TWI773778B - Pharmaceutical composition containing water-soluble thickener - Google Patents

Abstract

The present invention provides a pharmaceutical composition containing a water-soluble viscosifying agent, wherein the viscosity reduction of the pharmaceutical composition is suppressed. The pharmaceutical composition of the present invention contains a water-soluble thickener, and is contained in an ethylene oxide gas sterilization container.

Description

Pharmaceutical composition containing water-soluble thickener

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

Aqueous liquid preparations such as eye drops are directly administered to the eye, which is a particularly sensitive organ in the human body, so it is strictly required to maintain the sterile state until the eye drop container is opened. Containers for storing aqueous liquids are different from injections filled in glass containers, and most of them are resin containers formed by molding synthetic resins such as polyethylene, polypropylene, and propylene-ethylene copolymer. Since these resin containers have poor heat resistance, for example, it is not easy to heat and sterilize the resin container after filling the aqueous liquid agent. Therefore, the resin container itself is required to be sterile before filling 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, etc. are known.

On the other hand, in eye drops, in order to improve the persistence of the drug effect or the intraocular migration by adjusting the viscosity so that it can remain on the ocular surface for a long time, a viscosifying agent is used in the industry. However, it is known that water-soluble thickeners are generally added to eye drops, but on the other hand, the viscosity of the liquid preparation is often reduced during long-term storage due to preparation with aqueous liquid preparations. As a method of suppressing the decrease in viscosity of an aqueous solution containing a water-soluble thickening agent, for example, Patent Document 1 describes the preparation of polyoxygen in an aqueous solution containing hypromellose and/or hydroxyethyl cellulose. Vinyl hardened castor oil and/or polyoxystearate stearate; In Patent Document 2, it is described that a nonionic surfactant and a specific vegetable oil are blended into a cellulose-based viscosifying agent; In the water-soluble polymer compound, dibutylhydroxytoluene, butylhydroxyanisole, ascorbic acid or its salt and/or sulfite or its salt are prepared, and then the packaging can be made into an inert gas atmosphere around the container, or the use of deoxygenation In this way, a particularly excellent viscosity reduction prevention 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 thickener. [Prior Art Literature] [Patent Literature]

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

[Problems to be Solved by Invention]

It is a subject of great interest to provide a pharmaceutical composition containing a water-soluble thickening agent and suppressing the decrease in viscosity. [Technical means to solve problems]

The inventors of the present invention have made intensive studies to suppress the decrease in the viscosity of a pharmaceutical composition containing a water-soluble viscosifying agent, and as a result, unexpectedly found that the sterilization method of a container for containing a pharmaceutical composition containing a water-soluble viscosifying agent will affect the above-mentioned The reduction in the viscosity of the pharmaceutical composition has an influence, and further, by housing the pharmaceutical composition containing the water-soluble thickener in a container sterilized with ethylene oxide gas, the reduction in the viscosity of the pharmaceutical composition is suppressed, thereby reducing the viscosity of the pharmaceutical composition. The present invention has been completed. Specifically, the present invention provides the following.

(1) A pharmaceutical composition containing a water-soluble thickening agent and housed in an ethylene oxide gas sterilization container. (2) The pharmaceutical composition as described in (1), wherein the water-soluble thickening agent is selected from the group consisting of cellulose-based polymers, polyvinylpyrrolidone, carboxyvinyl polymers and polyols One or more water-soluble thickeners. (3) The pharmaceutical composition according to (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-based polymers. (4) The pharmaceutical composition according to any one of (1) to (3), wherein the content of the water-soluble thickener 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-made container. (6) The pharmaceutical composition according to (5), wherein the resin-made container is made of polyethylene, polypropylene, or polyethylene terephthalate. (7) A pharmaceutical composition containing a cellulose-based polymer as a water-soluble viscosifying agent and housed 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 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, Timolol or a salt thereof, and hydroxyethyl cellulose as a water-soluble thickener as active ingredients, and contained in In a container made of ethylene oxide gas sterilizing resin. (12) A method for suppressing the decrease in viscosity of a pharmaceutical composition, which suppresses the decrease in viscosity of a pharmaceutical composition by housing the pharmaceutical composition containing a water-soluble thickener in an ethylene oxide gas sterilization container. (13) A method for improving the stability of a pharmaceutical composition, which improves the stability of the pharmaceutical composition by accommodating the pharmaceutical composition containing a water-soluble thickener in an ethylene oxide gas sterilization container.

