JP7758466B2 - Ophthalmic composition - Google Patents

Description

The present invention relates to an ophthalmic composition.

When manufacturing pharmaceuticals such as eye drops and eyewash, it is necessary to fill containers with an accurate amount of medicinal liquid. Typically, during the filling process, the medicinal liquid is filled into the container via a filling needle, and filling an accurate amount of medicinal liquid can be achieved by precisely controlling the amount of liquid that drips from the filling needle.

On the other hand, chondroitin sulfate or its salts are incorporated into ophthalmic compositions for the purposes of promoting energy metabolism, relieving eye fatigue by promoting metabolism and cellular respiration, and replenishing tear components (see, for example, Patent Document 1).

JP 2011-148791 A

The inventors have discovered a new problem: when benzalkonium chloride, used as a preservative, is added to an ophthalmic composition containing a high concentration (e.g., 1.0 w/v % or more) of chondroitin sulfate or a salt thereof, the liquid does not drain well from the filling needle, making it difficult to control the amount of droplets, and making it impossible to fill an accurate amount of the ophthalmic composition into a container.

The present invention aims to provide an ophthalmic composition that contains a high concentration of chondroitin sulfate or a salt thereof, is antiseptic, and allows for more accurate filling of the liquid volume into a container.

The inventors have discovered that by incorporating zinc chloride or edetic acid or a salt thereof into an ophthalmic composition containing a high concentration of at least one member selected from the group consisting of chondroitin sulfate and its salts, it is possible to ensure preservative properties while improving drainage from the filling needle and filling a container with a more accurate amount of ophthalmic composition. The present invention is based on this finding and provides the following inventions.

[1]
An ophthalmic composition comprising (A) at least one selected from the group consisting of chondroitin sulfate and salts thereof, and (B) at least one selected from the group consisting of (B-1) zinc chloride and (B-2) a chelating agent, and not containing benzalkonium chloride, wherein the content of component (A) is 0.7 w/v % or more based on the total amount of the ophthalmic composition.
[2]
The ophthalmic composition according to [1], wherein the content of component (A) is 1.0 w/v% or more based on the total amount of the ophthalmic composition.
[3]
The ophthalmic composition according to [1], wherein the content of component (A) is 3.0 w/v% or more based on the total amount of the ophthalmic composition.
[4]
The ophthalmic composition according to any one of [1] to [3], wherein the component (B-2) is at least one selected from the group consisting of edetic acid and salts thereof.
[5]
The ophthalmic composition according to any one of [1] to [4], wherein the content of the component (B-2) is 0.05 w/v % or more based on the total amount of the ophthalmic composition.
[6]
The ophthalmic composition according to any one of [1] to [5], further comprising (C) a buffering agent.
[7]
The ophthalmic composition according to any one of [1] to [6], which does not further contain any preservative other than benzalkonium chloride.

The present invention provides an ophthalmic composition that contains a high concentration of chondroitin sulfate or a salt thereof, has guaranteed preservative properties, and allows for more accurate filling of the liquid volume into a container. The ophthalmic composition of the present invention is preferable because it does not contain a preservative such as benzalkonium chloride.

The following describes in detail the embodiments of the present invention. However, the present invention is not limited to the following embodiments.

In this specification, unless otherwise specified, the unit of content "%" means "w/v%" and is synonymous with "g/100 mL."

[1. Ophthalmic composition]
The ophthalmic composition according to this embodiment contains at least one component selected from the group consisting of chondroitin sulfate and salts thereof (also simply referred to as "component (A)").

[Component (A)]
The ophthalmic composition according to this embodiment contains (A) at least one selected from the group consisting of chondroitin sulfate and salts thereof (also simply referred to as "component (A)").

There are no particular restrictions on the chondroitin sulfate and its salts, which are component (A), as long as they are pharmaceutically, pharmacologically (pharmaceutical), or physiologically acceptable. The molecular weight of chondroitin sulfate and its salts is not particularly limited, as long as they are pharmaceutically, pharmacologically (pharmaceutical), or physiologically acceptable, but typically, those with a weight-average molecular weight of approximately 1,000 to 100,000, preferably approximately 5,000 to 50,000, and more preferably approximately 10,000 to 40,000 can be used.

Examples of salts of chondroitin sulfate include alkali metal salts and alkaline earth metal salts. Examples of alkali metal salts include sodium salt and potassium salt. Examples of alkaline earth metal salts include magnesium salt and calcium salt.

As chondroitin sulfate and its salts, chondroitin sulfate and alkali metal salts of chondroitin sulfate are preferred, chondroitin sulfate and sodium chondroitin sulfate are more preferred, and sodium chondroitin sulfate is even more preferred.

Chondroitin sulfate and its salts can also be commercially available products. Chondroitin sulfate and its salts can be used alone or in combination of two or more types.

