Aqueous pharmaceutical composition

Abstract

To provide an aqueous pharmaceutical composition that contains a specific thickener and barely shows a decrease in preservation efficacy.SOLUTION: An aqueous pharmaceutical composition contains (A) at least one selected from the group consisting of hydroxyethyl celluloses and salts thereof, and (B) at least one selected from the group consisting of antioxidants and buffer agents.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an aqueous pharmaceutical composition. [Background technology]

[0002] It is desirable that aqueous pharmaceutical compositions be prevented from spoiling due to microbial contamination during use. Therefore, various aqueous pharmaceutical compositions contain preservatives to prevent spoilage and improve storage stability (Patent Document 1). However, the effect of adding a thickening component to an aqueous pharmaceutical composition on the preservative effectiveness of the composition has not been clarified. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Publication No. 6-293638 Summary of the Invention [Problem to be solved by the invention]

[0004] An object of the present invention is to provide an aqueous pharmaceutical composition containing a specific thickener, in which the decrease in preservative effectiveness is suppressed, and to provide a method for enhancing the preservative effectiveness of the aqueous pharmaceutical composition. [Means for solving the problem]

[0005] The present inventors have unexpectedly found that adding an antioxidant and / or a buffer to an aqueous pharmaceutical composition containing hydroxyethyl cellulose as a thickener prevents a decrease in the preservative effectiveness of the aqueous pharmaceutical composition. The present invention is based on this novel finding.

[0006] The present invention provides, for example, the following inventions. (Section 1) An aqueous pharmaceutical composition comprising: (A) at least one selected from the group consisting of hydroxyethyl cellulose and salts thereof; and (B) at least one selected from the group consisting of antioxidants and buffering agents. (Section 2) A method for suppressing a decrease in preservative effectiveness in an aqueous pharmaceutical composition, comprising blending (B) at least one selected from the group consisting of antioxidants and buffering agents with an aqueous pharmaceutical composition containing (A) at least one selected from the group consisting of hydroxyethyl cellulose and salts thereof. [Effects of the Invention]

[0007] The aqueous pharmaceutical composition of the present invention has suppressed deterioration in preservative effectiveness. Therefore, even in aqueous pharmaceutical compositions that require particularly high safety against microbial contamination, contamination of the aqueous pharmaceutical composition during use and the risk of microbial infection can be reduced. Furthermore, the aqueous pharmaceutical composition of the present invention can be used safely, comfortably, and effectively over a long period of time. DETAILED DESCRIPTION OF THE INVENTION

[0008] In this specification, unless otherwise specified, "POE" means polyoxyethylene.

[0009] In this specification, unless otherwise specified, "POP" means polyoxypropylene.

[0010] In this specification, unless otherwise specified, the term "contact lenses" includes all types of contact lenses, such as hard, oxygen permeable hard, soft (including silicone hydrogel lenses), and colored lenses.

[0011] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments.

[0012] [1. Aqueous Pharmaceutical Composition] The aqueous composition according to this embodiment contains (A) hydroxyethyl cellulose (also referred to as "component (A)") and (B) at least one selected from the group consisting of antioxidants and buffering agents (also referred to as "component (B)").

[0013] [Component (A)] There are no particular limitations on the hydroxyethyl cellulose and salts thereof that are component (A), so long as they are medicamentally, pharmacologically (pharmaceutical) or physiologically acceptable.

[0014] Hydroxyethyl cellulose is a partially O-(2-hydroxyethyl) cellulose and is a known compound.

[0015] Examples of salts of hydroxyethyl cellulose include salts with alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and metals such as aluminum.

[0016] The molecular weight of hydroxyethyl cellulose is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable, but typically, hydroxyethyl cellulose with a weight-average molecular weight of about 5,000 to 5,000,000, preferably about 10,000 to 2.5 million, and more preferably about 100,000 to 1,000,000 can be used.