The present invention further relates to the following. (14) A pharmaceutical composition for treating and/or preventing eye diseases, which contains a water-soluble thickening agent and is housed in an ethylene oxide gas sterilization container. (15) A pharmaceutical composition, which is used for the treatment and/or prevention of eye diseases, contains a water-soluble thickener, and is housed in an ethylene oxide gas sterilization container. (16) Use of a pharmaceutical composition for the manufacture of a medicine for the treatment and/or prevention of eye diseases, wherein the pharmaceutical composition contains a water-soluble thickener and is contained in an ethylene oxide gas sterilization container . (17) A method for treating and/or preventing eye diseases, comprising administering an effective amount of a pharmaceutical composition containing a water-soluble viscosifying agent and contained in an ethylene oxide gas sterilization container to a subject in need thereof. (18) A medicinal product comprising a medicinal composition contained in an ethylene oxide gas sterilization container and containing a water-soluble viscosifying agent.

In addition, each of the above-mentioned structures (1) to (18) can be arbitrarily selected and combined with two or more kinds. [Effect of invention]

According to the present invention, a pharmaceutical composition containing a water-soluble thickening agent can be obtained, and the decrease in viscosity of the pharmaceutical composition can be suppressed.

Hereinafter, the present invention will be described in detail.

The so-called water-soluble thickener in the present invention may be any water-soluble thickener that can be used as an additive for pharmaceuticals, for example, cellulose-based polymers, polyvinylpyrrolidone, carboxyvinyl Polymers, mucopolysaccharides or polyols, and further hydrates or solvates thereof.

As a cellulose type polymer, nonionic cellulose, anionic cellulose, etc. are mentioned, for example. Examples of nonionic cellulose include methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose Methyl cellulose etc., as anionic cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl cellulose, for example Ethyl cellulose, cellulose acetate phthalate, etc., preferably non-ionic cellulose, more preferably hydroxymethyl cellulose, hydroxyethyl cellulose or hydroxypropyl methyl cellulose, and more preferably It is hydroxyethyl cellulose or hydroxypropyl methyl cellulose.

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

As a polyhydric alcohol, polyethylene glycol, polyvinyl alcohol, etc. are mentioned, for example.

As the water-soluble thickening agent in the present invention, it is preferably a cellulose-based polymer, polyvinylpyrrolidone or polyol, more preferably a cellulose-based polymer or polyvinylpyrrolidone, and more preferably hydroxyethyl alcohol cellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose or polyvinylpyrrolidone, particularly preferably hydroxyethylcellulose, hydroxypropylmethylcellulose or polyvinylpyrrolidone.

In the pharmaceutical composition of the present invention, one or two or more water-soluble thickeners can be used together.

The content of the water-soluble thickening agent formulated into the pharmaceutical composition of the present invention can be appropriately adjusted according to the type of the water-soluble thickening agent, etc., preferably 0.001-10% (w/v), more preferably 0.01%- 5% (w/v), more 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, unless otherwise specified, it is regarded as the same.

The so-called sterilization of ethylene oxide gas in the present invention is not particularly limited as long as it is a method of sterilization treatment using ethylene oxide gas. For example, it is carried out in the following order: under a specific temperature and a specific humidity, The container is exposed to ethylene oxide gas for a time sufficient for sterilization to perform sterilization, and thereafter, air distribution is performed in order to remove the ethylene oxide gas.

In the present invention, the temperature for sterilizing the ethylene oxide gas can be appropriately selected according to the characteristics of the container, and is preferably 30-60°C.

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

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

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

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

In the present invention, the air distribution for removing ethylene oxide gas does not necessarily need to be implemented. In the case of implementing air distribution, for example, air, nitrogen, argon, carbon dioxide, etc. can be used, and the air distribution time is preferably more than 8 hours. , more preferably 12 hours or more, still more preferably 24 hours or more.

In the present invention, the term "ethylene oxide gas sterilization container" refers to a container sterilized by ethylene oxide gas. The container to be used should just be a container which can be sterilized by ethylene oxide gas, and a resin-made container is preferable. As the material of the resin container, for example, polyethylene, polypropylene, polyethylene terephthalate, polybutylene terephthalate, polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic resin, poly Styrene, polycyclic olefin copolymer, etc. Furthermore, polyethylene is classified according to the density, and a low density polyethylene (LDPE), a medium density polyethylene (MDPE), a high density polyethylene (HDPE), etc. are mentioned.

