JP7037349B2 - Pharmaceutical composition containing a water-soluble thickening agent - Google Patents

Description

The present invention relates to a pharmaceutical composition containing a water-soluble thickening agent, which is contained in an ethylene oxide gas sterilized container.

Since an aqueous solution such as eye drops is directly administered to the eye, which is a particularly sensitive organ in the human body, it is strictly required to maintain a sterile state until the eye drop container is opened. Unlike injections and the like filled in glass containers, most of the containers for storing aqueous liquids are resin containers formed of synthetic resins such as polyethylene, polypropylene, and propylene-ethylene copolymer. Since these resin containers are inferior in heat resistance, for example, it is difficult to perform heat sterilization after filling the resin container with the aqueous liquid, and therefore, the resin container itself should be aseptic before filling with the aqueous liquid. Is required. As a method for sterilizing a resin container, gamma ray sterilization, electron beam sterilization, ethylene oxide gas (EOG) sterilization, hydrogen peroxide solution sterilization and the like are known.

On the other hand, a thickening agent is used in the ophthalmic solution for the purpose of adjusting its viscosity and allowing it to stay on the surface of the eye for a long period of time to enhance the sustainability of the medicinal effect and the transferability into the eye. However, while the water-soluble thickening agent is generally added to eye drops, it is known that the viscosity of the liquid agent often decreases during long-term storage when combined with the aqueous liquid agent. As a method for suppressing a decrease in viscosity in an aqueous solution containing a water-soluble thickening agent, for example, in Patent Document 1, a polyoxyethylene hydrogenated castor oil and / or stearic acid is added to an aqueous solution containing hypromellose and / or hydroxyethyl cellulose. Incorporating polyoxyl, in Patent Document 2, a nonionic surfactant and a specific vegetable oil are added to a cellulose-based viscous agent, and in Patent Document 3, dibutylhydroxytoluene and butyl are added to a water-soluble polymer compound. Particularly excellent viscosity reduction prevention is achieved by blending hydroxyanisole, ascorbic acid or a salt thereof and / or sulfite or a salt thereof, and packaging the container with an inert gas atmosphere, or by using a deoxidizing agent. It is described that the effect can be obtained.

However, it has not been known so far that the method of sterilizing the container affects the decrease in viscosity of the pharmaceutical composition containing the water-soluble thickening agent.

International WO2014-050301 Japanese Unexamined Patent Publication No. 2011-06684 JP-A-2004-123634

It is an interesting subject to provide a pharmaceutical composition containing a water-soluble thickening agent, wherein the decrease in viscosity of the pharmaceutical composition is suppressed.

As a result of diligent research to suppress the decrease in viscosity of the pharmaceutical composition containing the water-soluble thickening agent, the present inventors unexpectedly accommodate the pharmaceutical composition containing the water-soluble thickening agent. The method of sterilizing the container affects the decrease in viscosity of the pharmaceutical composition, and further, the pharmaceutical composition containing the water-soluble thickening agent is contained in a container sterilized with ethylene oxide gas. We have found that the decrease in viscosity of a pharmaceutical composition is suppressed, and have reached the present invention. Specifically, the present invention provides the following.

(1) A pharmaceutical composition containing a water-soluble thickening agent, which is contained in an ethylene oxide gas sterilization container.
(2) The water-soluble thickening agent is one or more water-soluble thickening agents selected from the group consisting of a cellulosic polymer, polyvinylpyrrolidone, a carboxyvinyl polymer and a polyhydric alcohol, according to (1). The pharmaceutical composition described.
(3) The pharmaceutical composition according to (2), wherein the cellulosic polymer is one or more cellulosic polymers selected from the group consisting of hydroxyethyl cellulose, hydroxymethyl cellulose and hydroxypropylmethyl cellulose.
(4) 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 containing a cellulosic polymer as a water-soluble thickening agent, which is contained in a container made of an ethylene oxide gas sterilized 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 therapeutic agent for glaucoma.
(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 containing dorzolamide or a salt thereof and timolol or a salt thereof as an active ingredient, and hydroxyethyl cellulose as a water-soluble thickening agent, which is contained in an ethylene oxide gas sterilized resin container. ..
(12) A method for suppressing a decrease in viscosity of a pharmaceutical composition by accommodating the 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 by accommodating the pharmaceutical composition containing a water-soluble thickening agent in an ethylene oxide gas sterilization container.