[0017] In this embodiment, the aldehyde content in component (A) is not particularly limited, but from the viewpoint of further exerting the effects of the present invention, it may be, for example, 10,000 ppm or less, preferably 5,000 ppm or less, more preferably 1,000 ppm or less, even more preferably 100 ppm or less, even more preferably 50 ppm or less, and particularly preferably 20 ppm or less. Note that, an example of a method for confirming the aldehyde content in component (A) is the method described in the Japanese Pharmacopoeia, Seventeenth Edition, Supplement 2 (Hydroxyethylcellulose, Purity Test (4) Aldehyde).

[0018] The content of component (A) in the aqueous pharmaceutical composition according to this embodiment is not particularly limited and is appropriately determined depending on the types of components (A) and (B), the intended use of the aqueous pharmaceutical composition, the formulation, etc. For example, based on the total amount of the aqueous pharmaceutical composition, the total content of component (A) is preferably 0.0005 to 5 w / w%, more preferably 0.001 to 4 w / w%, even more preferably 0.002 to 3 w / w%, and even more preferably 0.005 to 2 w / w%. When the aqueous pharmaceutical composition is an ophthalmic composition, the total content of component (A) is preferably 0.0005 to 5 w / w%, more preferably 0.001 to 4 w / w%, even more preferably 0.002 to 3 w / w%, even more preferably 0.005 to 2 w / w%, and particularly preferably 0.01 to 1 w / w%. When the aqueous pharmaceutical composition is a composition for external use, the total content of component (A) is preferably 0.0005 to 5 w / w%, more preferably 0.001 to 3 w / w%, even more preferably 0.002 to 3 w / w%, even more preferably 0.05 to 3 w / w%, and particularly preferably 0.1 to 1.5 w / w%.

[0019] Hydroxyethyl cellulose can be synthesized by known methods or obtained as a commercially available product. Hydroxyethyl cellulose can be used in accordance with the Japanese Pharmacopoeia, 17th Edition, Supplement 2. Hydroxyethyl cellulose and its salts can be used alone or in combination of two or more. Hydroxyethyl cellulose and its salts include, for example, HEC-CF-G (average molecular weight approximately 400,000), HEC-CF-H (average molecular weight approximately 700,000), HEC-CF-V (average molecular weight approximately 1 million). ), HEC-CF-W (average molecular weight approximately 1.3 million), HEC-CF-X (average molecular weight approximately 1.5 million), HEC-CF-Y (average molecular weight approximately 1.8 million) (manufactured by Sumitomo Seika Co., Ltd.); NATROSOL 250L PHARM (weight average molecular weight 90,000), NATROSOL 250G PHARM (weight average molecular weight 300,000), NATROSOL 250M PHARM (weight average molecular weight 720,000), NATROSOL 250HX PHARM (weight average molecular weight 1,000,000), NATROSOL 250HHX PHARM (weight average molecular weight 1,300,000) (Ashland Industries).

[0020] [(B) component] The antioxidant as component (B) includes fat-soluble antioxidants and water-soluble antioxidants, and is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable.

[0021] Specific examples of antioxidants include fat-soluble antioxidants such as dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), tocopherol and its derivatives, nordihydroguaiaretic acid, propyl gallate, and oil-soluble vitamin C derivatives, and water-soluble antioxidants such as sodium pyrosulfite and sodium edetate.

[0022] Among these antioxidants, dibutylhydroxytoluene (BHT) and sodium edetate are preferred. Commercially available antioxidants can also be used. One type of antioxidant may be used alone, or two or more types may be used in combination.

[0023] The buffering agent as component (B) includes inorganic buffering agents and organic buffering agents, and is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable.

[0024] Inorganic buffers are buffers derived from inorganic acids, such as borate buffers, phosphate buffers, and carbonate buffers.

[0025] Examples of borate buffers include boric acid or its salts (alkali metal borates, alkaline earth metal borates, etc.). Examples of phosphate buffers include phosphoric acid or its salts (alkali metal phosphates, alkaline earth metal phosphates, etc.). Examples of carbonate buffers include carbonic acid or its salts (alkali metal carbonates, alkaline earth metal carbonates, etc.). Furthermore, borate or phosphate hydrates may be used as borate buffers or phosphate buffers. More specific examples of borate buffers include boric acid or its salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); phosphate buffers include phosphoric acid or its salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); and carbonate buffers include carbonic acid or its salts (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.).

