TW201906597A - Medicinal composition containing water-soluble thickening agent - Google Patents

Abstract

Provided is a medicinal composition containing a water-soluble thickening agent, wherein a decrease in the viscosity of the medicinal composition is prevented. The medicinal composition according to the present invention, which contains a water-soluble thickening agent, is housed in an ethylene oxide gas-sterilized container.

Description

Pharmaceutical composition containing water-soluble viscosifying agent

The present invention relates to a pharmaceutical composition comprising a water-soluble viscosifying agent and contained in an ethylene oxide gas sterilization container.

Aqueous liquids such as eye drops are administered directly to the eye of a particularly sensitive organ in the human body, so it is strictly required to maintain sterility until the opening of the eye drop container. The container for storing the aqueous liquid is different from the injection for filling into a glass container, and many of them are resin containers formed by molding a synthetic resin such as polyethylene, polypropylene or propylene-ethylene copolymer. Since these resin containers are inferior in heat resistance, for example, it is not easy to fill the aqueous liquid container in a resin container and then heat-sterilize. Therefore, it is required to make the resin container itself sterilized before filling with the aqueous liquid agent. As a sterilization method of a resin container, gamma ray sterilization, electron beam sterilization, ethylene oxide gas (EOG) sterilization, hydrogen peroxide sterilization, and the like are known.

On the other hand, in the eye drops, in order to improve the persistence of the effect or the migration of the eye by adjusting the viscosity for a long time to stay on the surface of the eye, a thickening agent is used in the industry. However, it is known that a water-soluble thickening agent is added to an eye drop versatility in a versatile manner, and on the other hand, a viscosity of a liquid agent is often lowered during storage for a long period of time due to preparation with an aqueous liquid preparation. As a method of suppressing a decrease in viscosity of an aqueous liquid preparation containing a water-soluble thickening agent, for example, Patent Document 1 discloses that a polyoxygen is formulated into an aqueous liquid preparation containing hypromellose and/or hydroxyethylcellulose. Ethylene-hardened castor oil and/or polyoxyl stearate; in Patent Document 2, a non-ionic surfactant and a specific vegetable oil are blended into a cellulose-based thickener; and Patent Document 3 describes a direction. In the water-soluble polymer compound, dibutylhydroxytoluene, butylhydroxyanisole, ascorbic acid or a salt thereof and/or sulfurous acid or a salt thereof are prepared, and further, a package for making an inert gas atmosphere around the container or deoxidizing is used. In this way, a particularly excellent viscosity reduction preventing effect can be obtained.

However, it has not been known so far that the sterilization method of the container affects the viscosity reduction of the pharmaceutical composition containing the water-soluble thickening agent. [Prior Technical Literature] [Patent Literature]

[Patent Document 1] International Publication No. WO2014-050301 [Patent Document 2] Japanese Patent Laid-Open No. 2011-068684 [Patent Document 3] Japanese Patent Laid-Open No. 2004-123634

[The problem that the invention wants to solve]

It is a subject of great interest to provide a pharmaceutical composition containing a water-soluble viscosifying agent and having a reduced viscosity. [Technical means to solve the problem]

The inventors of the present invention have diligently studied to suppress the decrease in the viscosity of a pharmaceutical composition containing a water-soluble thickening agent, and as a result, it has been unexpectedly found that the sterilization method of the container containing the pharmaceutical composition containing the water-soluble thickening agent will be as described above. In the pharmaceutical composition containing the water-soluble thickening agent, the pharmaceutical composition containing the water-soluble thickening agent is contained in a container sterilized by ethylene oxide gas, thereby suppressing the decrease in the viscosity of the pharmaceutical composition. The present invention has been completed. Specifically, the present invention provides the following.

(1) A pharmaceutical composition comprising a water-soluble viscosifying agent and contained in an ethylene oxide gas sterilization container. (2) The pharmaceutical composition according to (1), wherein the water-soluble viscosifying agent is selected from the group consisting of a cellulose polymer, a polyvinylpyrrolidone, a carboxyvinyl polymer, and a polyhydric alcohol. One or more water soluble viscosifiers. (3) The pharmaceutical composition according to (2), wherein the cellulose-based polymer is one selected from the group consisting of hydroxyethylcellulose, hydroxymethylcellulose, and hydroxypropylmethylcellulose. Or a plurality of cellulose-based polymers. The pharmaceutical composition according to any one of (1) to (3), wherein the content of the water-soluble thickening agent is 0.001 to 10% (w/v). (5) The pharmaceutical composition according to any one of (1) to (4) wherein the container is a resin container. (6) The pharmaceutical composition according to (5), wherein the resin container is made of polyethylene, polypropylene, or polyethylene terephthalate. (7) A pharmaceutical composition comprising a cellulose-based polymer as a water-soluble viscosifying agent and contained in a container made of an ethylene oxide gas sterilizing resin. (8) The pharmaceutical composition according to any one of (1) to (7) which is an aqueous eye drop. (9) The pharmaceutical composition according to any one of (1) to (8) which is a glaucoma therapeutic agent. (10) The pharmaceutical composition according to any one of (1) to (9), which contains Dorzolamide or a salt thereof as an active ingredient. (11) A pharmaceutical composition comprising, as an active ingredient, dorzolamide or a salt thereof, and Timolol or a salt thereof, and hydroxyethylcellulose as a water-soluble viscosifying agent, and contained in Ethylene oxide gas sterilization resin container. (12) A method for inhibiting a decrease in viscosity of a pharmaceutical composition, which comprises inhibiting a decrease in viscosity of a pharmaceutical composition by containing a pharmaceutical composition containing a water-soluble thickening agent in an ethylene oxide gas sterilization container. (13) A method for improving the stability of a pharmaceutical composition, which comprises enhancing a stability of a pharmaceutical composition by accommodating a pharmaceutical composition containing a water-soluble thickening agent in an ethylene oxide gas sterilization container.

