JP2022131565A - Aqueous pharmaceutical composition - Google Patents

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

The present invention relates to aqueous pharmaceutical compositions.

It is desirable that the aqueous pharmaceutical composition is prevented from product spoilage due to microbial contamination or the like during use. Therefore, preservatives are added to various aqueous pharmaceutical compositions for the purpose of preventing putrefaction and improving storage stability (Patent Document 1). However, it has not been clarified about the effect of adding a thickening component to the aqueous pharmaceutical composition on the preservative efficacy of the aqueous pharmaceutical composition.

JP-A-6-293638

An object of the present invention is to provide an aqueous pharmaceutical composition containing a specific thickener in which deterioration in preservative efficacy is suppressed, and a method for enhancing the preservative efficacy of the aqueous pharmaceutical composition. is to provide

The present inventors have unexpectedly found that when an antioxidant and/or a buffering agent is added to an aqueous pharmaceutical composition containing hydroxyethylcellulose to be blended as a thickening agent, the decrease in preservative efficacy of the aqueous pharmaceutical composition is suppressed. found to be The present invention is based on this new finding.

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 buffers.
(Section 2)
(A) adding at least one selected from the group consisting of antioxidants and buffers to an aqueous pharmaceutical composition containing at least one selected from the group consisting of hydroxyethyl cellulose and salts thereof; A method for suppressing a decrease in preservative efficacy in the aqueous pharmaceutical composition.

The aqueous pharmaceutical composition of the present invention has suppressed deterioration in preservative efficacy. Therefore, even in aqueous pharmaceutical compositions that require particularly high safety against bacterial contamination, contamination of the aqueous pharmaceutical composition during use, risk of microbial infection, etc. can be reduced. In addition, the aqueous pharmaceutical composition of the present invention can be used safely and comfortably over a long period of time.

As used herein, unless otherwise specified, "POE" means polyoxyethylene.

As used herein, unless otherwise specified, "POP" means polyoxypropylene.

As used herein, unless otherwise specified, "contact lens" includes all types of contact lenses such as hard, oxygen-permeable hard, soft (including silicone hydrogel lenses), and color.

DETAILED DESCRIPTION OF THE INVENTION Embodiments for carrying out the present invention will be described in detail below. However, the present invention is not limited to the following embodiments.

[1. Aqueous pharmaceutical composition]
The aqueous composition according to the present embodiment includes (A) hydroxyethyl cellulose (also referred to as "(A) component"), and (B) at least one selected from the group consisting of antioxidants and buffers ("( B) (also referred to as "component").

[(A) component]
The (A) component hydroxyethyl cellulose and its salts are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable.

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

Salts of hydroxyethylcellulose include salts with alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and salts with metals such as aluminum.

The molecular weight of hydroxyethyl cellulose is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable, but the weight average molecular weight is usually about 5,000 to 5,000,000, preferably about 5,000 to 5,000,000. is about 10,000 to 2,500,000, more preferably about 100,000 to 1,000,000.

In the present embodiment, the content of aldehyde in the component (A) is not particularly limited, but from the viewpoint of further exhibiting the effects of the present invention, it may be, for example, 10000 ppm or less, preferably 5000 ppm or less, It is more preferably 1000 ppm or less, still more preferably 100 ppm or less, even more preferably 50 ppm or less, and particularly preferably 20 ppm or less. As a method for confirming the content of aldehyde in the component (A), the method described in the 17th Edition Japanese Pharmacopoeia Second Supplement (Hydroxyethylcellulose, Purity Test (4) Aldehydes) is exemplified.

The content of the component (A) in the aqueous pharmaceutical composition according to the present embodiment is not particularly limited, and is appropriately set according to the types of the components (A) and (B), the application of the aqueous pharmaceutical composition, the dosage form, and the like. be done. 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%. , more preferably 0.002 to 3 w/w%, 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%. , 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%. , more preferably 0.002 to 3 w/w%, even more preferably 0.05 to 3 w/w%, particularly preferably 0.1 to 1.5 w/w%.