The content of component (A) in the ophthalmic composition according to this embodiment is 0.7 w/v% or more, based on the total amount of the ophthalmic composition. The lower limit of the content of component (A) is not particularly limited as long as it is 0.7 w/v% or more, and is set appropriately depending on the type of component (A), the type and content of other components, the intended use and formulation of the ophthalmic composition, etc. From the viewpoint of more significantly achieving the effects of the present invention, the lower limit of the content of component (A) is, for example, preferably 0.7 w/v% or more, more preferably 1.0 w/v% or more, even more preferably 2.0 w/v% or more, even more preferably 2.5 w/v% or more, and particularly preferably 3.0 w/v% or more. The upper limit of the content of component (A) is not particularly limited, and is set appropriately depending on the type of component (A), the type and content of other components, the intended use and formulation of the ophthalmic composition, etc. From the viewpoint of more significantly achieving the effects of the present invention and from the viewpoint of usability, the upper limit of the content of component (A) is, for example, preferably 5.0 w/v% or less, more preferably 4.0 w/v% or less, even more preferably 3.5 w/v% or less, and even more preferably 3.0 w/v% or less. Furthermore, the content of component (A) in the ophthalmic composition according to this embodiment may be, for example, 0.7 to 5.0 w/v%, 0.7 to 4.0 w/v%, 0.7 to 3.5 w/v%, 0.7 to 3.0 w/v%, 0.7 to 1.5 w/v%, 0.7 to 1.0 w/v%, 1.0 to 5.0 w/v%, 1.0 to 4.0 w/v%, 1.0 to 3.5 w/v%, 1.0 to 3.0 w/v%, 2.0 to 5.0 w/v%, 2.0 to 4.0 w/v%, 2.0 to 3.5 w/v%, 2.0 to 3.0 w/v%, 2.5 to 5.0 w/v%, 2.5 to 4.0 w/v%, 2.5 to 3.5 w/v%, or 2.5 to 3.0 w/v%, based on the total amount of the ophthalmic composition. In another aspect, the content of component (A) in the ophthalmic composition according to this embodiment may be, for example, 1.0 w/v%, 2.0 w/v%, or 3.0 w/v%, based on the total amount of the ophthalmic composition.

[(B) component]
The ophthalmic composition according to this embodiment further contains, in addition to the component (A), at least one selected from the group consisting of (B) (B-1) zinc chloride (also simply referred to as "component (B-1)"), and (B-2) a chelating agent (also simply referred to as "component (B-2)"). (Hereinafter, components (B-1) and (B-2) will also be collectively referred to simply as "component (B)".) One type of component (B) may be used alone, or two or more types may be used in combination.

[(B-1) component]
There are no particular limitations on the zinc chloride used as component (B-1), so long as it is medicamentarily, pharmacologically (pharmaceutical) or physiologically acceptable.

The content of component (B-1) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type and content of other blended components, the intended use of the ophthalmic composition, the formulation, etc. From the perspective of more significantly achieving the effects of the present invention, the content of component (B-1) is, for example, preferably 0.00001 to 0.05 w/v%, more preferably 0.00005 to 0.02 w/v%, even more preferably 0.0001 to 0.01 w/v%, and even more preferably 0.0005 to 0.005 w/v%, based on the total amount of the ophthalmic composition.

The content ratio of component (B-1) relative to component (A) in the ophthalmic composition of this embodiment is not particularly limited and is set appropriately depending on the type of component (A), the types and contents of other blended components, the intended use and formulation of the ophthalmic composition, etc. From the perspective of further enhancing the effects of the present invention, the content ratio of component (B-1) relative to component (A) is, for example, preferably 0.000003 to 0.05 parts by mass, more preferably 0.000017 to 0.02 parts by mass, even more preferably 0.00003 to 0.01 parts by mass, and even more preferably 0.00017 to 0.005 parts by mass, of the total content of component (B-1) relative to 1 part by mass of the total content of component (A) contained in the ophthalmic composition of this embodiment.

[(B-2) component]
The chelating agent as component (B-2) is not particularly limited as long as it is medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable, and examples thereof include edetic acid and salts thereof, ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), and diethylenetriaminepentaacetic acid (DTPA), and among these, edetic acid or a salt thereof is preferably used.

Edetic acid is also known as ethylenediaminetetraacetic acid (EDTA) and is a known compound represented by C ₁₀ H ₁₆ N ₂ O ₈ .

Examples of salts of edetic acid include alkali metal salts such as sodium edetate, disodium edetate, and tetrasodium edetate, with disodium edetate being preferred.

The content of component (B-2) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (B-2), the types and contents of other blended components, the intended use and formulation of the ophthalmic composition, etc. From the perspective of further enhancing the preservative effect, the content of component (B-2) is, for example, preferably 0.01 w/v% or more, more preferably 0.03 w/v% or more, even more preferably 0.05 w/v% or more, even more preferably 0.07 w/v% or more, and particularly preferably 0.09 w/v% or more, based on the total amount of the ophthalmic composition. Furthermore, from the viewpoint of more significantly achieving the effects of the present invention, the content of component (B-2) is, for example, preferably 10 w/v% or less, more preferably 5 w/v% or less, even more preferably 3 w/v% or less, even more preferably 1 w/v% or less, and particularly preferably 0.5 w/v% or less, based on the total amount of the ophthalmic composition. Furthermore, the content of component (B-2) in the ophthalmic composition according to this embodiment may be, for example, 0.01 to 10 w/v%, 0.03 to 5 w/v%, 0.05 to 3 w/v%, 0.07 to 1 w/v%, or 0.09 to 0.5 w/v%, based on the total amount of the ophthalmic composition.

The content ratio of component (B-2) relative to component (A) in the ophthalmic composition of this embodiment is not particularly limited and is set appropriately depending on the types of components (A) and (B-2), the types and amounts of other blended components, the intended use and formulation of the ophthalmic composition, etc. From the perspective of further enhancing the effects of the present invention, the content ratio of component (B-2) relative to component (A) is, for example, preferably 0.003 to 10 parts by mass, more preferably 0.01 to 5 parts by mass, even more preferably 0.017 to 3 parts by mass, even more preferably 0.023 to 1 part by mass, and particularly preferably 0.03 to 0.5 parts by mass, of the total content of component (B-2) relative to 1 part by mass of the total content of component (A) contained in the ophthalmic composition of this embodiment.

[(C) component]
The ophthalmic composition according to this embodiment may further contain a buffer (C) (also simply referred to as "component (C)"). When the ophthalmic composition further contains component (C), the effects of the present invention are more pronounced.

