JP7770800B2 - Eyewash composition - Google Patents

Description

Related to eyewash compositions.

It is considered desirable to adjust the osmotic pressure of eyewashes to a value close to that of tears, and propylene glycol is often added as an isotonic agent. However, the addition of propylene glycol poses the problem of reduced antiseptic properties. While it is known that the use of preservatives such as benzalkonium chloride can improve antiseptic properties (Patent Document 1), the use of preservatives is undesirable due to concerns about their effect on the cornea and their adsorption to contact lenses.

JP 2012-167095 A

The inventors therefore aimed to provide an eyewash composition that contains propylene glycol yet has excellent antiseptic properties.

The present inventor has carried out intensive research in view of the above-mentioned problem, and has found that by using propylene glycol in eyewash composition in combination with 0.01 w/v% or more hyaluronic acid, even though no preservative is compounded, or even though propylene glycol is compounded, the eyewash composition can be given antiseptic properties.The present invention has been completed as a result of further research based on this finding, and is as follows:
Item 1. An eyewash composition comprising (A) 0.01 w/v % or more of at least one selected from the group consisting of hyaluronic acid and salts thereof, and (B) propylene glycol, and not containing a preservative selected from a quaternary ammonium salt-based preservative, a parahydroxybenzoic acid ester, chlorobutanol, and a sorbic acid.
Item 2. The eyewash composition according to Item 1, further comprising (C) 0.05 w/v % or more of at least one selected from the group consisting of edetic acid and salts thereof.
Item 3. The eyewash composition according to Item 1 or 2, further comprising (D) at least one selected from the group consisting of pyridoxine, chondroitin sulfate, and salts thereof.
Item 4. The eyewash composition according to any one of Items 1 to 3, which is used while wearing contact lenses.

By using 0.01 w/v% or more of at least one selected from the group consisting of hyaluronic acid and its salts in combination with propylene glycol, it is possible to provide an eyewash composition with excellent antiseptic properties, even without containing a preservative selected from quaternary ammonium salt-based preservatives, parahydroxybenzoic acid esters, chlorobutanol, and sorbic acids.

The following describes in more detail the embodiments included in this disclosure.

The present disclosure encompasses an eyewash composition that contains 0.01 w/v% or more of at least one member selected from the group consisting of hyaluronic acid and its salts, and propylene glycol, but does not contain a preservative selected from quaternary ammonium salt-based preservatives, parahydroxybenzoic acid esters, chlorobutanol, and sorbic acids.

At least one substance selected from the group consisting of hyaluronic acid and its salts (sometimes referred to as component (A)) is a conventionally known substance, and examples of salts of hyaluronic acid include alkali metal salts such as sodium salts. These may be used alone or in combination of two or more.

The content of component (A) in the eyewash composition of the present disclosure is not limited as long as it is 0.01 w/v% or more, and is preferably 0.01 to 0.08 w/v%, more preferably 0.01 to 0.02 w/v%, and even more preferably 0.015 to 0.02 w/v%, for example.

Propylene glycol (sometimes referred to as component (B)) is conventionally known. The amount of propylene glycol contained in the eyewash composition is not limited as long as the effects of the present disclosure are obtained, but examples of such an amount include preferably 0.01 to 2 w/v%, more preferably 0.05 to 1.5 w/v%, and even more preferably 0.1 to 1 w/v%. Furthermore, the amount of propylene glycol contained in the eyewash composition is not limited as long as the effects of the present disclosure are obtained, but examples of such an amount include preferably 1 to 100 parts by mass, more preferably 10 to 55 parts by mass, and even more preferably 20 to 50 parts by mass per part by mass of component (A) in the eyewash composition.

The eyewash composition of the present disclosure does not contain a preservative selected from quaternary ammonium salt-based preservatives, parahydroxybenzoic acid esters, chlorobutanol, and sorbic acids. These preservatives are conventionally known in the fields of eye drops and eyewashes. Examples of quaternary ammonium-based preservatives include benzalkonium chloride and benzethonium chloride. Examples of parahydroxybenzoic acid esters include parahydroxybenzoic acid esters such as methyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate, as well as salts of parahydroxybenzoic acid esters (e.g., alkali metal salts such as sodium salts). Examples of sorbic acids include sorbic acid and salts of sorbic acid (e.g., alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts).

The eyewash composition of the present disclosure may further contain at least one selected from the group consisting of edetic acid and its salts (sometimes referred to as component (C)). Edetic acid, also known as ethylenediaminetetraacetic acid (EDTA), is conventionally known. Examples of salts of edetic acid include monosodium edetate, disodium edetate, trisodium edetate, tetrasodium edetate, dipotassium edetate, tripotassium edetate, and tetrapotassium edetate (including hydrates). These may be used alone or in combination of two or more.