The present invention further relates to the following.
(14) A pharmaceutical composition containing a water-soluble thickening agent and contained in an ethylene oxide gas sterilized container for treating and / or preventing eye diseases.
(15) A pharmaceutical composition containing a water-soluble thickening agent for use in the treatment and / or prevention of eye diseases and contained in an ethylene oxide gas sterilized container.
(16) Use of a pharmaceutical composition containing a water-soluble thickening agent and contained in an ethylene oxide gas sterilized container for the production of a medicine for treating and / or preventing an eye disease.
(17) A method for treating and / or preventing eye diseases, wherein a pharmaceutical composition containing a water-soluble thickening agent and contained in an ethylene oxide gas sterilization container is effective for a subject in need thereof. A method comprising administering a dose.

It should be noted that each of the configurations (1) to (17) can be arbitrarily selected and combined with two or more.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to obtain a pharmaceutical composition containing a water-soluble thickening agent, wherein the decrease in viscosity of the pharmaceutical composition is suppressed.

Hereinafter, the present invention will be described in detail.

The water-soluble thickening agent in the present invention may be any water-soluble thickening agent that can be used as an additive for pharmaceuticals, and is, for example, a cellulosic polymer, polyvinylpyrrolidone, a carboxyvinyl polymer, a mucopolysaccharide or a mucopolysaccharide. Polyhydric alcohols are mentioned, and may be hydrates or solvates thereof.

Examples of the cellulosic polymer include nonionic cellulose and anionic cellulose. Examples of nonionic cellulose include methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose and the like, and examples of anionic cellulose include carboxymethyl cellulose and hydroxypropylmethyl cellulose acetate succi. Nate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate and the like can be mentioned, with preference given to nonionic cellulose, more preferably hydroxymethylcellulose, hydroxyethylcellulose or hydroxypropylmethylcellulose, still more preferably. It is hydroxyethyl cellulose or hydroxypropyl methyl cellulose.

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

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

As the water-soluble thickening agent in the present invention, a cellulosic polymer, polyvinylpyrrolidone or polyvalent alcohol is preferable, a cellulosic polymer or polyvinylpyrrolidone is more preferable, and hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropylmethyl cellulose or polyvinylpyrrolidone is further preferable. Hydroxyethyl cellulose, hydroxypropylmethyl cellulose or polyvinylpyrrolidone are particularly preferred.

In the pharmaceutical composition in the present invention, one kind or two or more kinds of water-soluble thickening agents may be used together.

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

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

Ethylene oxide gas sterility in the present invention is not particularly limited as long as it is a method for sterilizing using ethylene oxide gas, but for example, the container is sterilized under a predetermined temperature and a predetermined humidity for a sufficient time. It is exposed to ethylene oxide gas, sterilized, and then aerated to remove the ethylene oxide gas.

In the present invention, the temperature of ethylene oxide gas sterilization can be appropriately selected depending on the characteristics of the container, but is preferably 30 to 60 ° C.

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

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

In the present invention, the gas used for ethylene oxide gas sterility may be only ethylene oxide gas or a mixed gas with carbon dioxide or the like. When a mixed gas is used, the ratio of ethylene oxide gas to other gas is, for example, 5:95 to 50:50 in volume ratio, preferably 10:90 to 40:60, and 20:80 to 30:70. More preferred.

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

In the present invention, it is not always necessary to carry out aeration for removing the ethylene oxide gas, but when carrying out aeration, for example, air, nitrogen, argon, carbon dioxide and the like can be used, and the aeration time is set. , 8 hours or more is preferable, 12 hours or more is more preferable, and 24 hours or more is further preferable.

In the present invention, the ethylene oxide gas sterilized container means a container sterilized with ethylene oxide gas. The container used may be any container that can be sterilized with ethylene oxide gas, but 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, polystyrene, polycyclic olefin copolymer and the like. Further, polyethylene is classified according to its density, and examples thereof include low density polyethylene (LDPE), medium density polyethylene (MDPE), and high density polyethylene (HDPE).

As the resin container in the present invention, polyethylene, polypropylene, polyethylene terephthalate polypropylene-polyethylene copolymer or polycyclic olefin copolymer is preferable, and polyethylene or polypropylene is more preferable.