[0026] The organic buffer is a buffer derived from an organic acid or an organic base, and examples of the organic buffer include citrate buffer, acetate buffer, Tris buffer, epsilon aminocaproic acid buffer, and AMPD buffer.

[0027] Examples of citrate buffers include citric acid or its salts (such as alkali metal citrates and alkaline earth metal citrates). Examples of acetate buffers include acetic acid or its salts (such as alkali metal acetates and alkaline earth metal acetates). Furthermore, citrates or acetate hydrates may be used as citrate buffers or acetate buffers. More specific examples of citrate buffers include citric acid or its salts (such as sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, and disodium citrate); and acetate buffers include acetic acid or its salts (such as ammonium acetate, potassium acetate, calcium acetate, and sodium acetate). Examples of Tris buffers include trometamol or its salts (such as trometamol hydrochloride). Examples of epsilon aminocaproic acid buffers include epsilon aminocaproic acid or its salts. Examples of AMPD buffers include 2-amino-2-methyl-1,3-propanediol or its salts.

[0028] Among these buffers, borate buffers (e.g., a combination of boric acid and borax), phosphate buffers (e.g., a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate), and citrate buffers are preferred. Commercially available buffers can also be used. One buffer may be used alone, or two or more buffers may be used in combination.

[0029] The content of component (B) in the aqueous pharmaceutical composition according to this embodiment is not particularly limited and is appropriately determined depending on the types of components (A) and (B), the intended use of the aqueous pharmaceutical composition, the formulation, and the like. From the viewpoint of more significantly achieving the effects of the present invention, the content of component (B) is, for example, preferably 0.00001 to 10 w / w%, more preferably 0.0001 to 5 w / w%, and even more preferably 0.001 to 3 w / w%, based on the total amount of the aqueous pharmaceutical composition. When the aqueous pharmaceutical composition is an ophthalmic composition, the total content of component (B) is preferably 0.00001 to 10 w / w%, more preferably 0.0001 to 5 w / w%, and even more preferably 0.001 to 3 w / w%. When the aqueous pharmaceutical composition is a composition for external use, the total content of component (B) is preferably 0.001 to 0.5 w / w%, more preferably 0.005 to 0.2 w / w%, and even more preferably 0.01 to 0.1 w / w%.

[0030] The ratio of component (B) to component (A) in the aqueous pharmaceutical composition according to this embodiment is not particularly limited and is appropriately set depending on the types of components (A) and (B), the intended use of the aqueous pharmaceutical composition, the formulation, etc. From the viewpoint of further enhancing the effects of the present invention, the ratio of component (B) to component (A) is, for example, preferably 0.001 to 100 parts by mass, more preferably 0.01 to 50 parts by mass, and even more preferably 0.03 to 20 parts by mass, of the total content of component (B) per part by mass of the total content of component (A) in the aqueous pharmaceutical composition according to this embodiment. When the aqueous pharmaceutical composition is an ophthalmic composition, the total content of component (B) is preferably 0.01 to 100 parts by mass, more preferably 0.1 to 50 parts by mass, and even more preferably 1 to 20 parts by mass. When the aqueous pharmaceutical composition is a composition for external use, the total content of component (B) is preferably 0.001 to 5 parts by mass, more preferably 0.01 to 2.0 parts by mass, and even more preferably 0.03 to 1.0 part by mass.

[0031] When an antioxidant is contained as component (B), from the viewpoint of more significantly exhibiting the effects of the present invention, for example, the total content of the antioxidant is preferably 0.00001 to 2 w / w%, more preferably 0.0001 to 1 w / w%, and even more preferably 0.001 to 0.5 w / w%, based on the total amount of the aqueous pharmaceutical composition. When the aqueous pharmaceutical composition is an ophthalmic composition, the total content of the antioxidant is preferably 0.00001 to 2 w / w%, more preferably 0.0001 to 1 w / w%, and even more preferably 0.001 to 0.5 w / w%. When the aqueous pharmaceutical composition is a composition for external use, the total content of the antioxidant is preferably 0.001 to 0.5 w / w%, more preferably 0.005 to 0.2 w / w%, and even more preferably 0.01 to 0.1 w / w%.

