Medicinal composition containing chlorhexidine

Abstract

To find means for keeping the stability of chlorhexidine in a medicinal composition in order to keep the medicinal composition antiseptic.SOLUTION: The present invention relates to a medicinal composition containing chlorhexidine or a salt thereof, the composition being contained in a container sterilized with ethylene oxide gas. According to the invention, the content of the chlorhexidine or salt thereof in the medicinal composition is inhibited from decreasing with time.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition containing chlorhexidine or a salt thereof, which is contained in a container that has been sterilized with ethylene oxide gas (hereinafter also referred to as EOG). [Background technology]

[0002] Among pharmaceutical compositions, eye drops in particular are strictly required to be kept sterile until the time of administration because they are administered directly to the eye. Therefore, when manufacturing eye drops, the containers must be sterilized, and sterilization processes such as gamma ray sterilization, electron beam sterilization, EOG sterilization, hydrogen peroxide sterilization, and high-pressure steam sterilization are used.

[0003] Patent Document 1 describes that a pharmaceutical composition containing a prostaglandin derivative containing a fluorine atom in the molecule is placed in a container that has been sterilized with EOG.

[0004] Furthermore, to prevent microbial contamination after opening, preservatives such as benzalkonium chloride and chlorhexidine are usually added to eye drops. However, it was not known that the content of chlorhexidine or a salt thereof in a pharmaceutical composition decreases over time. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] US Patent Application Publication No. 2008 / 0139648 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a pharmaceutical composition that is safe and that can suppress the decrease over time in the content of chlorhexidine or a salt thereof and maintain antiseptic properties for a long period of time. [Means for solving the problem]

[0007] As a result of extensive research, the present inventors have found that when a pharmaceutical composition containing chlorhexidine or a salt thereof is placed in a container that has been sterilized by electron beam, the content of chlorhexidine or a salt thereof decreases over time, and further found that when a pharmaceutical composition containing chlorhexidine or a salt thereof is placed in a container that has been sterilized by ethylene oxide gas, the decrease in the content of chlorhexidine or a salt thereof over time due to heat or light can be suppressed, thereby completing the present invention. Specifically, the present invention provides the following.

[0008] (1) A pharmaceutical composition containing chlorhexidine or a salt thereof, contained in an ethylene oxide gas sterilized container.

[0009] (2) The pharmaceutical composition according to (1), wherein the content of chlorhexidine or a salt thereof is 0.0001 to 0.1% (w / v).

[0010] (3) The pharmaceutical composition according to (1) or (2), further comprising edetic acid or a salt thereof.

[0011] (4) The pharmaceutical composition according to (3), wherein the content of edetic acid or a salt thereof is 0.0001 to 3% (w / v).

[0012] (5) The pharmaceutical composition according to any one of (1) to (4), further comprising bimatoprost, latanoprost, or travoprost.

[0013] (6) The pharmaceutical composition according to (5), wherein the content of bimatoprost is 0.01 to 0.05% (w / v).

[0014] (7) The pharmaceutical composition according to (5), wherein the content of latanoprost or travoprost is 0.001 to 0.01% (w / v).

[0015] (8) The pharmaceutical composition according to any one of (1) to (7), wherein the container is made of polyethylene or polypropylene.

[0016] (9) The pharmaceutical composition according to any one of (1) to (8), wherein the residual ethylene oxide concentration in the ethylene oxide gas sterilization container is 0 to 10 ppm.

[0017] (10) The pharmaceutical composition according to any one of (1) to (9), which is an eye drop.

[0018] (11) The pharmaceutical composition according to any one of (1) to (10), which is an aqueous solution.

[0019] (12) A method for stabilizing chlorhexidine or a salt thereof by placing a pharmaceutical composition containing chlorhexidine or a salt thereof in an ethylene oxide gas sterilized container.

[0020] (13) A method for producing a pharmaceutical product, comprising sterilizing a container with ethylene oxide gas and placing a pharmaceutical composition containing chlorhexidine or a salt thereof therein.

[0021] (14) A pharmaceutical product obtained by sterilizing a container with ethylene oxide gas and placing a pharmaceutical composition containing chlorhexidine or a salt thereof therein.