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 either a one-piece type eye drop container, a two-piece type eye drop container, or a three-piece type eye drop container. It may be housed in. For example, in the case of a 3-piece type eye drop container, it is formed from a container body holding the pharmaceutical composition of the present invention, an inner plug, and a cap, and is an integrally molded type in which blow molding and chemical filling are performed at the same time. The container is also included in the above-mentioned eye drop container according to the number of members. Further, when the container is formed of a plurality of members, it may be formed of a member made of the same material or a member made of a different material. Further, the material may constitute a part or all of the member or may be coated. These materials are the materials mentioned above, that is, polyethylene (including LDPE, MDPE, HDPE), polypropylene, polyethylene terephthalate, polybutylene terephthalate, polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic resin, polystyrene, polycyclic. Refers to olefin copolymers and the like.

In the present invention, the ethylene oxide gas sterilization vessel has a residual ethylene oxide gas concentration of, for example, 0 to 10 ppm, preferably 0 to 5 ppm, more preferably 0 to 1 ppm, and most preferably not detected. The residual ethylene oxide gas concentration can be measured according to the "Quantitative Method of Residual Ethylene Oxide in Medical Devices" of the Japan Medical Plastics Association.

The pharmaceutical composition in the present invention is housed in an ethylene oxide gas sterilized container.

The pharmaceutical composition in the present invention can be orally or parenterally administered to a patient, and examples of the administration form include oral administration, local administration to the eye, intravenous administration, transdermal administration and the like. , Topical administration to the eye is more preferable.

In the present invention, the topical administration to the eye refers to eye drop administration, intraconjunctival administration, intravitreal administration, subconjunctival administration, subconjunctival administration and the like.

If necessary, the pharmaceutical composition of the present invention can be formulated into a dosage form suitable for administration together with a pharmaceutically acceptable additive. Dosage forms suitable for parenteral administration are preferable, and examples thereof include eye drops, injections, eye ointments, inserts, etc., but eye drops or injections are more preferable, eye drops are more preferable, and aqueous eye drops are particularly preferable. preferable.

The pharmaceutical composition of the present invention may contain the active ingredient of the drug. The active ingredient is not particularly limited and may be appropriately selected depending on the intended purpose. For example, when it is used as an eye drop, isopropylunoprost, carteolol, dystigmine, dipibephrine and tafluprost are used for the treatment of glaucoma. , Timolol, travoprost, dolzoramide, nipradilol, vimatoprost, pilocarpine, bunazocin, brimonidin, brinzoramid, betaxolol, latanoprost, lipasdyl, levobnorol or salts thereof, and acyclovir, erythromycin, offloxane for antibacterial and antiviral treatment. Dexamethasone, dexamethasone metasulfosone, dexamethasone, dexamethasone metasulfobenzo Acid esters, dexamethasone phosphate esters, hydrocortisone acetate esters, fradiomycin, fluoromethron, prednisolone acetate esters, betamethasone phosphate esters, azulene sulfonic acid, glycyrrhizinic acid, diclofenac, nepafenac, planoprofen, bromphenac or salts thereof are preferred. For dry eye / corneal treatment, chondroitin sulfate, diquafosol, hyaluronic acid, flavinadenine dinucleotide, levamipid or salts thereof are preferable, and for antiallergic treatment, acidazanolast, anlexanox, ibudilast, epinastine, oropatadine, cromoglycic acid, Ketotiphen, cyclosporin, tachlorimus, tranilast, pemilolast, levocabastine or salts thereof are preferred, and for the treatment of cataracts, eye drops and others, atropin, oxybuprokine, oxymethasone, glutathione, cyanocobalamine, cyclopentratate, tropicamide, Nafazoline, neostigmin, pyrenoxin, phenilefurin, lysoteam, zinc sulfate or salts thereof are preferred. For the treatment of glaucoma, isopropylunoprost, carteolol, dystigmin, dipibefurin, tafluprost, timolol, travoprost, dorzolamide, nipradilol, bimatoprost, pilocarpine, bunazocin, brimonidin, brinzoramid, betaxolol, latanoprost, lipasrol, latanoprost, lipasol. More preferably, timolol, dorzolamide or salts thereof are even more preferred.

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 pharmaceutically acceptable salt. 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 an organic amine. Examples include salt.

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 salts with organic acids include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, and methanesulfonic acid. , Alanin, lactic acid, horse uric acid, 1,2-ethandisulfonic acid, isetionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, Examples thereof include salts with p-toluene sulfonic acid, lauryl sulfate, methyl sulfate, naphthalene sulfonic acid, sulfosalicylic acid and the like.