[0032] When a buffering agent is contained as component (B), from the viewpoint of more significantly exhibiting the effects of the present invention, the total content of the buffering agent is, for example, preferably 0.01 to 10 w / w%, more preferably 0.05 to 5 w / w%, and even more preferably 0.01 to 3 w / w%, based on the total amount of the aqueous pharmaceutical composition.

[0033] The aqueous pharmaceutical composition according to this embodiment may further contain a surfactant (C) (also referred to as "component (C)"). When the aqueous pharmaceutical composition further contains component (C), the effects of the present invention are more pronounced. The surfactant is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical), or physiologically acceptable, and may be any of a nonionic surfactant, amphoteric surfactant, anionic surfactant, and cationic surfactant.

[0034] Examples of nonionic surfactants include POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monopalmitate (polysorbate 40), POE (20) sorbitan monostearate (polysorbate 60), POE (20) sorbitan tristearate (polysorbate 65), and POE (20) sorbitan monooleate (polysorbate 80) and other POE sorbitan fatty acid esters; POE (40) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40), POE (60) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60), and other POE hydrogenated castor oils. Examples include castor oil; POE castor oils such as POE(3) hydrogenated castor oil (polyoxyethylene castor oil 3), POE(10) castor oil (polyoxyethylene castor oil 10), and POE(35) castor oil (polyoxyethylene castor oil 35); POE alkyl ethers such as POE(9) lauryl ether; POE-POP alkyl ethers such as POE(20)POP(4) cetyl ether; and polyoxyethylene-polyoxypropylene block copolymers such as POE(196)POP(67) glycol (poloxamer 407, Pluronic F127) and POE(200)POP(70) glycol. In the compounds listed above, the numbers in parentheses indicate the number of moles added.

[0035] Examples of amphoteric surfactants include alkyldiaminoethylglycine and salts thereof (for example, hydrochloride salts).

[0036] Examples of anionic surfactants include alkylbenzene sulfonates, alkyl sulfates, polyoxyethylene alkyl sulfates, aliphatic α-sulfomethyl esters, and α-olefin sulfonic acids.

[0037] Examples of cationic surfactants include cetylpyridinium chloride, benzalkonium chloride, and benzethonium chloride.

[0038] Among these surfactants, nonionic surfactants are preferred, and POE sorbitan fatty acid esters, POE hydrogenated castor oil, and POE-POP block copolymers are more preferred. Commercially available surfactants can also be used. One surfactant may be used alone, or two or more surfactants may be used in combination.

[0039] The content of component (C) in the aqueous pharmaceutical composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (C), the intended use of the aqueous pharmaceutical composition, the dosage form, etc. From the viewpoint of more significantly exhibiting the effects of the present invention, the content of component (C) is, for example, preferably 0.001 to 3 w / w%, more preferably 0.005 to 2 w / w%, even more preferably 0.01 to 1 w / w%, and particularly preferably 0.05 to 1 w / w%, based on the total amount of the aqueous pharmaceutical composition.

[0040] The pH of the aqueous pharmaceutical composition according to this embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical), or physiologically acceptable range. The pH of the aqueous pharmaceutical composition according to this embodiment may be, for example, 2.0 to 9.5, preferably 3.0 to 8.0, and more preferably 4.0 to 7.5.

[0041] The aqueous pharmaceutical composition according to this embodiment can be adjusted, as needed, to have an osmotic pressure ratio within a biologically acceptable range. The appropriate osmotic pressure ratio can be appropriately determined depending on the intended use, formulation, and method of use of the aqueous pharmaceutical composition, but can be, for example, 0.5 to 5.0, preferably 0.6 to 3.0, more preferably 0.7 to 2.0, and even more preferably 0.9 to 1.55. The osmotic pressure ratio is defined as the ratio of the osmotic pressure of the sample to 286 mOsm (the osmotic pressure of a 0.9 w / v% sodium chloride aqueous solution) in accordance with the Japanese Pharmacopoeia, 17th Edition, and is measured using the osmotic pressure measurement method (freezing-point depression method) described in the Japanese Pharmacopoeia. The standard solution for measuring osmolality ratios (0.9 w / v% sodium chloride aqueous solution) can be prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C for 40-50 minutes, allowing it to cool in a desiccator (silica gel), accurately weighing 0.900 g of the solution, and dissolving it in purified water to make exactly 100 mL; alternatively, a commercially available standard solution for measuring osmolality ratios (0.9 w / v% sodium chloride aqueous solution) can be used.