[0022] The present invention further relates to the following:

[0023] (15) A pharmaceutical composition for treating and / or preventing eye diseases, containing chlorhexidine or a salt thereof and contained in an ethylene oxide gas sterilized container.

[0024] (16) A pharmaceutical composition for use in the treatment and / or prevention of eye diseases, comprising chlorhexidine or a salt thereof, and packaged in an ethylene oxide gas sterilized container.

[0025] (17) Use of a pharmaceutical composition containing chlorhexidine or a salt thereof and contained in an ethylene oxide gas sterilized container for the manufacture of a medicament for treating and / or preventing an eye disease.

[0026] (18) A method for treating and / or preventing an eye disease, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition containing chlorhexidine or a salt thereof and contained in an ethylene oxide gas sterilized container.

[0027] (19) A pharmaceutical product in which a pharmaceutical composition containing chlorhexidine or a salt thereof is contained in an ethylene oxide gas sterilized container.

[0028] It should be noted that any two or more of the above configurations (1) to (19) can be selected and combined. [Effects of the Invention]

[0029] According to the present invention, it is possible to suppress the decrease in the content of chlorhexidine or a salt thereof in a pharmaceutical composition over time, and to provide a pharmaceutical composition containing chlorhexidine or a salt thereof that maintains antiseptic properties for a long period of time and is packaged in an ethylene oxide gas sterilized container. Furthermore, the pharmaceutical composition of the present invention has low cytotoxicity and can be used safely as a medicine. DETAILED DESCRIPTION OF THE INVENTION

[0030] The present invention will be described in detail below, but the present invention is not particularly limited thereto.

[0031] The pharmaceutical composition of the present invention is a pharmaceutical composition containing chlorhexidine or a salt thereof, which is placed in an ethylene oxide gas sterilized container.

[0032] The chlorhexidine contained in the pharmaceutical composition of the present invention is represented by the formula (1): [ka] It is a compound represented by the chemical name 1-[amino-[6-[amino-[amino-(4-chlorophenyl)amino-methylidene]amino-methylidene]aminohexylimino]methyl]imino-N-(4-chlorophenyl)-methanediamine, etc.

[0033] The chlorhexidine contained in the pharmaceutical composition of the present invention may be a salt of chlorhexidine, and is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of chlorhexidine salts include salts with inorganic acids and salts with organic acids.

[0034] Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, etc., and hydrochlorides are preferred.

[0035] Examples of salts with organic acids include salts with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid, and the like, with gluconate and acetate being preferred.

[0036] In the pharmaceutical composition of the present invention, chlorhexidine and its salts may be in the form of a hydrate or solvate.

[0037] In the pharmaceutical composition of the present invention, the content of chlorhexidine or a salt thereof is not particularly limited as long as it is a pharmaceutically acceptable amount, but the lower limit is, for example, 0.0001% (w / v), preferably 0.0005% (w / v), more preferably 0.0007% (w / v), even more preferably 0.001% (w / v), and particularly preferably 0.002% (w / v), and the upper limit is, for example, 0.1% (w / v), preferably 0.01% (w / v), more preferably 0.007% (w / v), even more preferably 0.006% (w / v), and particularly preferably 0.005% (w / v). Furthermore, these upper and lower limits can be used in appropriate combinations. For example, by combining the lower limit of 0.002% (w / v) with the upper limits of 0.1% (w / v), 0.01% (w / v), 0.007% (w / v), 0.006% (w / v), and 0.005% (w / v), the ranges can be set as follows: 0.002 to 0.1% (w / v), 0.002 to 0.01% (w / v), 0.002 to 0.007% (w / v), 0.002 to 0.006% (w / v), and 0.002 to 0.005% (w / v). More specifically, the content of chlorhexidine or a salt thereof in the pharmaceutical composition of the present invention is, for example, preferably 0.0001 to 0.1% (w / v), more preferably 0.0005 to 0.01% (w / v), even more preferably 0.0007 to 0.007% (w / v), particularly preferably 0.001 to 0.006% (w / v), and most preferably 0.002 to 0.005% (w / v). When a chlorhexidine salt is contained in a pharmaceutical composition in which the preservative of the present invention is used, these values ​​are the content based on the mass of the salt. Note that "% (w / v)" refers to the mass (g) of the target component (here, chlorhexidine) contained in 100 mL of the pharmaceutical composition of the present invention. The same applies when the target component is an additive such as a surfactant, and when a salt or hydrate thereof is contained, these values ​​are the content based on the mass of the salt or hydrate.