Hydroxyethyl cellulose may be synthesized by a known method and also available as a commercial product. As the hydroxyethyl cellulose, one conforming to the Japanese Pharmacopoeia 17th Edition Supplement 2 can be used. Hydroxyethyl cellulose and salts thereof may be used singly or in combination of two or more. Hydroxyethyl cellulose and salts thereof include, for example, HEC-CF-G (average molecular weight of about 400,000), HEC-CF-H (average molecular weight of about 700,000), HEC-CF-V (average molecular weight of about 1,000,000), HEC -CF-W (average molecular weight of about 1.3 million), HEC-CF-X (average molecular weight of about 1.5 million), HEC-CF-Y (average molecular weight of about 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 ) (manufactured by Ashland Industries).

[(B) Component]
(B) component antioxidants include lipid-soluble antioxidants and water-soluble antioxidants, and if they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable, they are particularly limited not.

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

Among these antioxidants, dibutylhydroxytoluene (BHT) and sodium edetate are preferred. In addition, a commercially available antioxidant can also be used. The antioxidants may be used singly or in combination of two or more.

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

Inorganic buffers are buffers derived from inorganic acids. Examples of inorganic buffers include borate buffers, phosphate buffers, carbonate buffers and the like.

Boric acid buffers include boric acid or salts thereof (alkali metal borates, alkaline earth metal borates, etc.). Phosphate buffers include phosphoric acid and salts thereof (alkali metal phosphate, alkaline earth metal phosphate, etc.). Carbonic acid buffers include carbonic acid or salts thereof (alkali metal carbonates, alkaline earth metal carbonates, etc.). Borate or phosphate hydrates may also be used as the borate buffer or phosphate buffer. More specific examples include boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.) as a borate buffer; Salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); and salts thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.).

Organic buffers are buffers derived from organic acids or organic bases. Examples of organic buffers include citrate buffers, acetate buffers, Tris buffers, epsilon aminocaproate buffers, AMPD buffers and the like.

Citric acid buffers include citric acid or salts thereof (alkali metal citrate, alkaline earth metal citrate, etc.). The acetate buffer includes acetic acid or salts thereof (alkali metal acetate, alkaline earth metal acetate, etc.). In addition, a citrate or acetate hydrate may be used as the citrate buffer or acetate buffer. More specific examples include citric acid or a salt thereof (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.) as a citric acid buffer; acetic acid as an acetic acid buffer Alternatively, salts thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.) can be exemplified. Tris buffers include, for example, trometamol or salts thereof (trometamol hydrochloride, etc.). Epsilon aminocaproic acid buffers include, for example, epsilon aminocaproic acid or salts thereof. AMPD buffers include, for example, 2-amino-2-methyl-1,3-propanediol or salts thereof.

Among these buffers, borate buffers (such as a combination of boric acid and borax), phosphate buffers (such as a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate), citrate buffers, agents are preferred. Commercially available buffers can also be used. A buffering agent may be used individually by 1 type, or may be used in combination of 2 or more types.

The content of component (B) in the aqueous pharmaceutical composition according to the present embodiment is not particularly limited, and is appropriately set according to the types of components (A) and (B), the application and formulation form of the aqueous pharmaceutical composition, and the like. be done. As the content of component (B), from the viewpoint of exhibiting the effects of the present invention more remarkably, for example, based on the total amount of the aqueous pharmaceutical composition, the total content of component (B) is 0.00001 to 10 w / w % is preferred, 0.0001 to 5 w/w % is more preferred, and 0.001 to 3 w/w % is even more preferred. 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%. Preferably, it is 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%, preferably 0.005 to 0.2 w/w%. more preferably 0.01 to 0.1 w/w%.

In the aqueous pharmaceutical composition according to the present embodiment, the content ratio of component (B) to component (A) is not particularly limited, and the types of components (A) and (B), uses and dosage forms of the aqueous pharmaceutical composition etc., and is set as appropriate. As the content ratio of component (B) to component (A), from the viewpoint of further enhancing the effect of the present invention, for example, the total content of component (A) contained in the aqueous pharmaceutical composition according to the present embodiment is 1 mass. parts, the total content of component (B) is preferably 0.001 to 100 parts by mass, more preferably 0.01 to 50 parts by mass, and 0.03 to 20 parts by mass. It is even more preferable to have 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, It is more preferably 1 to 20 parts by weight. 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 weight, more preferably 0.01 to 2.0 parts by weight. Preferably, it is more preferably 0.03 to 1.0 parts by mass.