[0042] The viscosity of the aqueous pharmaceutical composition according to this embodiment is not particularly limited, as long as it is within a pharmaceutically, pharmacologically (pharmaceutical), or physiologically acceptable range. The viscosity of the aqueous pharmaceutical composition according to this embodiment may be, for example, 1 to 1000 mPa s, preferably 1 to 500 mPa s, at 25°C as measured using a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34' x R24).

[0043] The aqueous pharmaceutical composition according to this embodiment may contain, in addition to the above-mentioned components, appropriate amounts of various pharmacologically active components and / or physiologically active components, either singly or in appropriate combination, as long as the effects of the present invention are achieved. Such components are not particularly limited, and specific examples include the following components: Antihistamines or antiallergic agents: for example, iproheptine, diphenhydramine hydrochloride, chlorpheniramine maleate, ketotifen fumarate, pemirolast potassium, sodium cromoglycate, etc. Hemangioconstrictors: for example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline sulfate, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, etc. (B) Vitamins other than the ingredients: For example, flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, etc. Amino acids: for example, potassium aspartate, magnesium aspartate, sodium chondroitin sulfate, etc. Anti-inflammatory agents: for example, bromfenac sodium, dipotassium glycyrrhizinate, pranoprofen, allantoin, azulene, sodium azulene sulfonate, guaiazulene, berberine chloride, berberine sulfate, lysozyme chloride, zinc sulfate, zinc lactate, licorice, salicylic acid and its derivatives (for example, glycol salicylate, methyl salicylate), etc. Bactericidal ingredients: for example, isopropylmethylphenol, etc. Local anesthetic ingredients: for example, ethyl aminobenzoate, oxypolyethoxydodecane, dibucaine, dibucaine hydrochloride, lidocaine, lidocaine hydrochloride, etc. Antipruritic ingredients: for example, crotamiton. Hair nourishing and hair growth ingredients: For example, piroctone olamine, carrot extract, Swertia japonica extract, pantothenyl ethyl ether, D-pantothenyl alcohol, seaweed extract, minoxidil, finasteride, carpronium chloride, hinokitiol, estradiol benzoate ester, pyridoxine hydrochloride, potassium pantothenate, resorcinol, ginseng tincture, cashew tincture, arnica tincture, dl-α-tocopherol, 2-L-ascorbic acid phosphate diester potassium salt, 6-benzylaminopurine, etc. Others: For example, sodium hyaluronate, sulfamethoxazole, sulfamethoxazole sodium, ammonia water, etc.

[0044] The aqueous pharmaceutical composition of this embodiment may contain one or more suitable bases or carriers, selected in a conventional manner depending on the intended use, formulation, etc., as long as the effects of the invention are achieved. Representative components include, for example, aqueous bases such as water; hydrocarbons such as liquid paraffin, squalane, petrolatum, gelling hydrocarbons (such as Plastibase), ozokerite, α-olefin oligomers, and light liquid paraffin; silicone oils such as methyl polysiloxane, crosslinked methyl polysiloxane, highly polymerized methyl polysiloxane, cyclic silicone, alkyl-modified silicone, crosslinked alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, crosslinked polyether-modified silicone, crosslinked alkyl polyether-modified silicone, silicone / alkyl chain co-modified polyether-modified silicone, silicone / alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branched silicone, polyglycerin-modified branched silicone, acrylic silicone, phenyl-modified silicone, and silicone resin; cetanol, cetostearyl alcohol, stearic acid, methyl methyl siloxane ... higher alcohols such as butyl alcohol and behenyl alcohol; sterols such as cholesterol, phytosterol, and phytosteryl hydroxystearate; vegetable oils such as jojoba oil, meadowfoam oil, sunflower oil, grape seed oil, camellia oil, squalane, shea butter, and rice germ oil; animal oils such as lanolin, orange roughy oil, squalane, and horse oil; polyvinyl butyrate; polyethylene glycol; dioxane; butylene glycol adipate polyester; esters such as isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, pentaerythrityl tetra-2-ethylhexanoate, jojoba oil, and caprylic / capric triglyceride; polysaccharides such as dextrin and maltodextrin; polyhydric alcohols having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups; and organic acids such as succinic acid, glycolic acid, and gluconic acid.