[0038] The pharmaceutical composition of the present invention may contain additives as needed, such as surfactants, buffering agents, isotonicity agents, stabilizers, preservatives, antioxidants, thickening agents, and pH adjusters.

[0039] The pharmaceutical composition of the present invention can be appropriately blended with a surfactant that can be used as an additive for pharmaceuticals, such as an anionic surfactant, a cationic surfactant, or a nonionic surfactant.

[0040] Examples of anionic surfactants include phospholipids, and examples of phospholipids include lecithin.

[0041] Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl-2-alkylimidazolines, and 1-hydroxylethyl-2-alkylimidazolines.

[0042] Examples of nonionic surfactants include polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid esters, vitamin E TPGS, etc. Polyoxyethylene hydrogenated castor oil is preferred, and polyoxyethylene hydrogenated castor oil 40 is most preferred.

[0043] When a surfactant is incorporated into the pharmaceutical composition of the present invention, the content of the surfactant can be adjusted as appropriate depending on the type of surfactant, etc., but is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), even more preferably 0.1 to 3% (w / v), and most preferably 0.2 to 2% (w / v).

[0044] The pharmaceutical composition of the present invention may contain a buffering agent that can be used as a pharmaceutical additive. Examples of the buffering agent include phosphoric acid or a salt thereof, boric acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, ε-aminocaproic acid, trometamol, etc., or hydrates thereof.

[0045] Examples of phosphates include sodium phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, anhydrous sodium monohydrogen phosphate, disodium hydrogen phosphate, disodium hydrogen phosphate dodecahydrate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, etc.; examples of boric acid salts include borax, sodium borate, potassium borate, etc.; examples of citrates include citric acid monohydrate, sodium citrate, disodium citrate, etc.; examples of acetates include sodium acetate, potassium acetate, etc.; examples of carbonates include sodium carbonate, sodium hydrogen carbonate, etc.; and examples of tartrates include sodium tartrate, potassium tartrate, etc.

[0046] When a buffer is incorporated into the pharmaceutical composition of the present invention, the content of the buffer can be adjusted as appropriate depending on the type of buffer, etc., but is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), even more preferably 0.1 to 3% (w / v), and most preferably 0.2 to 2% (w / v).

[0047] The pharmaceutical composition of the present invention can be appropriately blended with an isotonicity agent that can be used as an additive for pharmaceuticals. Examples of the isotonicity agent include ionic isotonicity agents and nonionic isotonicity agents. Examples of the ionic isotonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc., with sodium chloride being preferred. Examples of the nonionic isotonicity agents include glycerin, propylene glycol, sorbitol, mannitol, etc., with mannitol being preferred.

[0048] When an isotonicity agent is incorporated into the pharmaceutical composition of the present invention, the content of the isotonicity agent can be adjusted as appropriate depending on the type of isotonicity agent, etc., but is preferably 0.01 to 10% (w / v), more preferably 0.05 to 8% (w / v), even more preferably 0.1 to 7% (w / v), and most preferably 0.5 to 5% (w / v).

[0049] The pharmaceutical composition of the present invention may be appropriately formulated with a stabilizer that can be used as a pharmaceutical additive. Examples of stabilizers include edetic acid or a salt thereof, and citric acid or a salt thereof. Examples of stabilizers include edetic acid, monosodium edetate, disodium edetate, tetrasodium edetate, sodium citrate, etc., with disodium edetate being preferred and disodium edetate dihydrate being particularly preferred.

[0050] When a stabilizer is incorporated into the pharmaceutical composition of the present invention, the content of the stabilizer can be adjusted as appropriate depending on the type of stabilizer, etc., but is preferably 0.0001 to 3% (w / v), more preferably 0.0005 to 1% (w / v), even more preferably 0.001 to 0.1% (w / v), and most preferably 0.01 to 0.05% (w / v).

[0051] In addition to chlorhexidine and its salts, the pharmaceutical composition of the present invention may contain preservatives that can be used as pharmaceutical additives, such as benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, and chlorobutanol.