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

In the case of using the pharmaceutical composition of the present invention as an eye drop, the eye drop container can be formed of one component or a plurality of components, and can be accommodated in a 1-piece eye-drop container, a 2-piece eye-drop container, or 3 pieces in any of the eye drop containers. Furthermore, for example, in the case of a 3-piece eye drop container, it is formed by the container body holding the pharmaceutical composition of the present invention, the middle stopper, and the three members of the lid, and simultaneously, blow molding and drug solution filling are performed as one unit. The molded container is also contained in the above-mentioned eye drop container according to the number of components. Furthermore, when the container is formed of a plurality of members, the container may be formed of members of the same material, or may be formed of members of different materials. Furthermore, it may be a part or all of the material constituting member, or the case of coating. These so-called materials refer to the materials listed above, that is, polyethylene (including LDPE, MDPE, HDPE), polypropylene, polyethylene terephthalate, polybutylene terephthalate, polypropylene-polypropylene Ethylene copolymer, polyvinyl chloride, acrylic resin, polystyrene, polycyclic olefin copolymer, etc.

In the present invention, in the ethylene oxide gas sterilization container, the residual ethylene oxide gas concentration is, for example, 0 to 10 ppm, preferably 0 to 5 ppm, more preferably 0 to 1 ppm, and most preferably not detected. . Furthermore, the residual ethylene oxide gas concentration can be measured in accordance with the "Measurement Method of Residual Ethylene Oxide in Medical Devices" by the Japan Medical Plastics Association.

The pharmaceutical composition in the present invention is housed in an ethylene oxide gas sterilization container. The present invention provides a medicinal product comprising a medicinal composition contained in an ethylene oxide gas sterilization container and containing a water-soluble thickener. Furthermore, the present invention provides a pharmaceutical product comprising a pharmaceutical composition containing a water-soluble viscosifying agent, and an ethylene oxide gas sterilization container containing the pharmaceutical composition. Furthermore, the present invention provides a medicinal product containing a medicinal composition containing a water-soluble viscosifying agent in an ethylene oxide gas sterilization container. Furthermore, the present invention provides a medicinal product comprising a medicinal 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 viscosifying agent is housed in an ethylene oxide gas sterilization container. The medicinal product is preferably an ophthalmic product, an otolaryngology product, and a skin product, more preferably an ophthalmic product. Examples of ophthalmic products include products such as eye drops, injections, eye ointments, and inserts.

The pharmaceutical composition of the present invention can be administered orally or parenterally to a patient, and as an administration form, oral administration, topical administration to the eyes, topical administration to the ear and nose, and inhalation administration can be exemplified , spray administration, intravenous administration, subcutaneous administration, percutaneous administration, etc., preferably local administration to the eye.

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

The pharmaceutical composition of the present invention can be formulated into a dosage form suitable for administration together with pharmaceutically acceptable additives, if necessary. Preferable dosage forms suitable for parenteral administration include, for example, eye drops, nasal drops, ear drops, inhalants, injections, eye ointments, inserts, transdermal preparations, external liquids, A spray or the like is more preferably an eye drop or an injection, more preferably an eye drop, and particularly preferably an aqueous eye drop.