The present invention is also related to the following. (14) A pharmaceutical composition for treating and/or preventing an eye disease, which comprises a water-soluble viscosifying agent and is contained in an ethylene oxide gas sterilization container. (15) A pharmaceutical composition for use in the treatment and/or prevention of an eye disease, comprising a water-soluble viscosifying agent, and being contained in an ethylene oxide gas sterilization container. (16) A pharmaceutical composition for use in the manufacture of a medicament for treating and/or preventing an eye disease, and the pharmaceutical composition comprising a water-soluble thickening agent and contained in an ethylene oxide gas sterilization container . (17) A method for treating and/or preventing an eye disease, comprising administering an effective amount of a pharmaceutical composition containing a water-soluble viscosifying agent and contained in an ethylene oxide gas sterilizing container to a subject in need thereof. (18) A pharmaceutical product comprising a pharmaceutical composition contained in an ethylene oxide gas sterilization container and containing a water-soluble viscosifying agent.

Further, each of the above configurations (1) to (18) may be arbitrarily selected by combining two or more types. [Effects of the Invention]

According to the present invention, a pharmaceutical composition containing a water-soluble viscosifying agent can be obtained, and the viscosity reduction of the above pharmaceutical composition can be suppressed.

Hereinafter, the present invention will be described in detail.

The water-soluble thickening agent in the present invention may be a water-soluble thickening agent which can be used as an additive for pharmaceuticals, and examples thereof include a cellulose polymer, a polyvinylpyrrolidone, and a carboxyvinyl group. The polymer, mucopolysaccharide or polyol may further be a hydrate or solvate thereof.

Examples of the cellulose-based polymer include nonionic cellulose and anionic cellulose. Examples of the nonionic cellulose include methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, and hydroxypropyl group. Examples of the anionic cellulose include methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose succinate, hydroxypropyl methyl cellulose phthalate, and carboxymethyl. The ethyl ethyl cellulose, cellulose acetate phthalate or the like is preferably nonionic cellulose, more preferably hydroxymethyl cellulose, hydroxyethyl cellulose or hydroxypropyl methyl cellulose, and further preferably. It is hydroxyethyl cellulose or hydroxypropyl methylcellulose.

Examples of the mucopolysaccharide include hyaluronic acid, chondroitin sulfate, and heparin.

Examples of the polyhydric alcohol include polyethylene glycol and polyvinyl alcohol.

The water-soluble thickening agent in the present invention is preferably a cellulose-based polymer, a polyvinylpyrrolidone or a polyhydric alcohol, more preferably a cellulose-based polymer or a polyvinylpyrrolidone, and more preferably a hydroxyethyl group. Cellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose or polyvinylpyrrolidone, preferably hydroxyethylcellulose, hydroxypropylmethylcellulose or polyvinylpyrrolidone.

In the pharmaceutical composition of the present invention, two or more kinds of water-soluble viscosifying agents may be used singly or in combination.

The content of the water-soluble thickening agent to be added to the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the water-soluble thickening agent, etc., and is preferably 0.001 to 10% (w/v), more preferably 0.01%. 5% (w/v), further preferably 0.1 to 2% (w/v), particularly preferably 0.2 to 1% (w/v).

In addition, "% (w/v)" means the mass (g) of the target component contained in 100 mL of the pharmaceutical composition of this invention. Hereinafter, it is considered the same unless otherwise specified.

The sterilizing of the ethylene oxide gas in the present invention is not particularly limited as long as it is a method of sterilizing using ethylene oxide gas, and is carried out, for example, in the following order: at a specific temperature and a specific humidity. The container is exposed to ethylene oxide gas for a sufficient period of time for sterilization, and is sterilized, and thereafter, air is dispensed for the purpose of removing the ethylene oxide gas.

In the present invention, the temperature at which the ethylene oxide gas is sterilized can be appropriately selected depending on the characteristics of the container, and is preferably from 30 to 60 °C.

In the present invention, the humidity (relative humidity) at which the ethylene oxide gas is sterilized can be appropriately selected depending on the characteristics of the container, and is preferably from 30 to 80%.

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

In the present invention, the gas used for the sterilization of the ethylene oxide gas may be only ethylene oxide gas or a mixed gas with carbon dioxide or the like. The ratio of ethylene oxide gas to other gases in the case of using a mixed gas is, for example, 5:95 to 50:50, preferably 10:90 to 40:60, more preferably 20:80 to vol. 30:70.

In the present invention, the concentration of the gas used in the sterilization of the ethylene oxide gas can be appropriately selected depending on the characteristics of the container, and is preferably from 120 to 1200 mg/L.