[0052] When a preservative is incorporated into the pharmaceutical composition of the present invention, the content of the preservative can be adjusted as appropriate depending on the type of preservative, etc., but is preferably 0.0001 to 3% (w / v), more preferably 0.0005 to 2% (w / v), even more preferably 0.0007 to 1% (w / v), and most preferably 0.001 to 0.1% (w / v).

[0053] The pharmaceutical composition of the present invention may contain an antioxidant that can be used as an additive in pharmaceuticals, such as ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, and sodium sulfite.

[0054] When an antioxidant is incorporated into the pharmaceutical composition of the present invention, the content of the antioxidant can be adjusted as appropriate depending on the type of antioxidant, etc., but is preferably 0.0001 to 1% (w / v), more preferably 0.0005 to 0.5% (w / v), even more preferably 0.01 to 0.1% (w / v), and most preferably 0.001 to 0.01% (w / v).

[0055] The pharmaceutical composition of the present invention can be appropriately blended with a thickening agent that can be used as an additive for pharmaceuticals. Examples of thickening agents include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, etc.

[0056] When a thickener is incorporated into the pharmaceutical composition of the present invention, its content can be appropriately adjusted depending on the type of thickener, etc. In the pharmaceutical composition of the present invention, the lower limit of the content of the thickener is, for example, 0.001% (w / v), preferably 0.0015% (w / v), more preferably 0.005% (w / v), even more preferably 0.01% (w / v), particularly preferably 0.1% (w / v), and most preferably 0.3% (w / v), and the upper limit is, for example, 5% (w / v), preferably 4% (w / v), more preferably 3% (w / v), even more preferably 2% (w / v), particularly preferably 1% (w / v), and most preferably 0.9% (w / v). Furthermore, these upper and lower limits can be used in appropriate combination. More specifically, the content of the thickener in the pharmaceutical composition of the present invention is, for example, 0.001 to 5% (w / v), preferably 0.0015 to 4% (w / v), more preferably 0.005 to 3% (w / v), even more preferably 0.01 to 2% (w / v), particularly preferably 0.1 to 1% (w / v), and most preferably 0.3 to 0.9% (w / v). The pharmaceutical composition of the present invention may not contain a thickener.

[0057] The pharmaceutical composition of the present invention may contain a pH adjuster that can be used as a pharmaceutical additive, such as hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, or sodium bicarbonate, with hydrochloric acid, sodium hydroxide, or citric acid being preferred.

[0058] The pH of the pharmaceutical composition of the present invention is not particularly limited as long as it is a pharmaceutically acceptable pH, and is preferably 4.0 to 8.5, more preferably 4.5 to 8.0, even more preferably 5.0 to 7.8, and most preferably 5.5 to 7.5.

[0059] The pharmaceutical composition of the present invention may contain one or more, preferably one to three, and more preferably one or two drugs. Examples of drugs include steroids such as fluorometholone, hydrocortisone, triamcinolone, fluocinolone, dexamethasone, and betamethasone; prostaglandin derivatives such as isopropyl unoprostone, latanoprost, bimatoprost, and travoprost; immunosuppressants such as cyclosporine, sirolimus, and FK506; antiallergic agents such as olopatadine and azelastine; nonsteroidal anti-inflammatory drugs such as indomethacin, bromfenac, and diclofenac; carbonic anhydrase inhibitors such as dorzolamide and brinzolamide; and beta-receptor blockers such as timolol and carteolol. The pharmaceutical composition of the present invention may further contain, preferably, an ophthalmic drug, more preferably a prostaglandin derivative, and even more preferably bimatoprost, latanoprost, or travoprost.

[0060] When a drug is incorporated into the pharmaceutical composition of the present invention, the content can be adjusted appropriately depending on the type of drug, etc., but is preferably 0.00001 to 10% (w / v), more preferably 0.0005 to 5% (w / v), even more preferably 0.001 to 3% (w / v), and most preferably 0.001 to 2% (w / v).

[0061] The pharmaceutical composition of the present invention is placed in an ethylene oxide gas sterilization container. After the pharmaceutical composition of the present invention is placed in the ethylene oxide gas sterilization container, the ethylene oxide gas sterilization container can be sealed in a conventional manner.