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

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

The aqueous pharmaceutical composition according to this embodiment may further contain (C) a surfactant (also referred to as “component (C)”). When the aqueous pharmaceutical composition further contains component (C), the effects of the present invention are exhibited more remarkably. Surfactants are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable, nonionic surfactants, amphoteric surfactants, anionic surfactants , cationic surfactants.

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

Amphoteric surfactants include, for example, alkyldiaminoethylglycine or salts thereof (eg, hydrochlorides, etc.).

Examples of anionic surfactants include alkylbenzenesulfonates, alkylsulfates, polyoxyethylene alkylsulfates, aliphatic α-sulfomethyl esters, α-olefinsulfonic acids and the like.

Examples of cationic surfactants include cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride and the like.

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. Surfactants may be used alone or in combination of two or more.

The content of component (C) in the aqueous pharmaceutical composition according to this embodiment is not particularly limited, and is appropriately set according to the type of component (C), the application of the aqueous pharmaceutical composition, the form of formulation, and the like. As the content of component (C), from the viewpoint of exhibiting the effects of the present invention more remarkably, for example, the total content of component (C) is 0.001 to 3 w/w based on the total amount of the aqueous pharmaceutical composition. w%, more preferably 0.005 to 2 w/w%, even more preferably 0.01 to 1 w/w%, and preferably 0.05 to 1 w/w% Especially preferred.

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 4.0 to 7.5. is more preferable.

The osmotic pressure ratio of the aqueous pharmaceutical composition according to this embodiment can be adjusted within a range acceptable to living organisms, if necessary. An appropriate osmotic pressure ratio can be appropriately set according to the application, formulation form, method of use, etc. of the aqueous pharmaceutical composition. , more preferably 0.7 to 2.0, even more preferably 0.9 to 1.55. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9 w/v% sodium chloride aqueous solution) based on the 17th revision of the Japanese Pharmacopoeia, and the osmotic pressure is the osmotic pressure measurement method described in the Japanese Pharmacopoeia. (freezing point depression method). The standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution) was obtained by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes and then placing it in a desiccator (silica gel). After allowing to cool, 0.900 g thereof is accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w/v % sodium chloride aqueous solution) can be used.

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. As the viscosity of the aqueous pharmaceutical composition according to the present embodiment, for example, the viscosity at 25 ° C. measured with a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor; 1 ° 34' × R24) is 1 to It may be 1000 mPa·s, preferably 1 to 500 mPa·s.

In the aqueous pharmaceutical composition according to the present embodiment, as long as the effect of the present invention is exhibited, in addition to the above components, various pharmacologically active ingredients and/or physiologically active ingredients are suitable alone or in appropriate combination. may contain a certain amount. 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 and the like.
Angiotropic agents: for example, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline sulfate, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride and the like.
Vitamins other than component (B): For example, flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, and the like.
Amino acids: For example, potassium aspartate, magnesium aspartate, sodium chondroitin sulfate, and the like.
Antiphlogistic 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 (eg, glycol salicylate, methyl salicylate) and the like.
Bactericidal component: For example, isopropylmethylphenol and the like.
Local anesthetic ingredients: for example, ethyl aminobenzoate, oxypolyethoxide decane, dibucaine, dibucaine hydrochloride, lidocaine, lidocaine hydrochloride and the like.
Antipruritic component: For example, crotamiton and the like.
Hair nourishing/hair growing ingredients: e.g. piroctone olamine, carrot extract, assembly extract, pantothenyl ethyl ether, D-pantothenyl alcohol, seaweed extract, minoxidil, finasteride, carpronium chloride, hinokitiol, estradiol benzoate, pyridoxine Hydrochloride, potassium pantothenate, resorcinol, ginseng tincture, cashew tincture, arnica tincture, dl-α-tocopherol, 2-L-ascorbic acid phosphate diester potassium salt, 6-benzylaminopurine and the like.
Others: For example, sodium hyaluronate, sulfamethoxazole, sulfamethoxazole sodium, aqueous ammonia and the like.