Active ingredients of medicines may be contained in the pharmaceutical composition of the present invention. The active ingredient is not particularly limited, and can be appropriately selected depending on the purpose. For example, if it is used in eye drops, it is used for glaucoma treatment, preferably Isopropyl unoprostone, carteolol (Carteolol), Distigmine (Distigmine), Dipivefrine (Dipivefrine), Tafluprost (Tafluprost), Dropmus, Travoprost (Travoprost), Dorzolamide, Nipradilol ), Bimatoprost, Pilocarpine, Bunazosin, Brimonidine, Brinzolamide, Betaxolol, Latanoprost (Latanoprost), Ripasudil, Levobunolol (Levobunolol) or their salts, as antibacterial and antiviral therapy, preferably aciclovir (aciclovir), erythromycin (Erythromycin), Ofloxacin, Gatifloxacin, Chloramphenicol, Gentamicin, Dibekacin, Cefmenoxime, Tosofloxacin (Tosufloxacin), Tobramycin, Norfloxacin, Vancomycin, Pimaricin, Moxifloxacin, Levofloxacin , Lomefloxacin (Lomefloxacin) or these salts, as anti-inflammatory treatment, preferably dexamethasone (Dexmethasone), dexamethasone m-sulfobenzoate, dexamethasone phosphate, hydrocortisone Acetate, fradiomycin, fluorometholone, prednisolone acetate, betamethasone phosphate, azulene sulfonic acid, Glycyrrhizic acid, Diclofenac, Pafenac (Nepafenac), Pranoprofen (Pranoprofen), Bromfenac (Bromfenac) or their salts, for dry eye, corneal treatment, preferably chondroitin sulfate, diquafosol (diquafosol) , hyaluronic acid, Flavin-adenine dinucleotide (Flavin-adenine dinucleotide), Rebamipide (Rebamipide) or their salts, as anti-allergic treatment, preferably Azalast, Amidexim promise( Amlexanox, ibudilast, Epinastine, Olopatadine, Cromoglycic acid, Ketotifen, Cyclosporine, Tacrolimus (Tacrolimus), Tranilast (Tranilast), Pemirolast (Pemirolast), Levocabastine (Levocabastine) or their salts, for cataract, eye fatigue, other treatment, preferably Atropine (Atropine) , Oxybuprocaine, Oxymetazoline, Glutathione, Cyanocobalamin, Cyclopentolate, Tropicamide, Naphazoline , Neostigmine, Pirenoxine, Phenylephrine, Lysozyme, Zinc Sulfate or their salts. For glaucoma treatment, more preferably isopropyl unoprostone, carteolol, destigmine, dipifolin, tafluprost, dramole, travoprost, dorzolamide, Prodilol, bimatoprost, pilocarpine, bunazol, brimonidine, brinzolamide, betaxolol, latanoprost, Ripasudil, levonolol, or any of these Salts, and more preferably Dromole, dorzolamide or their salts.

The active ingredients 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 salts with inorganic acids, salts with organic acids, quaternary ammonium salts, salts with halogen ions, salts with alkali metals, salts with alkaline earth metals, metal salts, and salts with organic amines Wait.

Examples of salts with inorganic acids 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, and glucoheptonic acid. , glucuronic acid, terephthalic acid, methanesulfonic acid, alanine, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, bisulfite Xinafoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid Equal salt.

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

As a salt with a halide ion, the salt with a chloride ion, a bromide ion, an iodide ion, etc. is mentioned, for example.

As a salt with an alkali metal, the salt with lithium, sodium, potassium, etc. is mentioned, for example.

As the salt of the alkaline earth metal, for example, salts with calcium, magnesium and the like can be mentioned.

As a metal salt, the salt with iron, zinc, etc. is mentioned, for example.

Examples of salts with organic amines include triethylenediamine, 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-ethyl Alkanediamine and other salts.

The active ingredient or its salt 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, still more preferably 0.1% (w/v) or more , the upper limit can be the concentration allowed as an ophthalmic preparation, for example, 5% (w/v). It is preferably 0.01-5% (w/v), more preferably 0.05-4% (w/v), still more preferably 0.1-3% (w/v), particularly preferably 0.5-1.5% (w/v) v). Furthermore, when the pharmaceutical composition of the present invention contains the salt of the active ingredient, the equivalent value is the content of the salt of the active ingredient. When the active ingredient or its salt is contained in the form of a hydrate or a solvate in the pharmaceutical composition of the present invention, these values are the content of the hydrate or solvate of the active ingredient or its salt.

In the pharmaceutical composition of the present invention, in addition to the water-soluble thickener and the active ingredient, additives that can be formulated into pharmaceuticals can be formulated within a range that does not impair the effects of the present invention. Especially in the case of preparations that can be administered topically to the eye, in addition to the water-soluble thickener and active ingredient, buffers, preservatives, surfactants, isotonic agents, stabilizers, antioxidants, pH adjusters may be added. agent, etc. These can be used individually by 1 type or in suitable combination of 2 or more types, respectively, and can mix|blend an appropriate amount.

When a buffer is prepared in the pharmaceutical composition of the present invention, a buffer that can be used as a pharmaceutical additive can be appropriately prepared, and examples include phosphoric acid or its salt, boric acid or its salt, borax, carbonic acid or Its salt or organic acid or its salt, etc., may also be these hydrates or solvates.

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, and these hydrates may also be used.