[0062] In the pharmaceutical composition of the present invention, the ethylene oxide gas sterilization container is not particularly limited as long as it is a container sterilized using ethylene oxide gas, and examples thereof include eye drop containers, preferably multi-dose eye drop containers. Multi-dose eye drop containers are eye drop containers with caps that can be freely opened and closed for multiple uses. They may also be placed in PFMD (Preservative-Free Multi-Dose) eye drop containers, which have special structures to provide antiseptic effects such as backflow prevention. The eye drop container may be formed from one or more components, and may be one-piece, two-piece, or three-piece. For example, a three-piece eye drop container is formed from three components: a container body that holds the pharmaceutical composition of the present invention, an inner stopper, and a cap. Furthermore, an integrally molded container that is simultaneously blow-molded and filled with a drug solution is also included in the above-mentioned eye drop container, depending on the number of components. Furthermore, when a container is formed from multiple components, the components may be formed from the same material or from different materials. Furthermore, a material may constitute or coat part or all of the components. The container may be commercially available or may be manufactured by a known method.

[0063] In the pharmaceutical composition of the present invention, the material of the ethylene oxide gas sterilization container is not particularly limited, and resins can be used, such as polyethylene (PE), polypropylene (PP), polypropylene-polyethylene copolymer, polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polyvinyl chloride, acrylic resin, and polystyrene. Polyethylene is further classified by density, and examples include low-density polyethylene (LDPE), medium-density polyethylene (MDPE), and high-density polyethylene (HDPE). Preferred examples include polyethylene, polypropylene, propylene-ethylene copolymer, and polyethylene terephthalate, with polypropylene and propylene-ethylene copolymer being particularly preferred. Here, the propylene-ethylene copolymer is not particularly limited as long as it is a propylene polymer containing an ethylene component, but is preferably a propylene polymer containing 10 mol% or less of an ethylene component.

[0064] In the present invention, the residual ethylene oxide concentration in the ethylene oxide gas sterilized container is, for example, 0 to 10 ppm, preferably 0 to 5 ppm, more preferably 0 to 1 ppm, even more preferably 0 to 0.5 ppm or less, and most preferably undetectable. This can be measured in accordance with the "Method for Determining Residual Ethylene Oxide in Medical Devices" of the Japan Medical Plastics Association.

[0065] In the present invention, the ethylene oxide gas sterilization is not particularly limited as long as it can sterilize the container using ethylene oxide gas. For example, the container can be sterilized by exposing it to ethylene oxide gas at a predetermined temperature and a predetermined relative humidity for a predetermined time, and then aeration can be performed, if necessary, to remove the ethylene oxide gas.

[0066] In the present invention, the gas used in ethylene oxide gas sterilization may be ethylene oxide gas alone or a mixed gas with carbon dioxide, etc. When a mixed gas is used, the volume ratio of ethylene oxide gas to other gases is, for example, 5:95 to 50:50, preferably 10:90 to 40:60, more preferably 15:85 to 30:70, and most preferably 20:80.

[0067] In the present invention, the temperature for ethylene oxide gas sterilization is, for example, 20 to 80°C, and preferably 30 to 60°C.

[0068] In the present invention, the relative humidity for ethylene oxide gas sterilization is, for example, 20 to 90%, preferably 30 to 80%.

[0069] In the present invention, the time for ethylene oxide gas sterilization is, for example, 1 to 10 hours, preferably 2 to 5 hours.

[0070] In the present invention, aeration is not necessarily required after ethylene oxide gas sterilization. However, if aeration is performed, air, nitrogen, argon, or carbon dioxide can be used, and the aeration time is preferably 8 hours or longer, more preferably 12 hours or longer, and most preferably 24 hours or longer.

[0071] Although chlorhexidine or a salt thereof remains stable for a long period of time in the pharmaceutical composition of the present invention even when stored at room temperature, chlorhexidine or a salt thereof can be maintained stable for an even longer period of time by storing it at a lower temperature. When storing the pharmaceutical composition of the present invention, the storage temperature is preferably −30° C. or higher and 30° C. or lower, more preferably −25° C. or higher and 25° C. or lower, and even more preferably −15° C. or higher and 15° C. or lower.