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

Examples of the salt with the halogen ion include salts with chloride ion, bromide ion, iodide ion and the like.

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

Examples of the salt with 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 the organic amine include triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2-. Examples thereof include salts with (hydroxymethyl) -1,3-propanediol, prokine, N, N-bis (phenylmethyl) -1,2-ethanediamine and the like.

The active ingredient or a salt thereof contained in the pharmaceutical composition of the present invention may 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, and 0.1% (w / v) or more. v) or more is more preferable, and the upper limit thereof may be a concentration acceptable for an ophthalmic preparation, for example, 5% (w / v). 0.01 to 5% (w / v) is preferable, 0.05 to 4% (w / v) is more preferable, 0.1 to 3% (w / v) is further preferable, and 0.5 to 1. 5% (w / v) is particularly preferable. When the pharmaceutical composition of the present invention contains a salt of the active ingredient, these values are the content of the salt of the active ingredient. When the active ingredient or a salt thereof is contained in the pharmaceutical composition of the present invention in the form of a hydrate or a solvate, these values are the values of the hydrate or the solvate of the active ingredient or the salt thereof. The content.

In the pharmaceutical composition of the present invention, in addition to the water-soluble thickening agent and the active ingredient, additives that can be blended into pharmaceutical products can be blended within a range that does not impair the effects of the present invention. In particular, in the case of a preparation that enables topical administration to the eye, in addition to a water-soluble thickening agent and an active ingredient, a buffer, a preservative, a surface activator, an isotonic agent, a stabilizer, and an antioxidant. Oxidizing agents, pH adjusters and the like can be added. These can be used individually by 1 type or in combination of 2 or more types, respectively, and an appropriate amount can be blended.

When a buffer is added to the pharmaceutical composition of the present invention, a buffer that can be used as an additive for pharmaceuticals can be appropriately added. For example, phosphoric acid or a salt thereof, boric acid or a salt thereof can be added. , Hosand, carbonic acid or a salt thereof, an organic acid or a salt thereof, and the like, and may be a hydrate or a buffer thereof.

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

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

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

Examples of the organic acid or a salt thereof include citric acid, acetic acid, ε-aminocaproic acid, gluconic acid, fumaric acid, lactic acid, ascorbic acid, succinic acid, maleic acid, malic acid, amino acids or their sodium salts and potassium salts. Etc., and may be hydrates thereof.

When a buffer is added to the pharmaceutical composition of the present invention, an organic acid or a salt thereof is preferable, citric acid or a salt thereof is more preferable, and sodium citrate is particularly preferable.

The content of the buffer when the buffer is added to the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the buffer and the like, but is preferably 0.001 to 10% (w / v), and is 0. 0.01 to 5% (w / v) is more preferable, 0.1 to 5% (w / v) is further preferable, and 0.1 to 1% (w / v) is particularly preferable.

When a preservative is blended in the pharmaceutical composition of the present invention, a preservative that can be used as an additive for a pharmaceutical product can be appropriately blended, and for example, inverted soaps, parabens, alcohols, etc. And organic acids or salts thereof.

In the present invention, the inverted soaps include, for example, benzalkonium chloride, benzalkonium bromide, benzethonium chloride, benzethonium bromide, chlorhexidine or a salt thereof, and the chlorhexidine or a salt thereof is, for example, chlorhexidine lucon. Acid acid, chlorhexidine hydrochloride, chlorhexidine acetic acid.

In the present invention, examples of the parabens are methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate.

In the present invention, the alcohols are, for example, chlorobutanol.

In the present invention, the organic acid or a salt thereof is, for example, sorbic acid or a salt thereof, sodium dehydroacetate, and the sorbic acid or a salt thereof is, for example, sodium sorbate or potassium sorbate.

The content of the preservative when the preservative is blended in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the preservative and the like, but it may be an amount that does not adversely affect the safety. 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, and 0.05% (w / v) or less. v) or less is more preferable, and 0.01% (w / v) or less is particularly preferable. Further, it suffices if there is an amount capable of exerting an antiseptic action, and the lower limit thereof is preferably 0.0001% (w / v) or more, and more preferably 0.001% (w / v) or more. The content of the preservative is preferably 0.0001 to 1% (w / v), more preferably 0.001 to 0.5% (w / v), and more preferably 0.001 to 0.1% (w / v). v) is more preferred.