There are no particular limitations on the buffering agent, as long as it is pharmaceutically, pharmacologically (pharmaceutical), or physiologically acceptable.

Examples of buffers include inorganic buffers, which are buffers derived from inorganic acids, and organic buffers, which are buffers derived from organic acids or organic bases.

Examples of inorganic buffers include borate buffers, phosphate buffers, and carbonate buffers. 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.). Hydrates of borate, phosphate, or carbonate may also be used as borate buffers, phosphate buffers, or carbonate buffers. More specific examples of borate buffers include boric acid or salts thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); phosphate buffers include phosphoric acid or salts thereof (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 salts thereof (sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.).

Examples of organic buffers include citrate buffers, acetate buffers, lactate buffers, succinate buffers, Tris buffers, and AMPD buffers. 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). Examples of lactate buffers include lactic acid or its salts (such as alkali metal lactates and alkaline earth metal lactates). Examples of succinate buffers include succinic acid or its salts (such as alkali metal succinates). Furthermore, hydrates of citrate, acetate, lactate, or succinate may also be used as citrate buffers, acetate buffers, lactate buffers, or succinate buffers. More specific examples of citrate buffers include citric acid or its salts (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.); acetate buffers include acetic acid or its salts (ammonium acetate, sodium acetate, potassium acetate, calcium acetate, etc.); lactate buffers include lactic acid or its salts (sodium lactate, potassium lactate, calcium lactate, etc.); and succinic acid buffers include succinic acid or its salts (monosodium succinate, disodium succinate, etc.). Examples of Tris buffers include trometamol or its salts (trometamol hydrochloride, etc.). Examples of AMPD buffers include 2-amino-2-methyl-1,3-propanediol or its salts.

Preferred buffers include boric acid 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 Tris buffers (e.g., trometamol), with boric acid buffers being more preferred, boric acid and its salts being even more preferred, and a combination of boric acid and borax being even more preferred.

Commercially available buffers may be used. Buffers may be used alone or in combination of two or more.

The content of component (C) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (C), the types and contents of other blended components, the intended use and formulation of the ophthalmic composition, etc. From the perspective of more significantly achieving the effects of the present invention, the content of component (C) is, for example, preferably 0.01 to 10 w/v%, more preferably 0.05 to 5 w/v%, and even more preferably 0.1 to 3 w/v%, based on the total amount of the ophthalmic composition.

The content ratio of component (C) to component (A) in the ophthalmic composition of this embodiment is not particularly limited and is set appropriately depending on the types of components (A) and (C), the types and contents of other blended components, the intended use and formulation of the ophthalmic composition, etc. From the perspective of further enhancing the effects of the present invention, the content ratio of component (C) to component (A) is, for example, preferably 0.01 to 10 parts by mass, more preferably 0.1 to 5 parts by mass, and even more preferably 0.5 to 3 parts by mass, of the total content of component (C) per 1 part by mass of the total content of component (A) in the ophthalmic composition of this embodiment.

[(D) component]
The ophthalmic composition according to this embodiment may further contain (D) an isotonic agent (also simply referred to as "component (D)"). When the ophthalmic composition further contains component (D), the effects of the present invention are more pronounced. There are no particular limitations on component (D), as long as it is medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable.

Examples of the tonicity adjusting agent (component (D)) include ionic tonicity adjusting agents and nonionic tonicity adjusting agents.

Examples of ionic tonicity agents include inorganic salts such as calcium chloride, magnesium chloride, sodium chloride, potassium chloride, ammonium chloride, calcium sulfate, magnesium sulfate, sodium sulfate, and potassium sulfate, as well as monoethanolamine, diethanolamine, and triethanolamine. Among ionic tonicity agents, sodium chloride and monoethanolamine are preferred, as they more significantly exhibit the effects of the present invention.

Examples of non-ionic tonicity agents include alcohols such as glycerin, propylene glycol, polyethylene glycol (400, 4000, 6000, etc.), glucose, sorbitol, mannitol, xylitol, and trehalose. Among non-ionic tonicity agents, mannitol is preferred from the viewpoint of more significantly achieving the effects of the present invention and preventing the formulation from becoming sticky.

Commercially available isotonicity agents can also be used. One isotonicity agent may be used alone, or two or more may be used in combination.

The total content of component (D) in the ophthalmic composition according to this embodiment is not particularly limited and is set appropriately depending on the type of component (D), the types and contents of other components, the intended use and formulation of the ophthalmic composition, and the like. From the perspective of more significantly achieving the effects of the present invention, the content of component (D) is, for example, preferably 0.0001 to 10 w/v%, more preferably 0.0005 to 7 w/v%, even more preferably 0.001 to 6 w/v%, even more preferably 0.005 to 5 w/v%, particularly preferably 0.005 to 4 w/v%, even more particularly preferably 0.005 to 3 w/v%, even more particularly preferably 0.01 to 2 w/v%, even more particularly preferably 0.01 to 1.5 w/v%, and most preferably 0.05 to 1 w/v%, based on the total amount of the ophthalmic composition.

The content ratio of component (D) to component (A) in the ophthalmic composition of this embodiment is not particularly limited and is set appropriately depending on the types of components (A) and (D), the types and amounts of other components, the intended use and formulation of the ophthalmic composition, and the like. From the perspective of more significantly achieving the effects of the present invention, the content ratio of component (D) to component (A) is, for example, preferably 0.00003 to 10 parts by mass, more preferably 0.00017 to 7 parts by mass, even more preferably 0.0003 to 6 parts by mass, even more preferably 0.0017 to 5 parts by mass, particularly preferably 0.0017 to 4 parts by mass, even more particularly preferably 0.0017 to 3 parts by mass, even more particularly preferably 0.003 to 2 parts by mass, even more particularly preferably 0.003 to 1.5 parts by mass, and most preferably 0.016 to 1 part by mass, of the total content of component (D) contained in the ophthalmic composition of this embodiment.