[0072] A pharmaceutical composition of the present invention can be said to be a pharmaceutically stable formulation if it retains a concentration of chlorhexidine or a salt thereof of at least 60% after a certain storage period compared to the amount at the time of preparation (i.e., if the residual rate is 60% or more). The pharmaceutical composition of the present invention maintains a concentration of chlorhexidine or a salt thereof in the pharmaceutical composition of 60 to 100%, preferably 70 to 99.9%, more preferably 80 to 99.8%, even more preferably 90 to 99.7%, particularly preferably 95 to 99.6%, and most preferably 97 to 99.5% after a certain storage period compared to the amount of chlorhexidine or a salt thereof at the time of preparation of the pharmaceutical composition.

[0073] The pharmaceutical composition of the present invention is stable over a storage period of 1 week to 5 years, preferably 1 month to 4 years, more preferably 3 months to 3 years, and most preferably 6 months to 2 years.

[0074] The dosage form of the pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a pharmaceutical, and may be, for example, an eye drop, which can be produced according to a conventional method in the art.

[0075] The pharmaceutical composition of the present invention may be, for example, a solution, a suspension, or an emulsion, and the solvent or dispersion medium is preferably water, and most preferably an aqueous solution.

[0076] The present invention provides a pharmaceutical product comprising a pharmaceutical composition containing chlorhexidine or a salt thereof contained in an ethylene oxide gas sterilization container.The present invention also provides a pharmaceutical product comprising a pharmaceutical composition containing chlorhexidine or a salt thereof and an ethylene oxide gas sterilization container containing the pharmaceutical composition.The present invention also provides a pharmaceutical product in which a pharmaceutical composition containing chlorhexidine or a salt thereof is contained in an ethylene oxide gas sterilization container.The pharmaceutical product of the present invention is a pharmaceutical composition containing chlorhexidine or a salt thereof contained in an ethylene oxide gas sterilization container.The pharmaceutical product is preferably an ophthalmic product, an otolaryngological product, or a dermatological product, and more preferably an ophthalmic product.Examples of ophthalmic products include eye drops, injections, eye ointments, and inserts.

[0077] The above detailed description of the pharmaceutical composition of the present invention also applies to the method of stabilizing chlorhexidine or a salt thereof, the method of producing a pharmaceutical product, the use of the pharmaceutical product, the pharmaceutical composition, the method of treating and / or preventing eye diseases, and the pharmaceutical product of the present invention.

[0078] The method of the present invention for stabilizing chlorhexidine or a salt thereof comprises placing a pharmaceutical composition containing chlorhexidine or a salt thereof into an ethylene oxide gas sterilization container.

[0079] According to the method of the present invention for stabilizing chlorhexidine or a salt thereof, the stability of chlorhexidine or a salt thereof in a pharmaceutical composition is maintained, and a decrease in its content is controlled.

[0080] The method for producing the pharmaceutical product of the present invention comprises sterilizing a container with ethylene oxide gas and placing a pharmaceutical composition containing chlorhexidine or a salt thereof therein. [Example]

[0081] Formulation examples and the results of stability tests and cytotoxicity tests are shown below, but these are intended to provide a better understanding of the present invention and are not intended to limit the scope of the present invention.

[0082] Formulation example Representative formulation examples of the present invention are shown below. Note that the amount of each ingredient in the formulation examples below is the content per 1 mL of the formulation.

[0083] Formulation Example 1 Sodium citrate monohydrate 0.2mg Chlorhexidine gluconate 0.01mg Edetate disodium dihydrate 0.1mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 6.5

[0084] Formulation Example 2 Disodium hydrogen phosphate dodecahydrate 5mg Chlorhexidine gluconate 0.03mg D-mannitol 30mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 7.5

[0085] Formulation Example 3 Bimatoprost 30mg Sodium citrate monohydrate 0.2mg Chlorhexidine gluconate 0.01mg Edetate disodium dihydrate 0.1mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 6.5

[0086] Formulation Example 4 Travoprost 4mg Disodium hydrogen phosphate dodecahydrate 5mg Chlorhexidine gluconate 0.03mg D-mannitol 30mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 7.5

[0087] The desired composition can be obtained by appropriately adjusting the types and amounts of chlorhexidine and additives in Formulation Examples 1 and 2, as well as the pH.