As the surfactant when the surfactant is blended in the pharmaceutical composition of the present invention, a surfactant that can be used as an additive for pharmaceuticals can be appropriately blended, and for example, cationic surfactant activation. Agents, anionic surfactants, nonionic surfactants and the like can be mentioned.

Examples of the cationic surfactant include an alkylamine salt, an alkylamine polyoxyethylene adduct, a fatty acid triethanolamine monoester salt, an acylaminoethyl diethylamine salt, a fatty acid polyamine condensate, an alkylimidazoline, and 1-acylaminoethyl. -2-alkylimidazolin, 1-hydroxylethyl-2-alkylimidazolin and the like can be mentioned.

Examples of the anionic surfactant include lipid phosphates such as lecithin.

Examples of the nonionic surfactant include polyoxyethylene fatty acid esters such as polyoxyl 40 stearate; polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan triolate, and polysorbate 65. Polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60 and the like. Polyoxyl castor oil such as 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil; polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) Polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, etc. Polyoxyethylene polyoxypropylene glycol; sucrose fatty acid ester such as sucrose stearate; tocopherol polyethylene glycol 1000 succinic acid ester (vitamin E TPGS) and the like.

When a surfactant is added to the pharmaceutical composition of the present invention, a nonionic surfactant is more preferable, a polyethylene sorbitan fatty acid ester is further preferable, and polysorbate 80 is particularly preferable.

The content of the surfactant when the surfactant is blended in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the surfactant and the like, but is 0.01 to 1% (w / 1). v) is preferable, 0.05 to 0.5% (w / v) is more preferable, and 0.05% to 0.2% (w / v) is even more preferable.

When the isotonic agent is blended in the pharmaceutical composition of the present invention, the isotonic agent that can be used as an additive of the pharmaceutical product can be appropriately blended, and for example, ionic isotonicization. Examples thereof include agents and nonionic isotonic agents.

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

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

The content of the tonicity agent when the tonicity agent is blended in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the tonicity agent and the like, but is 0.001 to 10% (w /). v) is preferable, 0.01% to 5% (w / v) is more preferable, 0.1 to 3% (w / v) is further preferable, and 0.5 to 2% (w / v) is particularly preferable. ..

As the stabilizer when the stabilizer is blended in the pharmaceutical composition of the present invention, a stabilizer that can be used as an additive of a pharmaceutical product can be appropriately blended, and examples thereof include edetic acid or a salt thereof. Be done.

Examples of the edetic acid or a salt thereof include edetic acid, disodium edetate, tetrasodium edetate and the like.

The content of the stabilizer when the stabilizer is blended in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the stabilizer and the like, but is 0.001 to 5% (w / v). Preferably, 0.01% to 1% (w / v) is more preferable, and 0.01 to 0.1% (w / v) is even more preferable.

When an antioxidant is added to the pharmaceutical composition of the present invention, an antioxidant that can be used as an additive for a pharmaceutical agent can be appropriately added, and for example, ascorbic acid, tocopherol, and dibutylhydroxytoluene can be added. , Sodium sulfite and the like.

The content of the antioxidant when the antioxidant is blended in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the antioxidant and the like, but is 0.001 to 5% (w / v). Preferably, 0.01% to 3% (w / v) is more preferable, and 0.1 to 1% (w / v) is even more preferable.

When the pH adjuster is added to the pharmaceutical composition of the present invention, the pH adjuster that can be used as an additive for a pharmaceutical agent can be appropriately added, and is, for example, an acid or a base, as an acid. For example, hydrochloric acid, phosphoric acid, citric acid, acetic acid and the like, and examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like.

The pH of the pharmaceutical composition of the present invention may be in the range acceptable for pharmaceutical products, preferably in the range of 4.0 to 8.5 or 4.0 to 8.0, and preferably 5.0 to 8.0. Is more preferable, and 5.5 to 7.5 is even more preferable. Particularly preferred pH is 5.5-7.0, but 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 and 7.0 are also even more preferable.

The osmotic pressure ratio of the pharmaceutical composition of the present invention may be within an acceptable range as a pharmaceutical product, for example, 0.5 to 2.0, preferably 0.7 to 1.6, and 0.8 to 1. 4 is more preferable, and 0.9 to 1.2 is even more preferable.