The ophthalmic composition according to this embodiment does not contain benzalkonium chloride. This prevents side effects of benzalkonium chloride, such as inflammation of the cornea and conjunctiva and allergies, and also more significantly enhances the effects of the present invention.

The pH of the ophthalmic composition according to this embodiment is not particularly limited, as long as it is within a medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable range. The pH of the ophthalmic composition according to this embodiment may be, for example, 4.0 to 9.5, preferably 4.0 to 9.0, more preferably 4.5 to 9.0, even more preferably 4.5 to 8.5, even more preferably 5.0 to 8.5, particularly preferably 5.5 to 8.0, and especially more preferably 6.0 to 7.8.

The ophthalmic composition of this embodiment can be adjusted to an osmotic pressure ratio within a biologically acceptable range, as needed. The appropriate osmotic pressure ratio varies depending on the application site, dosage form, etc.; however, to more significantly achieve the effects of the present invention, it is preferably 0.05 to 6, more preferably 0.4 to 5, even more preferably 0.6 to 3, and even more preferably 0.8 to 2. The osmotic pressure ratio may also be 0.3 to 4, 0.5 to 3, or 0.7 to 1.4. Adjustment of the osmotic pressure can be performed using inorganic salts, polyhydric alcohols, etc., using methods known in the art. The osmotic pressure ratio is 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) according to the 17th Revised Japanese Pharmacopoeia. The osmotic pressure is measured using the 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, and dissolving it in purified water to make exactly 100 mL; alternatively, commercially available standard solutions for measuring osmolality ratios (0.9 w/v% sodium chloride aqueous solution) can be used.

The viscosity of the ophthalmic composition according to this embodiment is not particularly limited, as long as it is within a medicamentarily, pharmacologically (pharmaceutical), or physiologically acceptable range. For example, the viscosity of the ophthalmic composition according to this embodiment, measured at 20°C using a rotational viscometer (TV-20 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34' x R24), is preferably 0.1 to 10,000 mPa·s, more preferably 1 to 3,000 mPa·s, even more preferably 1 to 1,000 mPa·s, even more preferably 1 to 100 mPa·s, particularly preferably 1 to 50 mPa·s, particularly more preferably 1 to 10 mPa·s, and even more preferably 1.3 to 5 mPa·s. Alternatively, the viscosity may be 1 to 5 mPa·s, 1 to 4 mPa·s, or 1 to 3 mPa·s.

The ophthalmic composition according to this embodiment may contain, in addition to the above-mentioned components, an appropriate amount of a combination of components selected from various pharmacologically active components and physiologically active components, as long as the effects of the present invention are not impaired. The components are not particularly limited, and examples thereof include active ingredients in ophthalmic drugs listed in the 2012 edition of the OTC Drug Manufacturing and Marketing Approval Standards (supervised by the Japan Society of Regulatory Science). Specific examples of components used in ophthalmic drugs include the following:
Antiallergic agents: for example, sodium cromoglycate, tranilast, pemirolast potassium, etc.
Antihistamines: for example, diphenhydramine hydrochloride, iproheptine, chlorpheniramine maleate, levocabastine hydrochloride, ketotifen fumarate, pemirolast potassium, olopatadine hydrochloride, etc.
Anti-inflammatory agents: for example, methyl salicylate, glycol salicylate, allantoin, tranexamic acid, lysozyme, lysozyme chloride, indomethacin, pranoprofen, ibuprofen, ibuprofen piconol, ketoprofen, felbinac, bendazac, piroxicam, bufexamac, butyl flufenamate, epsilon-aminocaproic acid, berberine chloride, berberine sulfate, sodium azulene sulfonate, etc.
Steroids: for example, fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone propionate, flunisolide, etc.
Decongestants: for example, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc.
Ocular muscle regulating drugs: for example, cholinesterase inhibitors having an active center similar to that of acetylcholine, specifically neostigmine methylsulfate, tropicamide, helenien, atropine sulfate, etc.
Vitamins: for example, retinol acetate, retinol palmitate, tocopherol acetate, flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, panthenol, calcium pantothenate, ascorbic acid, sodium ascorbate, etc.
Amino acids: for example, glutamic acid, aspartic acid, arginine, glycine, aminoethylsulfonic acid (taurine), trimethylglycine, and salts thereof.
Astringents: for example, zinc oxide, zinc lactate, zinc sulfate, etc.
Others: For example, sulfamethoxazole, sulfisoxazole, sulfisomidine and salts thereof.