[0088] Stability testing 1. Preparation of test formulations 0.06 g of bimatoprost, 0.716 g of disodium hydrogen phosphate dodecahydrate, 0.028 g of citric acid monohydrate, 0.02 g of edetate disodium dihydrate, 1.66 g of sodium chloride, and 2 mL of chlorhexidine gluconate solution diluted to 0.2% with water were dissolved in 180 mL of water, and sodium hydroxide / dilute hydrochloric acid was added to adjust the pH, and the total volume was adjusted to 200 mL to prepare the formulation of Example 1. Furthermore, the formulations of Examples 2 to 26 and Comparative Examples 1 to 5 were prepared in a similar manner.

[0089] 2. Test Method Example 5 mL resin containers (polyethylene, Petrothene, manufactured by Tosoh Corporation) were subjected to ethylene oxide gas sterilization (ethylene oxide / carbon dioxide concentrations of 20% / 80% (V / V), temperature 40°C, relative humidity 50%, sterilization for 3 hours), and then 5 mL of the formulations of Examples 1 to 26 were placed in the containers, stoppers were attached, and caps were attached. After storage for the periods listed in Tables 2 to 7 under conditions of temperature: 60°C or 50°C, humidity: normal and in the dark, or temperature: approximately 25°C, humidity: normal and 1000 lx / hr, the chlorhexidine concentration in the formulations was measured by high-performance liquid chromatography, and the residual chlorhexidine rate was calculated using the concentration at the start of storage as the reference (100%). The results are shown in Tables 1 to 7. High-performance liquid chromatography was performed using a Waters UPLC under the following conditions. The column, AQCUITY BEH C18 (100 mm x 2.1 mm, particle size 1.7 μm), was kept at a constant temperature of around 50°C, and measurements were performed using a pH 2.5 triethylamine-perchloric acid solution / acetonitrile at a flow rate of approximately 0.5 mL per minute, controlling the proportion of acetonitrile using the gradient function.

[0090] Comparison example For the preparations of Comparative Examples 1 to 5, the chlorhexidine content was calculated in the same manner as in Examples 1 to 26, except that the ethylene oxide gas sterilization treatment was changed to electron beam sterilization treatment (accelerating voltage 4.0 MV, electron current 20 mA, 18 kGy).

[0091] 3. Test results and discussion The test results are shown in Tables 1 to 7.

[0092] [Table 1]

[0093] [Table 2]

[0094] [Table 3]

[0095] [Table 4]

[0096] [Table 5]

[0097] [Table 6]

[0098] [Table 7]

[0099] As can be seen from Tables 1 to 7, the preparations of Examples 1 to 26 contained in containers sterilized by ethylene oxide gas showed higher chlorhexidine retention rates against both heat and light than the preparations of Comparative Examples 1 to 5 contained in containers sterilized by electron beam irradiation.These results demonstrate that, regardless of the presence or type of drug, placing a pharmaceutical composition containing chlorhexidine or a salt thereof in an ethylene oxide gas sterilized container maintains the stability of chlorhexidine or a salt thereof in the pharmaceutical composition against heat and light, and prevents a decrease in its content.

[0100] Cytotoxicity test 1. Preparation of test formulations In the same manner as in the preparation of Example 1, the preparations of Examples 27 to 29 and Comparative Example 6 were prepared.

[0101] 2. Test Method SV40-immortalized human corneal epithelial cells (HCE-T: RIKEN BioResource Center, Cell No.: RCB2280) were seeded in a 96-well plate (1 × 10 4The cells were cultured in D-MEM / F12 medium containing 10% FBS for 2 days. The medium was replaced with DMEM / F-12, or the formulations of Examples 27 to 29, or Comparative Example 6, and the corneal epithelial cells were then cultured for 30 or 60 minutes. The number of viable cells (corresponding to absorbance at 490 nm) was measured using a Cell Proliferation Assay Kit (Promega, catalog number: G3580). The percentage of the absorbance value of each Example and Comparative Example relative to the DMEM / F-12 group was calculated to obtain the cell viability (%).