As boric acid or its salt, boric acid, sodium borate, potassium borate, etc. are mentioned, for example, and these hydrates may be sufficient.

As carbonic acid or its salt, sodium carbonate, sodium bicarbonate, etc. are mentioned, for example, and these hydrates may be sufficient.

Examples of organic acids or salts thereof include citric acid, acetic acid, ε-aminocaproic acid, gluconic acid, fumaric acid, lactic acid, ascorbic acid, succinic acid, maleic acid, malic acid, amino acid Acids or these sodium salts, potassium salts, etc., can also be these hydrates.

When the buffer is formulated into the pharmaceutical composition of the present invention, it is preferably an organic acid or its salt, more preferably citric acid or its salt, and particularly preferably sodium citrate.

The content of the buffer in the case of preparing the buffer in the pharmaceutical composition of the present invention can be appropriately adjusted according to the type of the buffer, preferably 0.001-10% (w/v), more preferably 0.01-5 % (w/v), more preferably 0.1 to 5% (w/v), particularly preferably 0.1 to 1% (w/v).

When a preservative is formulated into the pharmaceutical composition of the present invention, a preservative that can be used as a pharmaceutical additive can be appropriately formulated, and examples thereof include reverse soaps, parabens, and alcohols. , and organic acids or their salts.

In the present invention, examples of the reverse soaps include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, and benzethonium bromide.

In the present invention, examples of parabens include methylparaben, ethylparaben, propylparaben, and butylparaben.

In the present invention, examples of alcohols include chlorobutanol.

In the present invention, examples of the organic acid or its salt include sorbic acid or its salt and sodium dehydroacetate, and among these examples of the sorbic acid or its salt include sodium sorbate and potassium sorbate.

In the case where the preservative is formulated into the pharmaceutical composition of the present invention, the content of the preservative can be appropriately adjusted according to the type of the preservative, etc., as long as it is an amount that does not adversely affect the safety, and the upper limit thereof is, for example, 1% (w/v) or less, preferably 0.5% (w/v) or less, more preferably 0.1% (w/v) or less, still more preferably 0.05% (w/v) or less, particularly preferably 0.01 %(w/v) or less. Moreover, what is necessary is just to exist in the amount which can exhibit a preservative effect, and the lower limit is preferably 0.0001% (w/v) or more, 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 still more preferably 0.001 to 0.1% (w/v).

In the case of preparing a surfactant in the pharmaceutical composition of the present invention, the surfactant can be appropriately prepared as a surfactant that can be used as a pharmaceutical additive, for example, a cationic surfactant, an anionic surfactant can be mentioned. , non-ionic interfacial activator, etc.

Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, amidoethyldiethylamine salts, fatty acid polyamine condensates, Alkyl imidazoline, 1-amidoethyl-2-alkyl imidazoline, 1-hydroxyethyl-2-alkyl imidazoline, etc.

As anionic surfactant, phospholipids, such as lecithin, etc. are mentioned, for example.

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

In the case of preparing the surfactant in the pharmaceutical composition of the present invention, it is more preferably a nonionic surfactant, and more preferably polyvinyl sorbitan fatty acid ester, especially polysorbate 80 .

The content of the surfactant in the case of preparing the surfactant in the pharmaceutical composition of the present invention can be appropriately adjusted according to the type of the surfactant, preferably 0.01-1% (w/v), more preferably 0.01-1% (w/v) 0.05 to 0.5% (w/v), more preferably 0.05 to 0.2% (w/v).

When an isotonic agent is prepared in the pharmaceutical composition of the present invention, an isotonic agent that can be used as an additive of a pharmaceutical can be appropriately prepared, for example, an ionic isotonic agent or a nonionic isotonic agent can be mentioned. agent, etc.

As an ionic isotonic agent, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc. are mentioned, for example.

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

When the isotonic agent is prepared in the pharmaceutical composition of the present invention, the content of the isotonic agent can be appropriately adjusted according to the type of the isotonic agent, and is preferably 0.001 to 10% (w/v), more preferably 0.01 to 5% (w/v), more preferably 0.1 to 3% (w/v), particularly preferably 0.5 to 2% (w/v).

When a stabilizer is prepared in the pharmaceutical composition of the present invention, a stabilizer that can be used as an additive of a pharmaceutical can be appropriately prepared, and examples thereof include ethylenediaminetetraacetic acid or a salt thereof.