The viscosity of the pharmaceutical composition of the present invention may be measured by a general-purpose method, and can be measured by using, for example, a capillary viscometer, a rotational viscometer, a falling ball viscometer, etc., particularly using an Ostwald viscometer. , Can be measured.

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

In the pharmaceutical composition of the present invention, when the water-soluble thickening agent, active ingredient or additive is a hydrate, the hydrated water may be a number that can be usually coordinated, for example, monohydrate. Dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nine hydrate, ten hydrate, eleven hydrate, 12 hydrates, 1/2 hydrates, 3/2 hydrates and the like.

In the pharmaceutical composition of the present invention, all the constituents may be dissolved or partially suspended, but a liquid in which all the constituents are dissolved is more preferable. 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 may be contained in either a multi-dose type container, a single-use unit dose type container, or a PFMD (Preservative Free Multi Dose) container.

The pharmaceutical composition of the present invention may be, for example, a pharmaceutical composition for treating and / or preventing an eye disease, and examples of the eye disease to be treated and / or prevented include glaucoma and infectious eyes. Diseases, inflammatory eye diseases, dry eyes, corneal diseases, allergic eye diseases, cataracts, eye fatigue, etc. are mentioned, and glaucoma is preferable.

In the present invention, suppressing the decrease in viscosity of the pharmaceutical composition means suppressing the decrease in viscosity of the pharmaceutical composition with time, and here, the decrease in viscosity with time means, for example, the pharmaceutical composition. It can be shown by comparing the viscosity immediately after preparation (or immediately after filling) with the viscosity after a certain period of time. Further, the degree of suppression of the decrease in viscosity in the present invention can be shown by comparison with, for example, the decrease in viscosity when stored in an electron beam sterilized container. In this case, the suppression of the decrease in viscosity in the present invention is defined as. It can be said that the decrease in viscosity is improved. The viscosity is measured by a predetermined viscosity measuring method.

The above-mentioned detailed description of the pharmaceutical composition of the present invention is also applied to a method of suppressing a decrease in viscosity of the pharmaceutical composition of the present invention and a method of improving the stability of the pharmaceutical composition.

The method for suppressing the decrease in viscosity of the pharmaceutical composition of the present invention comprises accommodating the pharmaceutical composition containing the water-soluble thickening agent in an ethylene oxide gas sterilization container.

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

In the present invention, improving the stability of a pharmaceutical composition means suppressing changes in the pharmaceutical composition over time, and includes, for example, suppressing a decrease in viscosity of the pharmaceutical composition over time.

The above-mentioned detailed description of the pharmaceutical composition of the present invention also applies to the following aspects of the present invention.

One aspect of the present invention is a pharmaceutical composition containing a water-soluble thickening agent and contained in an ethylene oxide gas sterilized container for the treatment and / or prevention of eye diseases.

One aspect of the present invention is a pharmaceutical composition containing a water-soluble thickening agent for use in the treatment and / or prevention of eye diseases and contained in an ethylene oxide gas sterilized container.

One aspect of the present invention is the use of a pharmaceutical composition containing a water-soluble thickening agent and contained in an ethylene oxide gas sterile container for the production of a pharmaceutical for treating and / or preventing eye diseases. Is.

One aspect of the present invention is a method of treating and / or preventing an eye disease, which requires a pharmaceutical composition containing a water-soluble thickening agent and contained in an ethylene oxide gas sterile container. A method comprising administering an effective dose to a subject to be treated.

The following are examples of pharmaceutical products and the results of the viscosity aging measurement test, but these are for better understanding of the present invention and do not limit the scope of the present invention.

[Formulation example]
A typical example of the pharmaceutical product of the present invention is shown below. In the following pharmaceutical example, the blending amount of each component is the content in 1 mL of the pharmaceutical product.