In the present invention, the air distribution for removing the ethylene oxide gas is not necessarily required, and in the case of performing the air distribution, for example, air, nitrogen, argon, carbon dioxide, or the like may be used, and the air distribution time is preferably 8 hours or longer. More preferably, it is 12 hours or more, and further preferably 24 hours or more.

In the present invention, the ethylene oxide gas sterilization container refers to a container which is sterilized by ethylene oxide gas. The container to be used may be a container which can be sterilized by using ethylene oxide gas, and is preferably a resin container. Examples of the material of the resin container include polyethylene, polypropylene, polyethylene terephthalate, polybutylene terephthalate, polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic resin, and poly Styrene, polycyclic olefin copolymer, and the like. Further, the polyethylene is classified according to its density, and examples thereof include low density polyethylene (LDPE), medium density polyethylene (MDPE), and high density polyethylene (HDPE).

The resin container in the present invention is preferably made of polyethylene, polypropylene, polyethylene terephthalate, polypropylene-polyethylene copolymer or polycyclic olefin copolymer, more preferably Made of polyethylene or polypropylene.

When the pharmaceutical composition of the present invention is used as an eye drop, the eye drop container may be formed of one member or a plurality of members, and may be housed in a one-piece eye drop container, a two-piece eye drop container, or three pieces. In any of the eye drop containers. Further, for example, in the case of a three-piece eye drop container, the container body of the pharmaceutical composition of the present invention is formed of three members of the middle plug and the lid, and at the same time, one of blow molding and liquid filling is performed. The molded container is also contained in the above-mentioned eye drop container depending on the number of members. Further, in the case where the container is formed of a plurality of members, it may be formed of members of the same material or may be formed of members of different materials. Further, it may be a part or all of the material constituent members or may be applied. These so-called materials refer to the materials listed above, namely, polyethylene (including LDPE, MDPE, HDPE), polypropylene, polyethylene terephthalate, polybutylene terephthalate, polypropylene-poly An ethylene copolymer, a polyvinyl chloride, an acrylic resin, a polystyrene, a polycyclic olefin copolymer, or the like.

In the present invention, the residual ethylene oxide gas concentration in the ethylene oxide gas sterilization container is, for example, 0 to 10 ppm, preferably 0 to 5 ppm, more preferably 0 to 1 ppm, and most preferably undetected. . Further, the residual ethylene oxide gas concentration can be measured in accordance with the "Measurement Method for Residual Ethylene Oxide of Medical Devices" by the Japan Medical Plastics Association.

The pharmaceutical composition of the present invention is contained in an ethylene oxide gas sterilization container. The present invention provides a medical product comprising a pharmaceutical composition contained in an ethylene oxide gas sterilization container and containing a water-soluble viscosifying agent. Moreover, the present invention provides a pharmaceutical product comprising a pharmaceutical composition containing a water-soluble thickening agent and an ethylene oxide gas sterilization container containing the pharmaceutical composition. Moreover, the present invention provides a pharmaceutical product comprising a pharmaceutical composition containing a water-soluble viscosifying agent in an ethylene oxide gas sterilization container. Moreover, the present invention provides a medical product obtained by accommodating a pharmaceutical composition containing a water-soluble viscosifying agent in an ethylene oxide gas sterilization container. Here, the pharmaceutical product of the present invention is in a state in which a pharmaceutical composition containing a water-soluble thickening agent is contained in an ethylene oxide gas sterilization container. The medical product is preferably an ophthalmic product, an otolaryngology product, a skin product, and more preferably an ophthalmic product. Examples of the ophthalmic product include products such as eye drops, injections, eye ointments, and inserts.

The pharmaceutical composition of the present invention can be administered to a patient orally or parenterally. Examples of the administration form include oral administration, topical administration to the eye, local administration to the ear and nose, and administration by inhalation. , spray administration, intravenous administration, subcutaneous administration, transdermal administration, etc., preferably administered to the eye.

In the present invention, the topical administration to the eye means eyedrop administration, intraconjunctival administration, intravitreal administration, subconjunctival administration, or intraocular capsular capsular administration.

The pharmaceutical composition of the present invention can be formulated into a dosage form suitable for administration, as needed, together with a pharmaceutically acceptable additive. A dosage form suitable for parenteral administration is preferred, and examples thereof include eye drops, nasal drops, ear drops, inhalants, injections, ophthalmic ointments, insertion agents, percutaneous absorption preparations, and external preparations. A spray or the like is more preferably an eye drop or an injection, and further preferably an eye drop, and particularly preferably an aqueous eye drop.