For the aqueous pharmaceutical composition according to the present embodiment, various bases or carriers are appropriately selected in accordance with conventional methods according to the application, dosage form, etc., as long as the effects of the invention are exhibited. An appropriate amount may be contained in combination with seeds or more. Representative components include, for example, aqueous bases such as water, liquid paraffin, squalane, petrolatum, gelling hydrocarbons (plastibase, etc.), ozokerite, α-olefin oligomers, and hydrocarbons such as light liquid paraffin; Siloxane, crosslinked methylpolysiloxane, highly polymerized methylpolysiloxane, 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, silicone resin, etc. higher alcohols such as cetanol, cetostearyl alcohol, stearyl alcohol, and behenyl alcohol; sterols such as cholesterol, phytosterol, and phytosteryl hydroxystearate; jojoba oil, meadowfoam oil, sunflower oil, grape seed oil, camellia oil, squalane, vegetable oils such as shea butter and rice germ oil; animal oils such as lanolin, orange roughy oil, squalane and horse oil; polyvinyl butyrate; polyethylene glycol; Esters such as isopropyl, cetyl palmitate, isononyl isononanoate, pentaerythrityl tetra-2-ethylhexanoate, jojoba oil, tri(caprylic/capric)glyceryl; polysaccharides such as dextrin and maltodextrin; 6, polyhydric alcohols having 2 to 4 hydroxyl groups; and organic acids such as succinic acid, glycolic acid and gluconic acid.

The aqueous pharmaceutical composition according to this embodiment means a pharmaceutical composition having a water content of 10 w/w% or more relative to the total amount of the aqueous pharmaceutical composition. The water content in the aqueous pharmaceutical composition is preferably 30 w/w% or more, more preferably 50 w/w% or more. When the aqueous pharmaceutical composition is an ophthalmic composition, it is preferably 70 w/w% or more, more preferably 80 w/w% or more, even more preferably 90 w/w%. As the water used in the aqueous pharmaceutical composition according to the present embodiment, pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable water may be used. is exemplified by distilled water, normal water, purified water, sterilized purified water, water for injection, distilled water for injection and the like.

In the aqueous pharmaceutical composition according to the present embodiment, as long as the effects of the invention are exhibited, various additives are appropriately selected according to a conventional method according to the application, formulation form, etc., one or More than that may be used in combination in an appropriate amount. Typical ingredients include the following additives.
Sugar: For example, cyclodextrin and the like.
Sugar alcohols: for example xylitol, sorbitol, mannitol and the like. These may be d-, l- or dl-isomers.
Preservatives, bactericides or antibacterial agents: e.g. zinc chloride, alkyldiaminoethylglycine hydrochloride, ethanol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, chlorhexidine gluconate, benzoic acid, sodium benzoate, paraoxybenzoic acid Methyl, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, isobutyl parahydroxybenzoate, isopropyl parahydroxybenzoate, benzyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, Glokyl (trade name, Rhodia) phenoxyethanol, benzyl alcohol, alkanediols, glycerin fatty acid esters and the like;
Cooling agents or terpenoids: monocyclic monoterpenes such as menthol, eugenol, thymol, limonene, anethole, cymene and terpineol; bicyclic monoterpenes such as camphor, borneol, cineol, pinene, camphene, isoborneol and fenchene Terpenes and acyclic monoterpenes such as geraniol, nerol, myrcene, myrcenol, linalool, linalool acetate and lavandulol, coolmint oil, peppermint oil, peppermint oil, eucalyptus oil, bergamot oil, spearmint oil, rose oil and camphor Essential oils and the like containing terpenoids such as oils.
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 and the like.
Irritation reducing agent: For example, licorice extract, sodium alginate, 2-methacryloyloxyethylphosphorylcholine and the like.
Oils: For example, sesame oil, castor oil, petrolatum, liquid paraffin and the like.
Colorants: For example, inorganic pigments, natural pigments, and the like.