The ophthalmic composition according to this embodiment may contain one or more additives selected appropriately in accordance with the intended use and formulation, in a suitable amount, as long as the effects of the present invention are not impaired. Examples of such additives include those listed in the Pharmaceutical Additives Dictionary 2007 (edited by the Japan Pharmaceutical Additives Association). Representative additives include the following:
Carrier: For example, an aqueous solvent such as water or aqueous ethanol.
Bases: for example, octyldodecanol, titanium oxide, potassium bromide, plastibase, etc.
pH adjusters: for example, hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, diisopropanolamine, etc.
Stabilizers: for example, sodium formaldehyde sulfoxylate (Rongalit), sodium hydrogen sulfite, sodium pyrosulfite, aluminum monostearate, glycerin monostearate, cyclodextrin, monoethanolamine, dibutylhydroxytoluene, etc.
Thickeners other than component (A): For example, cellulose-based polymer compounds (e.g., methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, etc.), polyvinyl-based polymer compounds (e.g., polyvinylpyrrolidone, polyvinyl alcohol, etc.), carboxyvinyl polymers, guar gum, hydroxypropyl guar gum, gum arabic, karaya gum, xanthan gum, agar, alginic acid and its salts (e.g., sodium salt), mucopolysaccharides (e.g., heparinoids, heparin, heparin, heparin sulfate, heparan sulfate, heparinoid, hyaluronic acid and its salts (e.g., sodium salt)), starch, chitin and its derivatives, chitosan and its derivatives, carrageenan, etc.
Sugars: for example, glucose, cyclodextrin, etc.
Anionic surfactants: for example, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates, alkylbenzenesulfonates, alkyl sulfates, N-acyltaurine salts, etc.
Amphoteric surfactants: for example, lauryl dimethylaminoacetic acid betaine.
Preservatives other than benzalkonium chloride: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, chlorhexidine and its salts (specifically, chlorhexidine hydrochloride, chlorhexidine acetate, chlorhexidine gluconate, etc.), dibutylhydroxytoluene, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexanide hydrochloride (polyhexamethylene biguanide), alexidine hydrochloride, etc.), GLOQIL (trade name manufactured by Rhodia), etc. From the viewpoint of further enhancing the effects of the present invention, the ophthalmic composition according to this embodiment preferably does not contain, in addition to benzalkonium chloride, any preservatives other than benzalkonium chloride.

From the viewpoint of being able to significantly achieve the effects of the present invention, the ophthalmic composition according to this embodiment preferably does not contain at least one selected from the group consisting of sodium cromoglycate, phenylephrine hydrochloride, pranoprofen, allantoin, chlorpheniramine maleate, naphazoline, tetrahydrozoline hydrochloride, neostigmine methylsulfate, potassium sorbate, and chlorhexidine gluconate.

The ophthalmic composition of this embodiment may be an aqueous composition (mainly containing an aqueous or hydrophilic base or carrier) or an oil-based composition (mainly containing an oil-based or hydrophobic base or carrier). When the ophthalmic composition is an aqueous composition, the water content is, for example, preferably 50% by weight or more, more preferably 75% by weight or more, even more preferably 80% by weight or more, even more preferably 85% by weight or more, and particularly preferably 90% by weight or more, based on the total weight of the ophthalmic composition. When the ophthalmic composition is an aqueous composition, the water content is, for example, preferably less than 100% by weight, more preferably 99.5% by weight or less, even more preferably 99.2% by weight or less, even more preferably 99.0% by weight or less, particularly preferably 97.0% by weight or less, and most preferably 96.5% by weight or less, based on the total weight of the ophthalmic composition. When the ophthalmic composition is an oil-based composition, the water content is, for example, preferably less than 50% by weight, more preferably 30% by weight or less, and even more preferably 20% by weight or less, based on the total amount of the ophthalmic composition. The ophthalmic composition according to this embodiment is preferably an aqueous composition.

The water used in the ophthalmic composition according to this embodiment may be any water that is medicamentally, pharmacologically (pharmaceutical), or physiologically acceptable. Examples of such water include distilled water, tap water, purified water, sterile purified water, water for injection, and distilled water for injection. These definitions are based on the 17th Edition of the Japanese Pharmacopoeia.

The ophthalmic composition according to this embodiment can be prepared, for example, by adding and mixing component (A), component (B), and, if necessary, other components to achieve the desired content. Specifically, the composition can be prepared, for example, by dissolving or suspending the above components in purified water, adjusting the pH and osmotic pressure to the desired level, and sterilizing the composition by filtration or other methods.

The ophthalmic composition according to this embodiment can be in various dosage forms depending on the purpose, such as a liquid, a gel, or a semi-solid (e.g., ointment). Of these, a liquid is preferred, and an aqueous liquid is more preferred.

The ophthalmic composition according to this embodiment can be used, for example, as eye drops (also referred to as eye drops or eye drops; eye drops include artificial tears and eye drops that can be applied to the eyes while wearing contact lenses), eyewash (also referred to as eyewash or eyewash; eyewashes include eyewashes that can be applied to the eyes while wearing contact lenses), or a composition for contact lenses [contact lens wetting solution, contact lens care composition (contact lens disinfectant, contact lens preservative, contact lens cleaner, contact lens cleaning and preservative), contact lens wetting solution that can be used both as a contact lens wetting solution and as an eye drop while wearing contact lenses, etc.]. Suitable examples of the ophthalmic composition according to this embodiment include eye drops, eyewash, and contact lens compositions, more suitable examples include eye drops that can be applied to the eyes while wearing contact lenses, eyewashes that can be applied to the eyes while wearing contact lenses, contact lens wetting solution, and contact lens wetting solution, and even more suitable examples include eye drops that can be applied to the eyes while wearing contact lenses. 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).
In addition, in this specification, "soft contact lenses" refers to a classification of soft contact lenses based on the "Classification Method for Soft Contact Lenses" prescribed in the Notification of the Director of the Evaluation and Licensing Division, Pharmaceutical and Medical Safety Bureau, Ministry of Health, Labour and Welfare (then the Ministry of Health and Welfare), dated March 31, 1999, entitled "Handling of Documents to be Attached to Applications for Approval to Manufacture (Import) Soft Contact Lenses and Soft Contact Lens Disinfectants," No. 645. Here, soft contact lenses are classified based on criteria such as water content and the mole percentage of anionic monomers. For example, soft contact lenses belonging to Group IV have common properties of having a water content of 50% or more and having 1% or more mole percentage of anionic monomers among the constituent monomers of the raw material polymer. This classification follows the classification method for soft contact lenses established by the FDA (U.S. Food and Drug Administration).