The pharmaceutical composition of the present invention may contain an active ingredient of the drug. The active ingredient is not particularly limited and may be appropriately selected depending on the purpose. For example, in the case of use in the case of eye drops, it is preferably used as a treatment for glaucoma, preferably Isopropyl unoprostone or carteolol. (Carteolol), Distigmine, Dipivefrine, Tafluprost, Dropper, Travoprost, Doxorubicin, Niprodilol ), Bimatoprost, Pilocarpine, Bunazosin, Brimonidine, Brinzolamide, Betaxolol, Latanoprost, Ripasudil, Levobunolol or such salts, for antibacterial and antiviral treatment, preferably aciclovir, erythromycin (Erythromycin), Ofloxacin, Gatifloxacin, Chloramphenicol, Gentamicin, Dibekacin, Cefmenoxime, Tosufloxacin (Tosufloxacin), Tobramycin, Norfloxacin, Wan Vancomycin, Pimaricin, Moxifloxacin, Levofloxacin, Lomefloxacin or these salts are used as anti-inflammatory treatments. Dexmethasone, dexamethasone sulfobenzoate, dexamethasone phosphate, hydrocortisone acetate, fradiomycin, fluorometholone, splash Nissonone acetate, betamethasone phosphate, sulfonic acid, glycyrrhizic acid, Diclofenac, Nepafenac, Pranoprofen, Brofenfenac Or such salts, as dry eye and corneal treatment, preferably chondroitin sulfate, diquafosol, hyaluronic acid, flavin-adenine dinucleotide, Rebamipide or such salt, for anti-allergy treatment, preferably azastat, Amlexanox, ibudistat, Epinastine, Oro Olopatadine, Cromoglycic acid, Ketotifen, cyclosporine (Cycl) Osporine), Tacrolimus, Tranilast, Pemirolast, Levocabastine or these salts, as cataracts, eye fatigue, other treatments, Preferred are Atropine, Oxybuprocaine, oxymetazoline, glutathione, Cyanocobalamin, Cyclopentolate, Tropicamide, Naphazoline, neostigmine, Pirenoxine, Phenylephrine, Lysozyme, zinc sulfate or the like. For glaucoma treatment, it is more preferably isopropyl unoprostone, carteolol, diazepam, dipivoxil, tafluprost, drip, travoprost, dorzolamide, nevi Pradilo, bimatoprost, pilocarpine, bunazolam, brimonidine, brinzolamide, betaxolol, latanoprost, Ripasudil, levobronol or these The salt is further preferably a dropper, dorzolamide or a salt thereof.

The active ingredient contained in the pharmaceutical composition of the present invention may be used alone or in combination of two or more.

The active ingredient contained in the pharmaceutical composition of the present invention may be a salt, and is not particularly limited as long as it is a salt which is acceptable as a medicine. Examples of the salt include a salt with an inorganic acid, a salt with an organic acid, a quaternary ammonium salt, a salt with a halogen ion, a salt with an alkali metal, a salt with an alkaline earth metal, a metal salt, and a salt with an organic amine. Wait.

Examples of the salt with the inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.

Examples of the salt with an organic acid include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, and glucoheptonic acid. , glucuronic acid, terephthalic acid, methanesulfonic acid, alanine, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionethane, lactobionic acid, oleic acid, gallic acid, double Hydroxynaphthoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid Wait for the salt.

Examples of the quaternary ammonium salt include salts with methyl bromide, methyl iodide and the like.

The salt with a halogen ion is, for example, a salt such as a chloride ion, a bromide ion, or an iodide ion.

Examples of the salt with an alkali metal include salts with lithium, sodium, potassium, and the like.

Examples of the salt of the alkaline earth metal include salts with calcium, magnesium, and the like.

Examples of the metal salt include salts with iron, zinc, and the like.

Examples of the salt with an organic amine include triethylethylene diamine, 2-aminoethanol, 2,2-iminobis(ethanol), and 1-deoxy-1-(methylamino). -2-D-sorbitol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine, N,N-bis(phenylmethyl)-1,2-B a salt of an alkyldiamine or the like.

The active ingredient or a salt thereof contained in the pharmaceutical composition of the present invention can be in the form of a hydrate or a solvate.

The amount of the active ingredient contained in the pharmaceutical composition of the present invention is preferably 0.01% (w/v) or more, more preferably 0.05% (w/v) or more, still more preferably 0.1% (w/v) or more. The upper limit may be a concentration which is acceptable as an ophthalmic preparation, for example, 5% (w/v). It is preferably 0.01 to 5% (w/v), more preferably 0.05 to 4% (w/v), still more preferably 0.1 to 3% (w/v), still more preferably 0.5 to 1.5% (w/ v). Further, in the case where the pharmaceutical composition of the present invention contains a salt of an active ingredient, the value is the content of the salt of the active ingredient. When the pharmaceutical composition of the present invention contains a hydrate or a solvate in the form of an active ingredient or a salt thereof, the value is the content of the hydrate or solvate of the active ingredient or a salt thereof.

In the pharmaceutical composition of the present invention, in addition to the water-soluble thickening agent and the active ingredient, an additive which can be formulated into a pharmaceutical product can be formulated within a range not impairing the effects of the present invention. In particular, in the case of a preparation which can be administered topically to the eye, a buffer, a preservative, an interfacial activator, an isotonic agent, a stabilizer, an antioxidant, a pH adjustment may be added in addition to the water-soluble thickening agent and the active ingredient. Agents, etc. These may be used singly or in combination of two or more kinds as appropriate, and may be formulated in an appropriate amount.

The buffering agent in the case of formulating the buffering agent in the pharmaceutical composition of the present invention can be appropriately formulated as a buffering agent for the additive of the pharmaceutical, and examples thereof include phosphoric acid or a salt thereof, boric acid or a salt thereof, borax, carbonic acid or The salt or the organic acid or a salt thereof may be a hydrate or a solvate thereof.