[0102] 3. Test results and discussion The test results are shown in Table 8.

[0103] [Table 8]

[0104] As can be seen from Table 8, the formulations of Examples 27 to 29, which contained chlorhexidine as a preservative, showed much higher cell viability than the formulation of Comparative Example 6, which contained SofZia (registered trademark) (a preservative system consisting of boric acid, propylene glycol, D-sorbitol, and zinc chloride).These results demonstrate that the pharmaceutical composition of the present invention has low cytotoxicity and can be used safely as a pharmaceutical.

Claims

1. A method for stabilizing chlorhexidine or a salt thereof by placing a pharmaceutical composition containing chlorhexidine or a salt thereof as an additive in an ethylene oxide gas sterilized container.

2. 2. The method according to claim 1, wherein the residual rate of chlorhexidine or a salt thereof after storage at 60°C for 4 weeks is 90% or more.

3. 2. The method according to claim 1, wherein the residual rate of chlorhexidine or a salt thereof after storage at 60°C for 4 weeks is 96% or more.

4. 2. The method according to claim 1, wherein the residual rate of chlorhexidine or a salt thereof after storage at 60°C for 4 weeks is 100% or more.

5. 2. The method according to claim 1, wherein the residual rate of chlorhexidine or a salt thereof after storage for 27 days under conditions of 1000 lx / hr is 96% or more.

6. 10. The method of claim 1, wherein chlorhexidine or a salt thereof is the antiseptic.

7. 2. The method of claim 1, wherein the pH of the pharmaceutical composition is 6.0 to 7.

3.

8. 2. The method of claim 1, wherein the pH of the pharmaceutical composition is 6.0 to 6.

5.

9. 2. The method according to claim 1, wherein the content of chlorhexidine or a salt thereof is 0.001 to 0.006% (w / v).

10. 2. The method according to claim 1, wherein the content of chlorhexidine or a salt thereof is 0.002 to 0.005% (w / v).

11. 2. The method according to claim 1, wherein the content of chlorhexidine or a salt thereof is 0.002% (w / v).

12. The method of claim 1, wherein the container is made of resin.

13. A method for stabilizing chlorhexidine or a salt thereof against heat, comprising placing a pharmaceutical composition containing 0.001 to 0.006% (w / v) of chlorhexidine or a salt thereof as an additive in a container for ethylene oxide gas sterilization, wherein the pH of the pharmaceutical composition is 6.0 to 7.3, and the container is made of resin.

14. 14. The method of claim 1, 12 or 13, wherein the container is made of polyethylene.

15. A method for stabilizing chlorhexidine or a salt thereof against heat and light, comprising placing a pharmaceutical composition containing 0.001 to 0.006% (w / v) of chlorhexidine or a salt thereof as an additive in a container for ethylene oxide gas sterilization, wherein the pH of the pharmaceutical composition is 6.0 to 7.3, and the container is made of polyethylene.

16. A method for stabilizing chlorhexidine or a salt thereof against heat and light, which comprises placing a pharmaceutical composition containing chlorhexidine or a salt thereof at a content of 0.001 to 0.006% (w / v) as an additive into an ethylene oxide gas sterilization container, wherein the pharmaceutical composition has a pH of 6.0 to 7.3, and the container is made of polyethylene; When stored at 60°C, the residual rate of chlorhexidine or its salts after 4 weeks is 96% or more, A method in which the residual rate of chlorhexidine or a salt thereof is 96% or more after 27 days when stored under conditions of 1000 lx / hr.

17. A method for stabilizing chlorhexidine or a salt thereof against heat, comprising placing a pharmaceutical composition containing 0.001 to 0.006% (w / v) of chlorhexidine or a salt thereof as an additive in an ethylene oxide gas sterilized container, wherein the pH of the pharmaceutical composition is 6.0 to 6.5, the container is made of polyethylene, and the residual rate of chlorhexidine or a salt thereof after storage at 60°C for 4 weeks is 100% or more.

18. A method for stabilizing chlorhexidine or a salt thereof by placing a pharmaceutical composition containing a drug and chlorhexidine or a salt thereof as an additive in an ethylene oxide gas sterilization container, wherein the drug is bimatoprost, latanoprost, travoprost, or sodium hyaluronate.

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