As ethylenediaminetetraacetic acid or its salt, ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetic acid, tetrasodium ethylenediaminetetraacetic acid, etc. are mentioned, for example.

When the stabilizer is formulated into the pharmaceutical composition of the present invention, the content of the stabilizer can be appropriately adjusted according to the type of the stabilizer, preferably 0.001-5% (w/v), more preferably 0.01%- 1% (w/v), more preferably 0.01 to 0.1% (w/v).

Antioxidants that can be used as additives for pharmaceuticals can be appropriately prepared when an antioxidant is prepared in the pharmaceutical composition of the present invention, for example, ascorbic acid, vitamin E, dibutylhydroxytoluene, sodium sulfite, etc. .

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

In the case where a pH adjuster is formulated into the pharmaceutical composition of the present invention, the pH adjuster can be appropriately formulated as a pH adjuster that can be used as an additive for pharmaceuticals. Examples include acids and bases. Examples of acids include: Hydrochloric acid, phosphoric acid, citric acid, acetic acid, and the like, and examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and the like.

The pH value of the pharmaceutical composition of the present invention may be within the acceptable range as a pharmaceutical product, preferably within 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 . The particularly preferred pH value is 5.5 to 7.0, and still more preferred is 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 should just be within a range acceptable as a pharmaceutical product, for example, 0.5 to 2.0, preferably 0.7 to 1.6, more preferably 0.8 to 1.4, and 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, a capillary viscometer, a rotational viscometer, a falling ball viscometer, etc. can be used to measure it, especially an Ostenometer viscometer.

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

In the pharmaceutical composition of the present invention, when the water-soluble thickener, active ingredient or additive is a hydrate, the water of hydration may be the number that can be usually coordinated, for example: 1 hydrate, 2 hydrate 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, all of the constituents may be dissolved or a part of them may be suspended, more preferably in a liquid state in which all of the constituents are dissolved. The solvent or dispersion medium is preferably water, most preferably an aqueous solution.

When using the pharmaceutical composition of the present invention as eye drops, it can be stored in a multi-dose container, a single-use unit-dose container or a PFMD (Preservative Free Multi Dose, preservative-free multi-dose) container. either.

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

In the present invention, the so-called inhibition of the viscosity reduction of the pharmaceutical composition refers to the inhibition of the time-dependent reduction of the viscosity of the pharmaceutical composition. (or just after filling) and the viscosity after a certain period of time is compared and expressed. In addition, the degree of suppression of viscosity reduction in the present invention can be expressed, for example, by comparing with the viscosity reduction in the case of being housed in a container subjected to electron beam sterilization treatment. In this case, the so-called viscosity reduction in the present invention is Inhibition can also be described as an improvement in viscosity reduction. In addition, the viscosity is measured by the specific viscosity measurement method.

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

The method of suppressing the viscosity reduction of the pharmaceutical composition of the present invention includes storing the pharmaceutical composition containing a water-soluble thickener in an ethylene oxide gas sterilization container.

The method of improving the stability of the pharmaceutical composition of the present invention includes storing the pharmaceutical composition containing a water-soluble viscous agent in an ethylene oxide gas sterilization container.

In the present invention, the improvement of the stability of the pharmaceutical composition refers to the inhibition of the temporal change of the pharmaceutical composition, including, for example, the inhibition of the temporal viscosity reduction of the pharmaceutical composition.

The above detailed description of the pharmaceutical composition of the present invention also applies to the aspects of the present invention as shown below.

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

One aspect of the present invention is a pharmaceutical composition, which is used for the treatment and/or prevention of eye diseases, contains a water-soluble thickener, and is contained in an ethylene oxide gas sterilization container.

One aspect of the present invention is the use of a pharmaceutical composition for the manufacture of a medicine for the treatment and/or prevention of eye diseases, wherein the pharmaceutical composition contains a water-soluble thickener and is contained in ethylene oxide gas sterilization container.

One aspect of the present invention is a method for treating and/or preventing eye diseases, which comprises administering to a subject in need thereof a pharmaceutical composition containing a water-soluble viscous agent and contained in an ethylene oxide gas sterilization container. quantity.

One aspect of the present invention is a method for producing a medicinal product, which includes accommodating a medicinal composition containing a water-soluble viscosifying agent in an ethylene oxide gas sterilization container. [Example]

The formulation examples and the results of the time-dependent viscosity change measurement test are shown below, but these are for better understanding of the present invention and do not limit the scope of the present invention.