When the eyewash composition of the present disclosure contains component (C), its content is not limited as long as the effects of the present disclosure are obtained, but examples of the content of component (C) in the eyewash composition include 0.02 w/v% or more, preferably 0.05 w/v% or more, more preferably 0.05 to 0.1 w/v%, and even more preferably 0.05 to 0.08 w/v%. Furthermore, the content of component (C) is not limited as long as the effects of the present disclosure are obtained, but examples of the content of component (C) in the eyewash composition include 1 to 8 parts by mass, more preferably 2 to 6 parts by mass, and even more preferably 2.5 to 5 parts by mass per part by mass of component (A).

The eyewash composition of the present disclosure may further contain at least one component selected from the group consisting of pyridoxine, chondroitin sulfate, and salts thereof (sometimes referred to as component (D)).

Pyridoxine and its salts are known substances and are not limited thereto. Examples of pyridoxine salts include inorganic acid salts such as hydrochloride (pyridoxine hydrochloride) and phosphate.

Chondroitin sulfate is a mucopolysaccharide having a structure in which sulfate is ester-bonded to a sugar chain consisting of repeating disaccharides of D-glucuronic acid and N-acetylgalactosamine. Examples of salts of chondroitin sulfate include, but are not limited to, alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as magnesium salt and calcium salt. Although not limited to, a preferred example of a salt of chondroitin sulfate is sodium chondroitin sulfate ester.

While the chondroitin sulfate and salts thereof used in this disclosure are not limited thereto, examples of molecular weights include weight-average molecular weights of approximately 5,000 to 45,000, more preferably approximately 10,000 to 40,000, and even more preferably approximately 15,000 to 30,000. The weight-average molecular weight is measured by gel filtration chromatography. Chondroitin sulfate and salts thereof are commercially available, for example, under the trade name Non-standard Sodium Chondroitin Sulfate (manufactured by Seikagaku Corporation, weight-average molecular weight 20,000).

Pyridoxine and its salts, and chondroitin sulfate and its salts may be used alone or in combination of two or more.

When the eyewash composition of the present disclosure contains component (D), its content is not limited as long as the effects of the present disclosure are obtained, but examples of the content of component (D) in the eyewash composition include preferably 0.001 to 0.1 w/v%, more preferably 0.01 to 0.07 w/v%, and even more preferably 0.04 to 0.06 w/v%. Furthermore, the content of component (D) is not limited as long as the effects of the present disclosure are obtained, but examples of the content of component (D) in the eyewash composition include preferably 1 to 10 parts by mass, more preferably 2 to 6 parts by mass, and even more preferably 2 to 4 parts by mass per part by mass of component (A).

Furthermore, although not limiting to the present disclosure, more preferably, at least one member selected from the group consisting of pyridoxine and its salts is present in the eyewash composition at a concentration of 0.008 to 0.01 w/v%, even more preferably 0.001 to 0.01 w/v%, and particularly preferably 0.005 to 0.01 w/v%.

Furthermore, although not limiting to the present disclosure, more preferably, at least one selected from the group consisting of chondroitin sulfate and its salts is contained in the eyewash composition at a concentration of 0.0055 to 0.05 w/v%, even more preferably 0.01 to 0.05 w/v%, and particularly preferably 0.025 to 0.05 w/v%.

The eyewash composition of the present disclosure may further contain any other component acceptable for use in eye drops or eyewashes. Examples of such other components include, but are not limited to, buffers, stabilizers, isotonicity agents, solvents (e.g., water), pH adjusters, medicinal ingredients, cooling agents, stimulants, thickeners, etc. These other components may be selected appropriately depending on the purpose, etc., as long as they do not interfere with the effects of the present disclosure. They may be used alone or in combination with two or more other components, and the amounts of these may be determined appropriately. Note that, although the components (A) to (D) are also known as medicinal ingredients, stabilizers, thickeners, etc., depending on the component, these components are not included in the definition of these other components in the present disclosure.

Examples of such other components include buffers, such as boric acid and borax. A single buffer may be used, or two or more buffers may be used in combination. For example, when the composition contains boric acid, the content of boric acid is not limited as long as it does not impair the effects of the present disclosure, and is preferably 0.1 to 2.5 w/v%, and more preferably 0.5 to 2 w/v% in the composition. For example, when the composition contains borax, the content of borax is not limited as long as it does not impair the effects of the present disclosure, and is preferably 0.005 to 0.5 w/v%, and more preferably 0.005 to 0.05 w/v% in the composition. The composition may or may not contain a buffer other than boric acid or borax. Alternatively, the composition may contain only either boric acid or borax.