[0045] The aqueous pharmaceutical composition according to this embodiment refers to a pharmaceutical composition having a water content of 10 wt% or more relative to the total amount of the aqueous pharmaceutical composition. The water content in the aqueous pharmaceutical composition is preferably 30 wt% or more, more preferably 50 wt% or more. When the aqueous pharmaceutical composition is an ophthalmic composition, the water content is preferably 70 wt% or more, more preferably 80 wt% or more, and even more preferably 90 wt%. The water used in the aqueous pharmaceutical composition according to this embodiment may be any water that is medicamentally, pharmacologically (pharmaceutical), or physiologically acceptable. Specific examples of such water include distilled water, tap water, purified water, sterile purified water, water for injection, and distilled water for injection.

[0046] The aqueous pharmaceutical composition according to this embodiment may contain one or more additives selected in appropriate amounts in accordance with the intended use, formulation, etc., in a conventional manner, as long as the effects of the invention are achieved. Representative additives include the following: Sugars: e.g., cyclodextrin, etc. Sugar alcohols: for example, xylitol, sorbitol, mannitol, etc. These may be in the d-, l- or dl-form. Preservatives, disinfectants, or antibacterial agents: for example, zinc chloride, alkyldiaminoethylglycine hydrochloride, ethanol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, chlorhexidine gluconate, benzoic acid, sodium benzoate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, isobutyl parahydroxybenzoate, isopropyl parahydroxybenzoate, benzyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, Gloquil (trade name, Rhodia), phenoxyethanol, benzyl alcohol, alkanediol, glycerin fatty acid esters, etc. Cooling agents or terpenoids: for example, monocyclic monoterpenes such as menthol, eugenol, thymol, limonene, anethole, cymene, and terpineol; bicyclic monoterpenes such as camphor, borneol, cineole, pinene, camphene, isoborneol, and fengchen; acyclic monoterpenes such as geraniol, nerol, myrcene, myrcenol, linalool, linalool acetate, and lavandulol; essential oils containing terpenoids such as cool mint oil, peppermint oil, peppermint oil, eucalyptus oil, bergamot oil, spearmint oil, rose oil, and camphor oil; and the like. Thickeners other than component (A): For example, gum arabic powder, sodium alginate, propylene glycol alginate, sorbitol, dextran 70, tragacanth powder, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone (K25, K30, K90, etc.), macrogol 4000, etc. pH adjusters: for example, inorganic acids (hydrochloric acid, sulfuric acid, etc.), organic acids (lactic acid, sodium lactate, citric acid, sodium citrate, succinic acid, sodium succinate, etc.), inorganic bases (potassium hydroxide, sodium hydroxide, etc.), organic bases (triethanolamine, diisopropanolamine, triisopropanolamine, etc.), etc. Stabilizers: for example, sodium polyacrylate. Irritation reducers: for example, licorice extract, sodium alginate, 2-methacryloyloxyethyl phosphorylcholine, etc. Oils: For example, sesame oil, castor oil, petrolatum, liquid paraffin, etc. Coloring agents: for example, inorganic pigments, natural dyes, etc.

[0047] The aqueous pharmaceutical composition according to this embodiment can be prepared by adding and mixing component (A), component (B), and, if necessary, other components to a desired concentration. For example, it can be prepared by dissolving or dispersing these components in purified water, adjusting the pH and osmotic pressure to a predetermined level, and sterilizing the composition by filtration or other methods.

[0048] The aqueous pharmaceutical composition according to this embodiment can be in various formulation forms depending on the purpose, such as a liquid, a gel, a semisolid (e.g., ointment), a suspension, an emulsion, a cream, a liniment, a lotion, and an aerosol.