Examples of the phosphoric acid or a salt thereof include phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate, and the like.

Examples of the boric acid or a salt thereof include boric acid, sodium borate, potassium borate, and the like, and these hydrates may also be used.

Examples of the carbonic acid or a salt thereof include sodium carbonate, sodium hydrogencarbonate, and the like, and these may be hydrates.

Examples of the organic acid or a salt thereof include citric acid, acetic acid, ε-aminohexanoic acid, gluconic acid, fumaric acid, lactic acid, ascorbic acid, succinic acid, maleic acid, malic acid, and amine group. The acid or the sodium salt, potassium salt or the like may also be the hydrate.

In the case of formulating a buffer to the pharmaceutical composition of the present invention, an organic acid or a salt thereof is preferred, and citric acid or a salt thereof is more preferred, and sodium citrate is preferred.

The content of the buffering agent in the case where the buffering agent is formulated in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the buffering agent, etc., preferably 0.001 to 10% (w/v), more preferably 0.01 to 5 % (w/v), further preferably 0.1 to 5% (w/v), particularly preferably 0.1 to 1% (w/v).

The preservative in the case where the preservative is formulated in the pharmaceutical composition of the present invention can be appropriately formulated with a preservative which can be used as an additive for pharmaceuticals, and examples thereof include reverse soaps, parabens, and alcohols. And organic acids or their salts.

In the present invention, examples of the inverse soap include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, and benzethonium bromide.

In the present invention, examples of the p-hydroxybenzoic acid esters include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, and butyl p-hydroxybenzoate.

In the present invention, examples of the alcohol include chlorobutanol.

In the present invention, examples of the organic acid or a salt thereof include sorbic acid or a salt thereof and sodium dehydroacetate. Examples of the sorbic acid or a salt thereof include sodium sorbate and potassium sorbate.

The content of the preservative in the case of preparing the preservative in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the preservative, etc., as long as it is an amount which does not adversely affect the safety, and the upper limit is, for example, 1% (w/v) or less, preferably 0.5% (w/v) or less, more preferably 0.1% (w/v) or less, further preferably 0.05% (w/v) or less, and particularly preferably 0.01. %(w/v) or less. Further, the lower limit is preferably 0.0001% (w/v) or more, and more preferably 0.001% (w/v) or more, as long as it has an antiseptic effect. The content of the preservative is preferably 0.0001 to 1% (w/v), more preferably 0.001 to 0.5% (w/v), still more preferably 0.001 to 0.1% (w/v).

When the interface activator is formulated in the pharmaceutical composition of the present invention, the interface activator can be appropriately formulated as an interface activator which can be used as an additive for pharmaceuticals, and examples thereof include a cationic interface activator and an anionic interface activator. , nonionic surfactant activator, etc.

Examples of the cationic interface activator include an alkylamine salt, an alkylamine polyoxyethylene adduct, a fatty acid triethanolamine monoester salt, a decylaminoethylamine salt, and a fatty acid polyamine condensate. Alkyl imidazoline, 1-nonylamino-2-alkylimidazoline, 1-hydroxyethyl-2-alkylimidazoline, and the like.

Examples of the anionic interface activator include a phosphate lipid such as lecithin.

Examples of the nonionic surfactant activator include polyoxyethylene fatty acid esters such as polyoxyl stearate 40; polysorbate 80, polysorbate 60, polysorbate 40, and poly Polyoxyethylene sorbitan fatty acid ester such as oxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65; polyoxyethylene hardened castor oil 10, poly Oxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 50, polyoxyethylene hardened castor oil 60 and other polyoxyethylene hardened castor oil; castor oil polyoxyl ester 5, castor oil polyoxyl ester 9, castor oil polyhydrocarbon Oxygen ester 15, castor oil polyoxyl ester 35, castor oil polyoxyl ester 40 and other castor oil polyoxyl ester; polyoxyethylene (160) polyoxypropylene (30) glycol ester, polyoxyethylene (42) poly Oxypropylene (67) glycol ester, polyoxyethylene (54) polyoxypropylene (39) glycol ester, polyoxyethylene (196) polyoxypropylene (67) glycol ester, polyoxyethylene (20) polyoxypropylene (20) polyoxyethylene polyoxypropylene glycol ester such as glycol ester; sucrose fatty acid ester such as sucrose stearate; vitamin E polyethylene glycol 1000 succinate (vitamin E TPGS).

When the interface activator is formulated in the pharmaceutical composition of the present invention, it is more preferably a nonionic surfactant, more preferably a polyethylene sorbitan fatty acid ester, and particularly preferably a polysorbate 80. .

The content of the interface activator in the case where the interface activator is formulated in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the interface activator, etc., preferably 0.01 to 1% (w/v), more preferably 0.05 to 0.5% (w/v), more preferably 0.05% to 0.2% (w/v).

In the case where the isotonic agent is formulated in the pharmaceutical composition of the present invention, the isotonic agent may be appropriately formulated as an isotonic agent which can be used as an additive for a pharmaceutical, and examples thereof include an ionic isotonic agent or a nonionic isotonic agent. Agents, etc.

