamoebacysts. In addition, as in Pharmacological Test 2, the combination group of caspofungin and polyhexanide hydrochloride does not require long-term exposure for 24 hours or more, and is in accordance with the actual use of contact lens care agents such as multipurpose solutions for contact lens care. The effect was shown by the exposure time.
As a result of the above pharmacological tests 1 to 3) When Micafungin or Andurafungin, a so-called candin antifungal to which caspofungin or a salt thereof belongs, and Artesunate, Artemeta or Quinine, which is an antimalarial agent, are used alone 2) Micafungin and a biguanide compound such as polyhexanide hydrochloride are used in combination, and 3) Antidactergic action is hardly observed when andrundafungin and a biguanide compound such as polyhexanide hydrochloride are used in combination. In addition, it was confirmed that caspofungin or a salt thereof and a biguanide compound such as polyhexanide hydrochloride were specifically observed.

[Formulation example]
The antiprotozoan composition of the present invention will be described more specifically with reference to formulation examples.

Formulation Example 1: Multipurpose solution for contact lens care (in 100 ml)
Caspofungin diacetate 3mg
Polyhexanide hydrochloride 0.1mg
Edetate disodium 50mg
Boric acid 500mg
Surfactant 500mg
Isotonic agent Appropriate amount pH adjuster Appropriate amount Sterilized purified water Appropriate amount

  The above-mentioned multipurpose solution for contact lens care can be prepared by adding caspofungin / diacetate and / or other salts and other additives to sterilized purified water and mixing them well. In addition, the composition containing caspofungin / diacetate or caspofungin / diacetate and other components contains part or all of components other than sterilized purified water or caspofungin / diacetate immediately before use. It may be used after being dissolved using sterilized purified water.

Formulation Example 2: Eye drops (in 5 ml)
Caspofungin diacetate 25mg
Polyhexanide hydrochloride 1mg
Sodium chloride 45mg
Benzalkonium chloride 0.5mg
Sodium hydroxide Appropriate amount Hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount

  The eye drop can be prepared by adding caspofungin / diacetate and / or other salts and other additives to sterilized purified water and mixing them well. In addition, the composition containing caspofungin / diacetate or caspofungin / diacetate and other components contains part or all of components other than sterilized purified water or caspofungin / diacetate immediately before use. It may be used after being dissolved using sterilized purified water.

Claims (13)

  An antiprotozoan composition comprising caspofungin or a salt thereof, and a biguanide compound or a salt thereof.   The antiprotozoan composition according to claim 1, which is an aqueous composition.   The antiprotozoan composition according to claim 1 or 2, wherein the caspofungin or a salt thereof is caspofungin diacetate.   The antiprotozoan composition according to any one of claims 1 to 3, wherein the biguanide compound or a salt thereof is at least one compound selected from the group consisting of polyhexanide, chlorhexidine, alexidine, and salts thereof.   The antiprotozoan composition according to any one of claims 1 to 4, wherein the biguanide compound or a salt thereof is polyhexanide hydrochloride.   The antiprotozoan composition according to any one of claims 1 to 5, wherein the protozoa is at least one protozoan selected from the group consisting of amoebae and microsporidia.   The antiprotozoan composition according to any one of claims 1 to 5, wherein the protozoan is an amoeba.   The antiprotozoan composition according to any one of claims 1 to 5, wherein the protozoan is Acanthamoeba.   The antiprotozoan composition according to any one of claims 1 to 8, which is a contact lens care agent.   The antiprotozoan composition according to claim 9, wherein the contact lens care agent is a contact lens care multipurpose solution.   The antiprotozoan composition according to any one of claims 1 to 8, which is an ophthalmic composition.   The antiprotozoan composition according to claim 11, which is a preventive and / or therapeutic agent for keratitis.   The antiprotozoan composition according to claim 12, wherein the keratitis is Acanthamoeba keratitis.