[0049] The aqueous pharmaceutical composition according to this embodiment can be used as an ophthalmic composition, such as eye drops (also called eye drops or eye drops; eye drops include eye drops that can be applied while wearing contact lenses), artificial tears, eyewash (also called eyewash or eyewash; eyewashes include eyewashes that can be used while wearing contact lenses), and contact lens compositions (contact lens wetting solution, contact lens care compositions (contact lens disinfectants, contact lens preservatives, contact lens cleaners, contact lens cleaning and preservatives), etc.). The term "contact lenses" includes hard contact lenses and soft contact lenses (including both ionic and non-ionic contact lenses, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

[0050] In this embodiment, when the aqueous pharmaceutical composition is an eye drop, the dosage and administration method are not particularly limited as long as they are effective and have few side effects. For example, for adults (15 years of age or older) and children 7 years of age or older, one to two drops may be instilled into the eyes four times a day, or two to three drops may be instilled into the eyes five to six times a day.

[0051] The aqueous pharmaceutical composition according to this embodiment can also be used as an external preparation, such as a skin topical preparation. When the aqueous pharmaceutical composition according to this embodiment is an external preparation, the dosage and administration method are not particularly limited as long as they are effective and cause few side effects. For example, for adults (15 years of age or older) and children aged 7 years of age or older, an appropriate amount (e.g., about 0.5 to 2 g, or 0.5 to 2 ml (preferably 1 ml)) may be applied to the skin several times a day (e.g., about 1 to 5 times, preferably 1 to 3 times). The application method may be by painting or spraying, depending on the dosage form.

[0052] As a container for holding the aqueous pharmaceutical composition according to this embodiment, a container that is commonly used as a container for holding an aqueous pharmaceutical composition can be used.

[0053] When the aqueous pharmaceutical composition is an ophthalmic composition, the container may be made of glass or plastic. When a plastic container is used to store the aqueous pharmaceutical composition of the present invention, the constituent material of the plastic container is not particularly limited, and examples thereof include any one of polyethylene naphthalate, polyarylate, polyethylene terephthalate, polypropylene, polyethylene, and polyimide, a copolymer thereof, or a mixture of two or more thereof.

[0054] Furthermore, when the aqueous pharmaceutical composition is an ophthalmic composition, the structure, constituent materials, etc. of the peripheral part of the container spout, such as a nozzle provided on the container to contain the composition, are not particularly limited. The structure of the peripheral part of the container spout, such as a nozzle, may be any structure that is commonly used as a spout (e.g., a nozzle) for a container for an ophthalmic composition (e.g., an eye drop container), and may be molded integrally with the container body or molded separately from the container body. Examples of the constituent materials of the peripheral part of the container spout, such as a nozzle, include the same materials as those of the plastic containers described above, but from the standpoints of flexibility and cost, constituent materials containing polyethylene or polypropylene are preferred.

[0055] When the aqueous pharmaceutical composition is an external preparation, examples of the container shape include bottles, tubes, jars, droppers, dispensers, pouches, and cheer packs. Examples of container materials include polyethylene terephthalate, polypropylene, polyethylene (e.g., HDPE, LDPE, and LLDPE), ABS resin, ethylene vinyl alcohol resin, polystyrene, glass, and metal (e.g., aluminum). Taking into consideration the strength, flexibility, and weather resistance of these materials, as well as the stability of the components contained in the container, containers containing these materials can be subjected to various coating treatments, or these materials can be combined, for example, by mixing, to form container materials, or layers made of these materials can be laminated to form container materials. Those skilled in the art can also appropriately select the diameter and material of the container nozzle and formulation discharge port to adjust the amount of formulation discharged from the container or reduce adhesion of the formulation to the container.

[0056] [2. Method for preventing deterioration of preservative effectiveness in aqueous pharmaceutical composition] As described above, by adding component (B) to an aqueous pharmaceutical composition containing component (A), it is possible to suppress a decrease in the preservative effectiveness of the aqueous pharmaceutical composition. Accordingly, one embodiment of the present invention provides a method for suppressing a decrease in the preservative effectiveness of an aqueous pharmaceutical composition, which comprises blending (B) at least one selected from the group consisting of antioxidants and buffering agents with an aqueous pharmaceutical composition containing (A) at least one selected from the group consisting of hydroxyethyl cellulose and salts thereof.