Examples of the ionic isotonic agent include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride.

Examples of the nonionic isotonic agent include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, and xylitol.

The content of the isotonic agent in the case where the isotonic agent is formulated in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the isotonic agent, etc., preferably 0.001 to 10% (w/v), more preferably From 0.01% to 5% (w/v), further preferably from 0.1 to 3% (w/v), particularly preferably from 0.5 to 2% (w/v).

In the case where the stabilizer is formulated in the pharmaceutical composition of the present invention, a stabilizer which can be used as an additive for a pharmaceutical product can be appropriately formulated, and examples thereof include ethylenediaminetetraacetic acid or a salt thereof.

Examples of the ethylenediaminetetraacetic acid or a salt thereof include ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, and tetrasodium ethylenediaminetetraacetate.

The content of the stabilizer in the case where the stabilizer is formulated in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the stabilizer or the like, and is preferably 0.001 to 5% (w/v), more preferably 0.01%. 1% (w/v), further preferably 0.01 to 0.1% (w/v).

The antioxidant in the case where the antioxidant is formulated in the pharmaceutical composition of the present invention can be appropriately formulated with an antioxidant which can be used as an additive for pharmaceuticals, and examples thereof include ascorbic acid, vitamin E, dibutylhydroxytoluene, sodium sulfite, and the like. .

The content of the antioxidant in the case where the antioxidant is formulated in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the antioxidant or the like, and is preferably 0.001 to 5% (w/v), more preferably 0.01%. 3% (w/v), further preferably 0.1 to 1% (w/v).

The pH adjuster in the case where the pH adjuster is formulated in the pharmaceutical composition of the present invention can be appropriately formulated with a pH adjuster which can be used as an additive for pharmaceuticals, and examples thereof include an acid or a base. Examples of the acid include, for example, an acid: Examples of the base such as hydrochloric acid, phosphoric acid, citric acid, and acetic acid include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogencarbonate.

The pH of the pharmaceutical composition of the present invention may be within the range permitted by the pharmaceutical, preferably in the range of 4.0 to 8.5 or 4.0 to 8.0, more preferably 5.0 to 8.0, still more preferably 5.5 to 7.5. . More preferably, the pH is 5.5 to 7.0, and more preferably 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0.

The osmotic pressure ratio of the pharmaceutical composition of the present invention may be in the range permitted as a pharmaceutical, and is, for example, 0.5 to 2.0, preferably 0.7 to 1.6, more preferably 0.8 to 1.4, still more preferably 0.9 to 1.2. .

The viscosity of the pharmaceutical composition of the present invention can be measured by a general method, for example, using a capillary viscometer, a rotary viscometer, a falling ball viscometer, or the like, and can be measured particularly by an Oswald viscometer.

The viscosity of the pharmaceutical composition of the present invention may be within a range acceptable as a pharmaceutical product, and is preferably 2 to 700 (mPa·s) at 25 ° C, more preferably 50 to 500 (mPa·s). It is preferably 65 to 200 (mPa·s). Here, the viscosity at 25 ° C is a value measured by an Oswald viscometer (relative viscosity).

In the pharmaceutical composition of the present invention, when the water-soluble thickening agent, the active ingredient or the additive is a hydrate, the hydration water may be a number which can be usually coordinated, and examples thereof include 1, hydrate, and 2 Hydrate, 3-hydrate, 4-hydrate, 5-hydrate, 6-hydrate, 7-hydrate, 8-hydrate, 9-hydrate, 10-hydrate, 11-hydrate, 12-hydrate, 1/2 hydrate, 3 /2 hydrate, etc.

In the pharmaceutical composition of the present invention, the constituent components may be completely dissolved or partially suspended, and more preferably, the constituent components are all dissolved in a liquid form. The solvent or dispersion medium is preferably water, most preferably an aqueous solution.

When the pharmaceutical composition of the present invention is used as an eye drop, it can be contained in a multi-dose container, a once-used unit dose type container or a PFMD (Preservative Free Multi Dose) container. Any one.

The pharmaceutical composition of the present invention may be, for example, a pharmaceutical composition for the treatment and/or prevention of an ocular disease, and examples of the eye diseases to be treated and/or prevented include glaucoma, infectious eye diseases, and inflammatory eyes. Disease, dry eye, corneal disease, allergic eye disease, cataract, eye fatigue, etc., preferably glaucoma.

In the present invention, the inhibition of the viscosity reduction of the pharmaceutical composition means that the temporal deterioration of the viscosity of the pharmaceutical composition is suppressed. Here, the decrease in the temporality of the viscosity can be achieved, for example, by the preparation of the pharmaceutical composition ( The viscosity of the material or after the filling is compared with the viscosity after a certain period of time. Further, the degree of suppression of the viscosity reduction in the present invention can be expressed, for example, by comparison with the viscosity reduction in the case of being contained in a container subjected to electron beam sterilization treatment, in which case the so-called viscosity reduction in the present invention is Inhibition can also be said to improve the viscosity. Further, the viscosity is measured by a specific viscosity measurement method.

The above detailed description of the pharmaceutical composition of the present invention is also applicable to a method for inhibiting the viscosity reduction of the pharmaceutical composition of the present invention and a method for improving the stability of the pharmaceutical composition.