The aqueous pharmaceutical composition according to this embodiment can be prepared by adding and mixing components (A), (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 to a predetermined pH and osmotic pressure, and sterilizing by filtration sterilization or the like.

The aqueous pharmaceutical composition according to this embodiment can take various formulation forms depending on the purpose. Examples of dosage forms include liquids, gels, semi-solids (ointments, etc.), suspensions, emulsions, creams, liniments, lotions, and aerosols.

The aqueous pharmaceutical composition according to this embodiment includes, for example, eye drops (also referred to as eye drops or eye drops. Eye drops include eye drops that can be instilled while wearing contact lenses), artificial tears, and eye washes. (Also referred to as eyewash or eyewash. Eye wash includes eyewash that can be washed while wearing contact lenses.), contact lens compositions [contact lens wetting solution, contact lens care composition (contact lens lens disinfectant, contact lens preservative, contact lens cleaning agent, contact lens cleaning and preserving agent, etc.]. The term "contact lens" includes hard contact lenses and soft contact lenses (both ionic and non-ionic, including both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

In the present embodiment, when the aqueous pharmaceutical composition is eye drops, the usage and dosage are not particularly limited as long as they are effective and have few side effects. In the case of children as described above, a method of using 1 to 2 drops per time, 4 times a day, and a method of using 2 to 3 drops per time, 5 to 6 times a day can be exemplified.

The aqueous pharmaceutical composition according to this embodiment can also be used, for example, as an external preparation such as a skin preparation. When the aqueous pharmaceutical composition according to the present embodiment is an external preparation, its usage and dosage are not particularly limited as long as they are effective and have few side effects. For children over the age of 1, several times a day (eg, about 1 to 5 times, preferably 1 to 3 times), appropriate amount (eg, about 0.5 to 2 g, or 0.5 to 2 ml (preferably 1 mL)) should be applied to the skin. The application method may be coating, spraying, or the like, depending on the dosage form.

As a container for containing the aqueous pharmaceutical composition according to the present embodiment, a container that is usually used as a container for containing an aqueous pharmaceutical composition can be used.

When the aqueous pharmaceutical composition is an ophthalmic composition, the containing container may be made of glass or plastic. When a plastic container is used for containing the aqueous pharmaceutical composition of the present invention, the constituent material of the plastic container is not particularly limited, but examples include polyethylene naphthalate, polyarylate, polyethylene terephthalate, polypropylene, polyethylene, Any one of polyimides, a copolymer thereof, or a mixture of two or more thereof may be used.

In addition, when the aqueous pharmaceutical composition is an ophthalmic composition, there are no particular restrictions on the structure, constituent materials, etc. of the container spout periphery such as a nozzle provided in the containing container. The structure of the periphery of the container spout, such as a nozzle, may be any structure that is generally employed as a spout (e.g., nozzle) of a container for an ophthalmic composition (e.g., an eye drop container). It may be molded, or may be molded separately from the container body. Concerning the constituent material of the peripheral part of the container spout such as the nozzle, for example, the same constituent materials as those of the above-mentioned plastic container are exemplified, but constituent materials containing polyethylene or polypropylene are preferable in terms of flexibility and cost. .

When the aqueous pharmaceutical composition is an external preparation, examples of container shapes include bottle type, tube type, jar type, dropper type, dispenser type, pouch bag, and chia pack. Examples of container materials include polyethylene terephthalate, polypropylene, polyethylene (HDPE, LDPE, LLDPE, etc.), ABS resin, ethylene vinyl alcohol resin, polystyrene, glass, and metals (aluminum, etc.). In addition, considering the strength, flexibility, and weather resistance of these materials and the stability of the ingredients contained in the container, various coating treatments are applied to containers containing these materials, and these materials are mixed, for example. A container material can be obtained by combining these materials by, for example, mixing them, or by laminating layers made of these materials to obtain a container material. In addition, a person skilled in the art can appropriately select the diameter and material of the nozzle of the container and the discharge part of the preparation in order to adjust the discharge amount of the preparation from the container or reduce the adhesion of the preparation to the container. can be done.