When the ophthalmic composition according to this embodiment is in the form of eye drops, the effects of the present invention can be more pronounced. Therefore, the ophthalmic composition is preferably an eye drop that can be instilled while wearing contact lenses, more preferably an eye drop that can be instilled while wearing soft contact lenses (eye drops for soft contact lenses), and even more preferably an ophthalmic composition for Group IV soft contact lenses in the FDA contact lens classification. When the ophthalmic composition according to this embodiment is in the form of eye drops, 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, 1 to 2 drops at a time, 2 to 4 times a day, or 4 times a day, or 1 to 2 drops, 1 to 3 drops, or 2 to 3 drops at a time, 5 to 6 times a day, can be mentioned.

The ophthalmic composition according to this embodiment is also preferably an artificial tear, as this allows the effects of the present invention to be more pronounced. If the ophthalmic composition according to this embodiment is an artificial tear, it is preferable that the ophthalmic composition does not contain any of the following: anti-inflammatory agents, antiallergic agents, antihistamines, steroids, decongestants, eye muscle regulating agents, vitamins, astringents, sulfamethoxazole, sulfisoxazole, or sulfisomidine.

The ophthalmic composition according to this embodiment is provided in any container. The container for containing the ophthalmic composition according to this embodiment is not particularly limited and may be made of, for example, glass or plastic. Plastic is preferred. Examples of plastic include polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polypropylene, polyimide, copolymers of the monomers that constitute these, and mixtures of two or more of these. Polypropylene, polyethylene, and polyethylene terephthalate are preferred, and polyethylene terephthalate is more preferred. The container for containing the ophthalmic composition according to this embodiment may be a transparent container that allows the interior of the container to be seen, or an opaque container that makes it difficult to see the interior of the container. A transparent container is preferred. Here, "transparent container" includes both colorless transparent containers and colored transparent containers.

A nozzle may be attached to the container that holds the ophthalmic composition according to this embodiment. The material of the nozzle is not particularly limited and may be, for example, glass or plastic. Plastic is preferred. Examples of plastic include polybutylene terephthalate, polyethylene, polypropylene, polyethylene naphthalate, copolymers of the monomers that constitute these, and mixtures of two or more of these. From the viewpoint of further enhancing the effects of the present invention, polypropylene, polyethylene, polyethylene terephthalate, and polyethylene naphthalate are preferred as the material of the nozzle, with polyethylene being more preferred.

The container that holds the ophthalmic composition according to this embodiment may be a multi-dose type that holds an amount for multiple uses, or a unit-dose type that holds an amount for a single use, but a multi-dose type is preferred as this allows the effects of the present invention to be more pronounced.

The present invention will be specifically explained below based on test examples, but the present invention is not limited to these.

Test Example 1: Measurement of Contact Angle
Each ophthalmic composition (eye drops; 100 mL) shown in Table 1 was prepared by a conventional method. The units of each component in Table 1 are all w/v % unless otherwise specified in the table.
A droplet (approximately 1 μL) of each prepared ophthalmic composition was dropped onto a stainless steel metal plate (Ferrule cap Type CLF-B), and the contact angle (static contact angle) with the metal 0.5 seconds after dropping was measured using an automatic contact angle meter (Drop Master, DM-A501). The contact angle was measured 10 times for each ophthalmic composition, and the average value was calculated to be the contact angle of each ophthalmic composition. Here, a larger contact angle indicates better drainage, and a more accurate amount of liquid can be filled into a container.
The improvement rate of the contact angle of each ophthalmic composition relative to Reference Example 1-1 was calculated according to the following formula 1. The results are shown in Table 1.
[Formula 1] Contact angle improvement rate (%)={(contact angle of each ophthalmic composition−contact angle of Reference Example 1-1)/contact angle of Reference Example 1-1}×100
The sodium chondroitin sulfate used was non-standard sodium chondroitin sulfate (manufactured by Seikagaku Corporation, weight average molecular weight 20,000).

It was confirmed that when benzalkonium chloride was added to an ophthalmic composition containing 3.0 w/v% sodium chondroitin sulfate, the contact angle decreased and dryness significantly worsened (Comparative Example 1-2). On the other hand, it was confirmed that when zinc chloride or disodium edetate was added to an ophthalmic composition containing 3.0 w/v% sodium chondroitin sulfate, the contact angle improvement rate increased and dryness improved (Examples 1-1 and 1-2).

It was confirmed that the ophthalmic compositions of Examples 1-1 and 1-2 had significantly higher preservative efficacy than the ophthalmic composition of Comparative Example 1-1.