A method of inhibiting the viscosity reduction of the pharmaceutical composition of the present invention comprises containing a pharmaceutical composition containing a water-soluble viscosifying agent in an ethylene oxide gas sterilization container.

A method of improving the stability of the pharmaceutical composition of the present invention comprises containing a pharmaceutical composition containing a water-soluble viscosifying agent in an ethylene oxide gas sterilization container.

In the present invention, the improvement of the stability of the pharmaceutical composition means that the temporal change of the pharmaceutical composition is inhibited, and for example, the reduction of the temporal viscosity of the pharmaceutical composition is inhibited.

The above detailed description of the pharmaceutical composition of the present invention is also applicable to the following aspects of the present invention.

One aspect of the present invention is a pharmaceutical composition for treating and/or preventing an eye disease, which comprises a water-soluble viscosifying agent and is contained in an ethylene oxide gas sterilization container.

One aspect of the present invention is a pharmaceutical composition for use in the treatment and/or prevention of an ocular disease, comprising a water-soluble viscosifying agent and contained in an ethylene oxide gas sterilizing container.

One aspect of the present invention is a pharmaceutical composition for the manufacture of a medicament for treating and/or preventing an eye disease, and the pharmaceutical composition comprising a water-soluble viscosifying agent and contained in ethylene oxide In a gas sterilization container.

One aspect of the present invention is a method for treating and/or preventing an eye disease, which comprises administering a pharmaceutical composition containing a water-soluble viscosifying agent and immersed in an oxime gas sterilization container to a subject in need thereof. the amount.

One aspect of the present invention provides a method of producing a medical article comprising accommodating a pharmaceutical composition containing a water-soluble viscosifying agent in an ethylene oxide gas sterilization container. [Examples]

The results of the formulation examples and the viscosity change test are shown below, but these are not intended to limit the scope of the present invention in order to better understand the present invention.

[Formulation Example] Representative examples of the present invention are shown below. Further, the amount of each component in the following formulation examples was the amount in the preparation 1 mL.

Formulation Example 1 Doxoramine hydrochloride 10 mg Dropper maleate 5 mg Hydroxyethylcellulose 5 mg Sodium citrate hydrate 5 mg Dilute hydrochloric acid Amount of sodium hydroxide Appropriate amount of purified water Appropriate pH 6.5 Formulation Example 2 Doxoramine hydrochloride 10 mg Hydroxypropyl methylcellulose 5 mg Sodium citrate hydrate 5 mg Dilute hydrochloric acid Amount of sodium hydroxide Appropriate amount of purified water Appropriate pH 6.5 Formulation Example 3 Doxoramine hydrochloride 20 mg Polyvinylpyrrolidone 20 mg Sodium citrate hydrate 10 mg Dilute hydrochloric acid Amount of sodium hydroxide Appropriate amount of purified water Appropriate pH 6.5 Formulation Example 4 Drops of maleic acid salt 5 mg Hydroxyethyl cellulose 5 mg Citric acid Sodium hydrate 5 mg Dilute hydrochloric acid Appropriate amount of sodium hydroxide Appropriate amount Purified water Appropriate pH 6.5 Formulation Example 5 Doxoramine hydrochloride 10 mg Hydroxyethyl cellulose 10 mg Boric acid 5 mg Dilute hydrochloric acid Amount of sodium hydroxide Appropriate amount of purified water Appropriate pH Value 6.5

[Viscosity Change Test] <Test Formulation 1> (1) Preparation of test preparations Doxoramine hydrochloride (19.759 g), chlorhexidine maleate (12.127 g), citric acid Sodium hydrate (5.219 g), disodium edetate (0.178 g), and polysorbate 80 (1.78 g) were dissolved in purified water, and purified water was added in a total amount of 710 g. A portion (412.8 g) of this aqueous solution was taken out and mixed with a 0.8% hydroxyethylcellulose solution (612.75 g), and the pH was adjusted to 5.60 to 5.70 using a pH adjuster (hydrochloric acid and/or sodium hydroxide). Purified water was added in such a manner that the total amount was 1042 g, and the test preparation 1 was prepared.

(2) Test method Polyethylene which was subjected to ethylene oxide gas (EOG) sterilization treatment (ethylene oxide concentration: 480 mg/L, temperature: 40 ° C, relative humidity: 45%, treatment time: 3 hours) The test container 1 prepared in (1) was filled in a container. The test preparation 1 (Example 1) contained in the ethylene oxide gas sterilization container was stored for a maximum of 3 months at a temperature of 40 ° C or 60 ° C. The viscosity of the test preparation 1 was measured over time immediately after filling and after the start of storage. Further, the viscosity was measured by using a micro-Austenometer (manufactured by SI Analytics GmbH, model No. 51623), and the viscosity of the test preparation at 25 ° C ± 0.1 ° C was measured.

Further, the test preparation 1 (Comparative Example 1) prepared in (1) was filled in a polyethylene container subjected to electron beam sterilization treatment (50 kGy) instead of EOG sterilization treatment. The test formulation 1 was tested in the same manner as in Example 1 and the viscosity was measured.