Examples of such other ingredients include stabilizers such as polysorbates (polysorbate 80, polysorbate 60, etc.), polyoxyethylene (POE) hydrogenated castor oil (POE(80) hydrogenated castor oil, POE(60) hydrogenated castor oil, etc.; the number in parentheses indicates the average number of moles of ethylene oxide added), POE polyoxypropylene glycol, trometamol, etc. These may be used alone or in combination of two or more. When the composition contains a stabilizer, its content is not limited as long as it does not interfere with the effects of the present disclosure. Examples of the content of the stabilizer in the composition include preferably 0.01 to 1 w/v%, and more preferably 0.05 to 0.1 w/v%. When the composition contains a stabilizer, it may contain only one or two selected from, for example, polysorbate, POE hydrogenated castor oil, POE polyoxypropylene glycol, and trometamol. Also, when the composition contains polysorbate, for example, it can be prepared without blending POE hydrogenated castor oil, POE polyoxypropylene glycol, and/or trometamol.

Examples of such other ingredients include medicinal ingredients such as amino acids, anti-inflammatory agents, vitamins, and antihistamines. These may be used alone or in combination of two or more.

While not limiting the scope of the present disclosure, examples of amino acids include amino acids and their salts, such as glutamic acid and its salts; and amino acid analogs, such as taurine. These may be used alone or in combination of two or more. The eyewash composition of the present disclosure can also be prepared without adding amino acids and/or their salts. "Amino acids" as used here refer to amino acids that have both amino and carboxy functional groups and can be structural units of proteins, including, for example, L-aspartic acid. The eyewash composition of the present disclosure can also be prepared without adding amino acid analogs.

While not limiting the present disclosure, examples of anti-inflammatory agents include zinc sulfate, zinc lactate, epsilon-aminocaproic acid, allantoin, glycyrrhizic acid and its salts, and azulenes (azulene, dimethylisopropylazulene, dimethylethylazulene, salts thereof, etc.). These may be used alone or in combination of two or more. While not limiting the present disclosure, the composition preferably does not contain zinc sulfate and/or zinc lactate. The composition can also be prepared without incorporating epsilon-aminocaproic acid, allantoin, glycyrrhizic acid, and its salts.

While not limiting the present disclosure, examples of vitamins include vitamin A (retinol palmitate, retinol acetate, retinol, retinal, retinoic acid, etc.), vitamin B (flavin adenine dinucleotide, cyanocobalamin, etc.), and vitamin E (tocopherol acetate, tocopherol succinate, tocopherol nicotinate, tocopherol linoleate, etc.). These may be used alone or in combination of two or more. While not limiting the present disclosure, the composition may also be prepared without incorporating at least one of the vitamins.

While not limiting the scope of the present disclosure, examples of antihistamines include chlorpheniramine and its salts (e.g., chlorpheniramine maleate), diphenhydramine and its salts (e.g., diphenhydramine hydrochloride), etc. These may be used alone or in combination with two or more. The compositions of the present disclosure can also be prepared without incorporating an antihistamine.

When the composition of the present disclosure contains a medicinal ingredient, the content of the medicinal ingredient is not limited as long as it does not interfere with the effects of the present disclosure. For example, the content of the medicinal ingredient in the composition is preferably 0.05-0.3 w/v%, more preferably 0.1-0.3 w/v%, and even more preferably 0.2-0.27 w/v%.

An example of such other component is a cooling agent. Examples of cooling agents include menthol, camphor, and borneol. A single cooling agent may be used, or two or more cooling agents may be used in combination. The composition of the present disclosure may contain a cooling agent, or may be prepared without the incorporation of a cooling agent.

An example of such an additional ingredient is a stimulant, such as an aldehyde, such as propionaldehyde. While not limiting the present disclosure, the composition of the present disclosure may contain a stimulant, or may be prepared without the inclusion of a stimulant.

Examples of such other ingredients include thickeners, such as alginic acid and its salts, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymers, salts thereof, and glycerin. These may be used alone or in combination of two or more. The eyewash composition of the present disclosure can also be prepared without incorporating these thickeners.

The eyewash composition of the present disclosure can be produced by mixing the components (A) and (B), and, if necessary, the components (C) and (D), and the other components. There are no limitations on the mixing method as long as these components can be mixed, and they can be mixed according to conventional procedures.

The pH of the eyewash composition of the present disclosure is not limited as long as it is within a range that allows it to be used as an eye drop or eyewash, but examples of such a pH at room temperature (25°C) include a pH of 5 to 8, preferably a pH of 5.5 to 6.5, more preferably a pH of 5.5 to 6, and even more preferably a pH of 5.5 to 5.8.

The eyewash composition of the present disclosure is in a liquid form at room temperature, and as long as it can cleanse the eyes in a manner similar to that known in the art, there are no restrictions on how it can be used; it is typically used for eyewashing using an eyewash cup (eyecup) or by eye drops.