Test Example 2: Protein adhesion inhibition test
Each ophthalmic composition (eye drops; 100 mL) shown in Table 2 was prepared by a conventional method. The unit of each component in Table 2 is w/v %.
Contact lenses (etafilcon A lenses (manufactured by Johnson & Johnson, trade name: 2 Week Acuvue, FDA contact lens classification: Group IV)) were washed with 100 mL of physiological saline in a beaker, and the lenses were wiped dry with Bemcot (registered trademark) Lint-Free. The lenses were then immersed in 2 mL of each ophthalmic composition in a 24-well plate and shaken for 30 minutes in a shaker set at 34°C and 120 rpm.
In accordance with FDA guidelines, 2 mL of a protein solution (a buffer solution (sodium chloride: 0.9 w/v%, sodium dihydrogen phosphate dihydrate: 0.045 w/v%) to which egg white lysozyme, bovine serum albumin, and bovine globulin were added so as to achieve a concentration of 0.120 w/v%, 0.388 w/v%, and 0.161 w/v%) was dispensed into each 24-well plate containing the contact lens and each ophthalmic composition, and the plate was shaken for 30 minutes at 34°C and 120 rpm. The contact lens was then removed, immersed in 100 mL of physiological saline for approximately 1 second to rinse off excess protein solution, drained, and wiped dry with Bemcot (registered trademark) Lint-Free. The contact lens was then immersed in the protein solution and shaken for 1 hour at 34°C and 120 rpm. The contact lenses were then removed and quickly immersed (for approximately 1 second) in 100 mL of physiological saline to rinse off excess test solution. The water was then drained off and wiped off with a Bemcot® Lint-Free wipe. The lenses were then immersed in 2 mL of protein separation solution (aqueous solution containing 1% sodium carbonate and 1% SDS) in a 24-well plate. The lenses were shaken at room temperature for approximately 1 hour using a shaker set at 120 rpm, and the proteins adsorbed to the contact lenses were recovered in the protein separation solution. Using a BCA assay kit (Thermo Scientific, Pierce #23225), the amount of protein in the protein separation solution was quantified using albumin as a standard, and calculated as an albumin equivalent value, which was used as the protein adsorption amount on the contact lenses.
The protein adhesion inhibition rate of each ophthalmic composition relative to Reference Example 2-1 was calculated according to the following formula 2. The results are shown in Table 2.
[Formula 2] Protein adhesion inhibition rate (%)={(protein adsorption amount of Reference Example 2-1−protein adsorption amount of each ophthalmic composition)/protein adsorption amount of Reference Example 2-1}×100
The sodium chondroitin sulfate used was non-standard sodium chondroitin sulfate (manufactured by Seikagaku Corporation, weight average molecular weight 20,000).

Compared to Reference Example 2-1, which does not contain sodium chondroitin sulfate, Reference Example 2-2, which contains 0.5 w/v% sodium chondroitin sulfate, exhibited an inhibitory effect on protein adhesion to contact lenses, whereas Comparative Example 2-1, which contains 3.0 w/v% sodium chondroitin sulfate, exhibited a greater degree of protein adhesion. On the other hand, Example 2-1, which contains 3.0 w/v% sodium chondroitin sulfate combined with zinc chloride, showed an improved protein adhesion inhibition rate, and Example 2-2, which contains 3.0 w/v% sodium chondroitin sulfate combined with disodium edetate, showed a significantly improved protein adhesion inhibition rate.

Test Example 3: Protein Cleaning Test
Each ophthalmic composition (eye drops; 100 mL) shown in Table 3 was prepared by a conventional method. The unit of each component in Table 3 is w/v %.
In accordance with FDA guidelines, 2 mL of a protein solution (a buffer solution (sodium chloride: 0.9 w/v%, sodium dihydrogen phosphate dihydrate: 0.045 w/v%) to which egg white lysozyme, bovine serum albumin, and bovine globulin were added to make concentrations of 0.120 w/v%, 0.388 w/v%, and 0.161 w/v%) was dispensed into 10 mL glass screw vials. Next, soft contact lenses (etafilcon A lenses (manufactured by Johnson & Johnson, trade name: 2 Week Acuvue)) were washed with 100 mL of physiological saline solution placed in a beaker, wiped dry with Bemcot (registered trademark) Lint-Free, and then immersed individually in the protein solution and shaken for 8 hours in a shaker set at 34°C and 120 rpm. The contact lenses were removed, immersed in 100 mL of physiological saline for approximately 1 second to rinse off excess protein solution, then drained and wiped with Bemcot® Lint-Free. Each lens was then immersed individually in 2 mL of each ophthalmic composition, each contained in a 10 mL glass screw vial, and shaken at 34°C and 120 rpm for approximately 16 hours. The contact lenses were then removed, immersed in 100 mL of physiological saline for approximately 1 second to rinse off excess ophthalmic composition, drained, wiped with Bemcot® Lint-Free, and then immersed in 2 mL of a protein separation solution (aqueous solution containing 1% sodium carbonate and 1% SDS), each contained in a 10 mL glass screw vial. The lenses were shaken at room temperature for approximately 1 hour on a shaker set at 120 rpm, and the proteins adsorbed on the contact lenses were recovered in the protein separation solution. Using a BCA assay kit (Thermo Scientific, Pierce #23225), the amount of protein in the protein separation solution was quantified as an albumin equivalent value by quantifying it using albumin as a standard, and this was taken as the amount of protein adsorbed onto the contact lens.
The improvement rate of protein removal for each ophthalmic composition relative to Reference Example 3-1 was calculated according to the following formula 3. The results are shown in Table 3.
[Equation 3] Protein cleaning improvement rate (%)={(protein adsorption amount of Reference Example 3-1−protein adsorption amount of each ophthalmic composition)/protein adsorption amount of Reference Example 3-1}×100
The sodium chondroitin sulfate used was non-standard sodium chondroitin sulfate (manufactured by Seikagaku Corporation, weight average molecular weight 20,000).

In Comparative Example 3-1 containing zinc chloride, the protein cleaning effect was reduced compared to Reference Example 3-1 not containing zinc chloride. On the other hand, in Example 3-1 in which 3.0 w/v% sodium chondroitin sulfate was blended with zinc chloride, it was confirmed that the protein cleaning improvement rate was significantly improved compared to Reference Example 3-1 not containing zinc chloride.
In Comparative Example 3-2, which contained disodium edetate, the protein cleaning effect was slightly improved compared to Reference Example 3-1, which did not contain disodium edetate. On the other hand, in Example 3-2, in which 3.0 w/v% sodium chondroitin sulfate was added to disodium edetate, it was confirmed that the improvement rate in protein cleaning was significantly improved compared to Reference Example 3-1, which did not contain disodium edetate.