[0057] In the method according to this embodiment, as long as component (A) and component (B) coexist in the aqueous pharmaceutical composition, they may be added simultaneously or separately, and the order of addition is not particularly limited. The types of component (A) and component (B) used, their contents (or blending amounts), content ratios, types and contents (or blending amounts) of other components to be blended, the formulation form of the aqueous pharmaceutical composition, type of container, combinations, implementation methods, etc. are the same as those described above in "1. Aqueous Pharmaceutical Composition." In this specification, whether or not the loss of preservative effectiveness in the aqueous pharmaceutical composition is suppressed can be determined by the method described in the Examples below. [Example]

[0058] The present invention will be described in more detail below with reference to examples, etc. However, the present invention is not limited to the following examples.

[0059] [Test Example 1: Preservative Effectiveness Test] Purified water was supplemented with 0.6 wt% hydroxyethyl cellulose, 0.2 wt% polyoxyethylene hydrogenated castor oil 60, and 0.9 wt% sodium chloride, and the pH was adjusted to 6.5 using hydrochloric acid and sodium hydroxide to prepare the aqueous pharmaceutical composition of Comparative Example 1-1. The aqueous pharmaceutical composition of Comparative Example 1-1 was further supplemented with 0.2 wt% boric acid (Example 1-1), 0.005 wt% dibutylhydroxytoluene (Example 1-2), and 0.05 wt% sodium edetate (Example 1-3). NATROSOL 250M PHARM (weight-average molecular weight 720,000, manufactured by Ashland Industries) was used as the hydroxyethyl cellulose. Each prepared aqueous pharmaceutical composition was sterilized by filtration through a 0.2 μm membrane filter. Staphylococcus aureus (ATCC6538), Escherichia coli (ATCC8739), and Pseudomonas aeruginosa (ATCC9027) were inoculated onto the surface of a soybean-casein digest slant medium and cultured at 33°C for 24 hours. The cultured cells were aseptically collected with a platinum loop and suspended in an appropriate amount of sterile saline to obtain a concentration of approximately 1 × 10 7 A bacterial suspension containing viable bacteria at CFU / mL was prepared. The viable cell count in the suspension was measured by separate cultivation. Next, 20 mL of each of the filter-sterilized aqueous pharmaceutical compositions was filled into 50 mL Corning conical tubes (PET), and the viable cell count (final concentration) was adjusted to approximately 1 x 10 5 Various bacterial solutions (suspended in saline) were inoculated to give CFU / mL and mixed thoroughly to prepare samples. The samples were stored at 23°C in the dark for 7 to 14 days. The bacteria were then recovered using the agar pour plate method and placed in soybean-casein-digest agar medium, which was then allowed to stand at 33°C for 2 to 3 days. The number of viable bacteria in the medium was then visually counted to determine the number of viable bacteria per 1 mL of each aqueous pharmaceutical composition.

[0060] As a result, it was confirmed that the preservative effectiveness of all of the aqueous pharmaceutical compositions of Examples 1-1 to 1-3 was maintained at a higher level than that of the aqueous pharmaceutical composition of Comparative Example 1-1. Furthermore, when a preservative effectiveness test was carried out in the same manner as above, except that the aqueous pharmaceutical compositions of Comparative Example 1-1 and Examples 1-1 to 1-3 that had been stored at 60°C for 1 week were used, it was confirmed that the preservative effectiveness of all of the aqueous pharmaceutical compositions of Examples 1-1 to 1-3 was maintained at a higher level than that of the aqueous pharmaceutical composition of Comparative Example 1-1.

[0061] [Formulation example] Formulation examples are listed below. Formulation examples 1 to 10 are eye drops (ophthalmic compositions), formulation examples 11 to 22 are emulsions (compositions for external use), and formulation examples 23 to 25 are solutions (compositions for external use). NATROSOL 250M PHARM (weight average molecular weight 720,000, manufactured by Ashland Industries) was used as the hydroxyethyl cellulose.

[0062]

Table 1

[0063]

Table 2

[0064]

Table 3

Claims

[Claim 1] The invention described in the specification.

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