[Formulation Examples] Representative formulation examples of the present invention are shown below. In addition, the compounding quantity of each component in the following formulation example is the content in 1 mL of a formulation.

Formulation Example 1 Dorzolamide hydrochloride 10 mg Dropmus 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 Preparation Example 2 Dorzolamide hydrochloride 10 mg Hydroxypropyl methylcellulose 5 mg Sodium citrate hydrate 5 mg Dilute hydrochloric acid appropriate amount Sodium hydroxide appropriate amount Purified water appropriate amount pH 6.5 Formulation Example 3 Dorzolamide hydrochloride 20 mg Polyvinylpyrrolidone 20 mg Sodium citrate hydrate 10 mg Dilute hydrochloric acid appropriate amount Sodium hydroxide appropriate amount Purified water appropriate amount pH 6.5 Formulation Example 4 Drop Mule Maleate 5 mg Hydroxyethyl Cellulose 5 mg Citric Acid sodium hydrate 5 mg dilute hydrochloric acid appropriate amount Sodium hydroxide appropriate amount Purified water appropriate amount pH value 6.5 Formulation 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 value 6.5

[Viscosity change over time measurement test] <Test preparation 1> (1) Preparation of test preparation Dorzolamide hydrochloride (19.759 g), Dorazol maleate (12.127 g), citric acid Sodium hydrate (5.219 g), disodium EDTA (0.178 g), and polysorbate 80 (1.78 g) were dissolved in purified water, and purified water was added so that the total amount would be 710 g. A part (412.8 g) of this aqueous solution was taken out, mixed with a 0.8% hydroxyethylcellulose solution (612.75 g), and the pH was adjusted to 5.60-5.70 with a pH adjuster (hydrochloric acid and/or sodium hydroxide). Purified water was added so that the total amount would be 1042 g to prepare Test Preparation 1.

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

Moreover, the test preparation 1 (Comparative Example 1) prepared in (1) was filled in the polyethylene container which performed the electron beam sterilization process (50 kGy) instead of the EOG sterilization process. The test preparation 1 was tested in the same manner as in Example 1, and the viscosity was measured.

(3) Test results and investigation Table 1 shows the test results related to the test preparation 1. [Table 1]

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

<Test Formulations 2 to 5> (1) Preparation of Test Formulations Test formulations 2 to 5 shown in Table 2 were prepared by the same method as the test formulation 1. [Table 2]

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

Furthermore, the test preparations 2 to 5 (Comparative Examples 2 to 5) prepared in (1) were respectively filled into polyethylene containers 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 Examples 2 to 5, and the viscosity was measured.

(3) Test results and investigation The test results related to the tested formulations 2 to 5 are shown in Table 3 in the form of viscosity reduction rates. In addition, the viscosity reduction rate was computed by the following formula. [Viscosity reduction rate (%)]=100×([Viscosity 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 one of the test formulations 2 to 5, compared with the case of filling the container treated with electron beam sterilization, the test formulation was filled with ethylene oxide gas. In the case of the sterilization-treated container, the effect of suppressing the decrease in viscosity of the test preparation was shown. [Industrial Availability]

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

Claims (8)

A pharmaceutical composition containing a cellulose-based polymer as a water-soluble viscosifying agent, and contained in a container made of an ethylene oxide gas sterilizing resin. The pharmaceutical composition of claim 1, wherein the cellulose-based polymer is one or more cellulose-based polymers selected from the group consisting of hydroxyethyl cellulose, hydroxymethyl cellulose and hydroxypropyl methyl cellulose macromolecule. The pharmaceutical composition according to claim 1 or 2, wherein the content of the water-soluble thickener is 0.001-10% (w/v). The pharmaceutical composition according to claim 1, wherein the resin-made container is made of polyethylene, polypropylene, or polyethylene terephthalate. The pharmaceutical composition of claim 1, which is an aqueous eye drop. The pharmaceutical composition according to claim 1 or 5, which is a glaucoma therapeutic agent. The pharmaceutical composition according to claim 1 or 5, which contains dorzolamide or a salt thereof as an active ingredient. A pharmaceutical composition, which contains dorzolamide or its salt as active ingredients, Dropmus or its salt, and hydroxyethyl cellulose as water-soluble thickener, and is contained in ethylene oxide gas for sterilization in resin containers.