Test Example 4: Evaluation of Variation in Drop Amount
Each ophthalmic composition (eye drops; 100 mL) shown in Table 4 was prepared by a conventional method. The unit of each component in Table 4 is w/v %.
Next, 10 mL of each prepared ophthalmic composition was filled into a 10 mL polyethylene terephthalate eye drop container, and a polyethylene nozzle was attached to the container. The polyethylene nozzle was suitable for dispensing 30 to 50 μL. The eye drops in the container were dispensed while held horizontally, and the weight of each dispensed drop was measured. This procedure was repeated 10 times to determine the average dispensed amount (AVG: mg) and standard deviation (SD: mg). From these values, the variation in dispensed amount (coefficient of variation CV: %) was calculated using the following formula 4. Using the obtained coefficients of variation, the suppression rate of variation in dispensed amount for each ophthalmic composition relative to Reference Example 4-1 was calculated according to the following formula 5. The results are shown in Table 4.
[Equation 4] Variation in drip amount (coefficient of variation CV: %) = (SD/AVG) x 100
[Equation 5] Drop amount variation suppression rate (%)={(coefficient of variation of Reference Example 4-1−coefficient of variation of each ophthalmic composition)/coefficient of variation of Reference Example 4-1}×100
The sodium chondroitin sulfate used was non-standard sodium chondroitin sulfate (manufactured by Seikagaku Corporation, weight average molecular weight 20,000).

Ophthalmic compositions containing zinc chloride or disodium edetate showed worse variation in the amount dispensed compared to ophthalmic compositions not containing zinc chloride or disodium edetate (Comparative Examples 4-1 and 4-2). In contrast, it was confirmed that blending 3.0 w/v% sodium chondroitin sulfate into ophthalmic compositions containing zinc chloride or disodium edetate significantly reduced variation in the amount dispensed (Examples 4-1 and 4-2).

Test Example 5: Contact Angle Measurement (2)
Each ophthalmic composition (eye drops; 100 mL) shown in Table 5 was prepared by a conventional method. The units of each component in Table 5 are all w/v % unless otherwise specified in the table.
The contact angle of each ophthalmic composition was measured in the same manner as in Test Example 1 above, and the contact angle improvement rate of each ophthalmic composition relative to Reference Example 5-1 was calculated according to the following formula 6. The viscosity and osmotic pressure of each ophthalmic composition were also measured. The viscosity was measured at 20°C using a rotational viscometer (TV-20 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34' x R24) at a rotation speed of 100 rpm. The osmotic pressure was measured with reference to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. The results are shown in Table 5.
[Equation 6] Contact angle improvement rate (%)={(contact angle of each ophthalmic composition−contact angle of Reference Example 5-1)/contact angle of Reference Example 5-1}×100
The sodium chondroitin sulfate used was non-standard sodium chondroitin sulfate (manufactured by Seikagaku Corporation, weight average molecular weight 20,000).

It was confirmed that the ophthalmic composition of Comparative Example 5-1, which contained 1.0 w/v% sodium chondroitin sulfate, had a smaller contact angle and significantly worsened drainage compared to the ophthalmic composition of Reference Example 5-1, which did not contain sodium chondroitin sulfate. On the other hand, it was confirmed that the ophthalmic composition of Example 5-1, which contained 1.0 w/v% sodium chondroitin sulfate and added zinc chloride, had an increased contact angle improvement rate and improved drainage compared to the ophthalmic composition of Reference Example 5-1, which did not contain sodium chondroitin sulfate.

Test Example 6: Protein Cleaning Test (2)
Each ophthalmic composition (eye drops; 100 mL) shown in Table 6 was prepared by a conventional method. The unit of each component in Table 6 is w/v %.
The amount of protein adsorbed to the contact lens for each ophthalmic composition was quantified in the same manner as in Test Example 3, and the protein cleaning improvement rate for each ophthalmic composition relative to Reference Example 6-1 was calculated according to the following formula 7. The viscosity and osmotic pressure of each ophthalmic composition were also measured in the same manner as in Test Example 5. The results are shown in Table 6.
[Formula 7] Protein cleaning improvement rate (%)={(protein adsorption amount of Reference Example 6-1−protein adsorption amount of each ophthalmic composition)/protein adsorption amount of Reference Example 6-1}×100
The sodium chondroitin sulfate used was non-standard sodium chondroitin sulfate (manufactured by Seikagaku Corporation, weight average molecular weight 20,000).

In Example 6-1, in which zinc chloride was blended with 1.0 w/v% sodium chondroitin sulfate, it was confirmed that the protein cleaning improvement rate was significantly improved compared to Reference Example 6-1, which did not contain zinc chloride.
In Example 6-2, in which 1.0 w/v% sodium chondroitin sulfate was blended with disodium edetate, it was confirmed that the improvement rate of protein cleaning was significantly improved compared to Reference Example 6-1, in which disodium edetate was not blended.

[Formulation example]
Formulation examples are shown in Table 7 below. The units for each ingredient in Table 7 are all w/v % unless otherwise specified in the table.

Claims (3)

An ophthalmic composition comprising (A) at least one selected from the group consisting of chondroitin sulfate and salts thereof, and (B-1) zinc chloride, but not containing benzalkonium chloride, wherein the content of component (A) is 1.0 to 3.0 w/v % based on the total amount of the ophthalmic composition, and the content of component (B-1) is 0.002 to 0.003 w/v % based on the total amount of the ophthalmic composition. The ophthalmic composition of claim 1, further comprising (C) a buffering agent. 3. The ophthalmic composition according to claim 1, which does not further contain any preservatives other than benzalkonium chloride.