Pharmaceutical example 1
Dorzolamide hydrochloride 10 mg
Timolol maleate 5 mg
Hydroxyethyl cellulose 5 mg
Sodium citrate hydrate 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 6.5
Pharmaceutical example 2
Dorzolamide hydrochloride 10 mg
Hydroxypropyl Methyl Cellulose 5 mg
Sodium citrate hydrate 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 6.5
Pharmaceutical example 3
Dorzolamide hydrochloride 20mg
Polyvinylpyrrolidone 20 mg
Sodium citrate hydrate 10 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 6.5
Pharmaceutical example 4
Timolol maleate 5 mg
Hydroxyethyl cellulose 5 mg
Sodium citrate hydrate 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 6.5
Pharmaceutical example 5
Dorzolamide hydrochloride 10 mg
Hydroxyethyl cellulose 10 mg
Boric acid 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 6.5

[Viscosity change measurement test]
<Test product 1>
(1) Preparation of test preparation Dorzolamide hydrochloride (19.759 g), thymorol maleate (12.127 g), sodium citrate hydrate (5.219 g), disodium edetate (0.178 g), polysorbate 80 (1.78 g) was dissolved in purified water, and purified water was added so that the total amount was 710 g. A part (412.8 g) of this aqueous solution is taken out, mixed with a 0.8% hydroxyethyl cellulose solution (612.75 g), and the pH is adjusted to 5.60 to 5. with a pH adjuster (hydrochloric acid and / or sodium hydroxide). Adjusted to 70. Purified water was added so that the total amount was 1042 g, and the test product 1 was prepared.

(2) Test method Ethylene oxide gas (EOG) sterilization treatment (ethylene oxide concentration: 480 mg / L, temperature: 40 ° C., relative humidity: 45%, treatment time: 3 hours) was applied to a polyethylene container (1). The test preparation 1 prepared in the above was filled. The test product 1 (Example 1) contained in this ethylene oxide gas sterilized container was stored at a temperature of 40 ° C. or 60 ° C. for a maximum of 3 months. The viscosity of the test product 1 was measured immediately after filling and over time after the start of storage. A microostwald (manufactured by SI Analytics GmbH, Type No. 51623) was used to measure the viscosity, and the viscosity of the test product at 25 ° C. ± 0.1 ° C. was measured.

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

(3) Test results and discussion Table 1 shows the test results for the test product 1.

As shown in Table 1, Example 1 in which the container treated with ethylene oxide gas sterilization was filled with the test preparation 1 was compared with Comparative Example 1 in which the container treated with electron beam sterility was filled with the test preparation 1. The effect of suppressing the decrease in viscosity of the test preparation 1 was shown.

<Test products 2-5>
(1) Preparation of test product The test products 2 to 5 shown in Table 2 were prepared by the same method as that of the test product 1.

(2) Test method Similar to Example 1, polyethylene subjected to ethylene oxide gas (EOG) sterility treatment (ethylene oxide concentration: 480 mg / L, temperature: 40 ° C., relative humidity: 45%, treatment time: 3 hours). The manufacturing container was filled with the test formulations 2 to 5 prepared in (1), respectively. The test products (Examples 2 to 5) contained in this ethylene oxide gas sterilized container were stored at a temperature of 50 ° C. for a maximum of 8 weeks. Immediately after filling and over time after the start of storage, the viscosities of the test formulations 2 to 5 were measured by the same method as in Example 1.

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

(3) Test results and discussion The test results for the test products 2 to 5 are shown in Table 3 as the viscosity reduction rate. The viscosity decrease rate was calculated by the following formula.
[Viscosity decrease rate (%)] = 100 × ([Viscosity value immediately after filling]-[Viscosity value at each measurement point]) / [Viscosity value immediately after filling]

As shown in Table 3, for all of the test products 2 to 5, when the test product is filled in a container treated with ethylene oxide gas sterility, compared with the case where the test product is filled in a container treated with electron beam sterility, It showed the effect of suppressing the decrease in viscosity of the test product.

The present invention provides a pharmaceutical composition containing a water-soluble thickening agent, which is contained in an ethylene oxide gas sterilized container.

Claims (6)

A pharmaceutical composition containing one or more nonionic celluloses selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose and hydroxypropylmethyl cellulose as a water-soluble thickening agent. The pharmaceutical composition contained in an ethylene oxide gas sterilized resin container. The pharmaceutical composition according to claim 1, wherein the content of nonionic cellulose is 0.001 to 10% (w / v). The pharmaceutical composition according to claim 1 or 2 , wherein the resin container is made of polyethylene, polypropylene, or polyethylene terephthalate. The pharmaceutical composition according to any one of claims 1 to 3 , which is an aqueous eye drop. The pharmaceutical composition according to any one of claims 1 to 4 , which contains a glaucoma therapeutic agent. The pharmaceutical composition according to any one of claims 1 to 5 , which contains dorzolamide or a salt thereof as an active ingredient.