(3) Test results and investigation The test results relating to the test formulation 1 are shown in Table 1. [Table 1]

As shown in Table 1, compared with Comparative Example 1 in which the test preparation 1 was filled in a container treated by electron beam sterilization, the container to be tested by the sterilization with ethylene oxide gas was filled with the test preparation 1 Example 1 showed an effect of suppressing the decrease in viscosity of the test preparation 1.

<Test preparations 2 to 5> (1) Preparation of test preparations The test preparations 2 to 5 shown in Table 2 were prepared in the same manner as in Test Example 1. [Table 2]

(2) Test method In the same manner as in Example 1, ethylene oxide gas (EOG) sterilization treatment (ethylene oxide concentration: 480 mg/L, temperature: 40 ° C, relative humidity: 45%, treatment time) was carried out. The polyethylene containers of 3 hours were filled with the test preparations 2 to 5 prepared in (1), respectively. The test preparations (Examples 2 to 5) contained in the ethylene oxide gas sterilization container were stored for a maximum of 8 weeks at a temperature of 50 °C. The viscosity of the test preparations 2 to 5 was measured by the same method as in Example 1 immediately after the filling and after the start of the storage.

Moreover, the test preparations 2 to 5 (Comparative Examples 2 to 5) prepared in (1) were each filled in a polyethylene container subjected to electron beam sterilization treatment (50 kGy) instead of EOG sterilization treatment. The test preparations 2 to 5 were tested in the same manner as in the examples 2 to 5, and the viscosity was measured.

(3) Test results and investigation The test results relating to the test preparations 2 to 5 are shown in Table 3 in the form of a viscosity reduction rate. Further, the viscosity reduction rate is calculated by the following formula. [Viscosity reduction rate (%)] = 100 × ([Visconess value immediately after filling] - [Viscosity value at each measurement point]) / [Viscosity value immediately after filling] [Table 3]

As shown in Table 3, with respect to any of the test formulations 2 to 5, the test formulation was filled to use ethylene oxide gas as compared with the case of being filled in a container treated by electron beam sterilization. In the case of sterilization in a container treated, it was shown to have an effect of suppressing the decrease in viscosity of the test preparation. [Industrial availability]

The present invention provides a pharmaceutical composition comprising a water-soluble viscosifying agent and contained in an ethylene oxide gas sterilization container.

Claims (18)

A pharmaceutical composition comprising a water-soluble viscosifying agent and contained in an ethylene oxide gas sterilization container. The pharmaceutical composition according to claim 1, wherein the water-soluble viscosifying agent is one or a plurality of water-soluble selected from the group consisting of a cellulose polymer, a polyvinylpyrrolidone, a carboxyvinyl polymer, and a polyhydric alcohol. Viscosity agent. The pharmaceutical composition according to claim 2, wherein the cellulose-based polymer is one selected from the group consisting of hydroxyethyl cellulose, hydroxymethyl cellulose, and hydroxypropyl methyl cellulose, or a plurality of cellulose systems. Polymer. The pharmaceutical composition according to any one of claims 1 to 3, wherein the water-soluble viscosifying agent is contained in an amount of from 0.001 to 10% (w/v). The pharmaceutical composition according to any one of claims 1 to 4, wherein the container is a resin container. The pharmaceutical composition according to claim 5, wherein the resin container is made of polyethylene, polypropylene, or polyethylene terephthalate. A pharmaceutical composition containing a cellulose-based polymer as a water-soluble viscosifying agent and stored in a container made of an ethylene oxide gas sterilizing resin. The pharmaceutical composition according to any one of claims 1 to 7, which is an aqueous eye drop. The pharmaceutical composition according to any one of claims 1 to 8, which is a glaucoma therapeutic agent. The pharmaceutical composition according to any one of claims 1 to 9, which contains dorzolamide or a salt thereof as an active ingredient. A pharmaceutical composition comprising doxoramine or a salt thereof as an active ingredient, a drip or a salt thereof, and hydroxyethylcellulose as a water-soluble viscosifying agent, and is contained in an ethylene oxide gas sterilization In a resin container. A method for suppressing a decrease in viscosity of a pharmaceutical composition by containing a pharmaceutical composition containing a water-soluble thickening agent in an ethylene oxide gas sterilization container to suppress a decrease in viscosity of the pharmaceutical composition. A method for improving the stability of a pharmaceutical composition by accommodating a pharmaceutical composition containing a water-soluble thickening agent in an ethylene oxide gas sterilization container to improve the stability of the pharmaceutical composition. A pharmaceutical composition for treating and/or preventing an eye disease, which comprises a water-soluble viscosifying agent and is contained in an ethylene oxide gas sterilization container. A pharmaceutical composition for the treatment and/or prevention of an eye disease, comprising a water-soluble viscosifying agent, and being contained in an ethylene oxide gas sterilization container. A pharmaceutical composition for use in the manufacture of a medicament for treating and/or preventing an eye disease, and the pharmaceutical composition comprising a water-soluble viscosifying agent and contained in an ethylene oxide gas sterilization container. A method for treating and/or preventing an eye disease, which comprises administering a pharmaceutical composition containing a water-soluble thickening agent and contained in an ethylene oxide gas sterilization container to an object in need thereof in an effective amount. A medical product comprising a pharmaceutical composition contained in an ethylene oxide gas sterilization container and containing a water-soluble viscosifying agent.