[2. Method for Suppressing Decrease in Preservative Efficacy in Aqueous Pharmaceutical Composition]
As described above, by adding the component (B) to the aqueous pharmaceutical composition containing the component (A), it is possible to suppress the deterioration of the preservative efficacy of the aqueous pharmaceutical composition. Therefore, as one embodiment of the present invention, (A) an aqueous pharmaceutical composition containing at least one selected from the group consisting of hydroxyethylcellulose and salts thereof, (B) from the group consisting of antioxidants and buffers Provided is a method for suppressing deterioration of preservative efficacy in the aqueous pharmaceutical composition, which comprises blending at least one of the selected ingredients.

In the method according to this embodiment, if the components (A) and (B) coexist in the aqueous pharmaceutical composition, they may be added simultaneously or separately, and the order It is not particularly limited. Types of components (A) and (B) to be used, their content (or blending amount), content ratio, type and content (or blending amount) of other components to be blended, formulation form of aqueous pharmaceutical composition , the type of container, combination, implementation method, etc. are the same as in the above "1. Aqueous pharmaceutical composition". In this specification, it is possible to determine whether or not the deterioration of the preservative efficacy of the aqueous pharmaceutical composition is suppressed by the method described in Examples below.

Hereinafter, the present invention will be described more specifically based on examples and the like. However, the present invention is not limited to the following examples.

[Test Example 1: Preservative efficacy test]
Purified water contains 0.6 w/w% hydroxyethyl cellulose, 0.2 w/w% polyoxyethylene hydrogenated castor oil 60, and 0.9 w/w% sodium chloride, and is adjusted to pH 6 using hydrochloric acid and sodium hydroxide. 0.5 to prepare an aqueous pharmaceutical composition of Comparative Example 1-1. The composition of Comparative Example 1-1 was further added with an aqueous pharmaceutical composition containing 0.2 w/w% boric acid (Example 1-1) and 0.005 w/w% dibutylhydroxytoluene. An aqueous pharmaceutical composition (Example 1-2) and an aqueous pharmaceutical composition containing 0.05 w/w% sodium edetate (Example 1-3) were prepared. NATROSOL 250M PHARM (weight average molecular weight 720,000, manufactured by Ashland Industries) was used as hydroxyethyl cellulose.
Each aqueous pharmaceutical composition prepared was filtered through a 0.2 μm membrane filter and sterilized. Staphylococcus aureus (ATCC6538), Escherichia coli (ATCC8739), and Pseudomonas aeruginosa (ATCC9027) were each 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 sterilized physiological saline to prepare a bacterial suspension containing about 1×10 ⁷ CFU/mL viable cells. The number of viable bacteria in the suspension was separately cultured and measured. Next, ⁵⁰ mL of CORNING conical tube (PET) was filled with 20 mL of each of the above aqueous pharmaceutical compositions that had been filtered and sterilized. A bacterial solution (suspended in physiological saline) was inoculated and well stirred to prepare a sample. Samples were stored for 7-14 days at 23°C protected from light. After that, the bacteria are collected according to the agar pour method, and left to stand at 33° C. for 2 to 3 days in a soybean/casein/digest agar medium. The number of viable bacteria per 1 mL of the composition was determined.

As a result, it was confirmed that the aqueous pharmaceutical compositions of Examples 1-1 to 1-3 all maintained high preservative efficacy compared to the aqueous pharmaceutical composition of Comparative Example 1-1. In addition, a storage efficacy test was conducted in the same manner as above, except that the aqueous pharmaceutical compositions of Comparative Example 1-1 and Examples 1-1 to 1-3 were stored at 60° C. for 1 week. , It was confirmed that the aqueous pharmaceutical compositions of Examples 1-1 to 1-3 all maintained high preservative efficacy compared to the aqueous pharmaceutical composition of Comparative Example 1-1.

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

Claims (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 buffers.