The eyewash composition of the present disclosure may be used with or without contact lenses. The contact lenses may be hard or soft.

The eyewash composition of the present disclosure is not limited as long as it can be used as described above. When used in an eyewash cup, it is usually placed in a conventional, commonly-known eyewash container (e.g., including the container body and cap). The volume of the container is also not limited, but from the perspective of ease of use, a preferred volume is, for example, 450 to 550 mL.

Eyewashing using an eyewash cup can be done according to the usual procedure. For example, pour an appropriate amount of the eyewash composition of the present disclosure from the container into the eyewash cup, for example, 4 to 6 mL per eye, and then press the cup against the area around one eye to bring the eyewash composition in the cup into contact with the eye, and then blink several times.

When the eyewash composition of the present disclosure is used for eyewashing by instillation, it is typically contained in an eyedropper container. There are no particular restrictions on the type of eyedropper container, as long as it can contain the composition and be used to instill it into the eyes. Examples of such containers include eyedropper containers used for conventionally known eyedrops and drop-type eyewashes (e.g., types in which at least two of the container body, inner stopper (nozzle), and cap are integrated). The volume of the container is not particularly limited, but from the perspective of ease of use, a volume of 8 to 20 mL is preferred.

Eyewashing by instillation can be performed in the usual manner, by instilling 4 to 6 drops of the eyewash composition of the present disclosure into each eye at a time. There are no restrictions on the amount of each drop, but a preferred amount is 35 to 40 μL per drop, for example.

The eyewash composition of the present disclosure does not contain a preservative selected from quaternary ammonium salt-based preservatives, parahydroxybenzoic acid esters, chlorobutanol, and sorbic acids, but by using at least one selected from the group consisting of hyaluronic acid and its salts in a concentration of 0.01 w/v % or more in combination with propylene glycol, it is possible to impart excellent antiseptic properties to the eyewash composition. Furthermore, by further incorporating at least one selected from the group consisting of edetic acid and its salts, or at least one selected from the group consisting of pyridoxine, chondroitin sulfate, and their salts, it is possible to impart even more excellent antiseptic properties to the eyewash composition despite the absence of a preservative, as shown in the examples described below. Furthermore, if the composition further contains the aforementioned medicinal ingredients, the beneficial effects of the medicinal ingredients can also be obtained.

The following examples will explain the present disclosure in more detail, but the present disclosure is not limited to these.

Test Example
1. Preparation of eyewash compositions The components were mixed according to the blending ratios shown in Table 1 below, and the resulting mixtures were passed through a sterilization filter (Examples 1 to 5, Reference Example, Comparative Examples 1 to 3). The pH of each composition was measured immediately after preparation. The pH was measured at room temperature (25°C) using a tabletop pH meter F-52 (manufactured by Horiba, Ltd.). Note that the sodium chondroitin sulfate ester in the table was non-standard sodium chondroitin sulfate (weight average molecular weight 20,000).

2. Antiseptic power evaluation <Candida>
Candida albicans was suspended in sterilized saline to prepare a bacterial solution (1 x ¹⁰ cfu/mL). 10 mL of each composition obtained as described above was inoculated with the bacterial solution to a concentration of 1 x ¹⁰ cfu/mL and stored at 30°C in a dark place for 14 days. After storage, 0.1 mL of each composition inoculated with Candida was applied to a commercially available GPLP agar medium (GPLP agar medium "Daigo", manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) with a conlarger stick. After 48 hours of incubation at 30°C, the number of colonies was visually counted, and the counted value multiplied by 100 was used as the bacterial count for each composition after 14 days of storage. The percentage of bacterial count (survival rate) for each composition after 14 days of storage was calculated, with the bacterial count at the time of inoculation being set at 100%. The antiseptic power of the eyewash composition was evaluated from the calculated values according to the following criteria.
[Evaluation criteria]
◎: The survival rate decreased to 0.1% or less of the inoculation amount. ○: The survival rate decreased to 1% or less of the inoculation amount. △: The survival rate decreased to 10% or less of the inoculation amount. ×: The above △ criteria were not met.

<Staphylococcus aureus>
Staphylococcus aureus was suspended in sterilized saline to prepare a bacterial suspension (1 x ¹⁰ cfu/mL). 10 mL of each composition obtained as described above was inoculated with the bacterial suspension to a concentration of 1 x ¹⁰ cfu/mL and stored at 35°C in a dark place for 14 days. After storage, 0.1 mL of each composition inoculated with Staphylococcus aureus was applied to a commercially available SCDLP agar medium (SCDLP agar medium "Daigo", manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) with a conlarger stick. After 48 hours of incubation at 35°C, the number of colonies was visually counted, and the counted value multiplied by 100 was used as the bacterial count for each composition after 14 days of storage. The percentage of bacterial count (survival rate) for each composition after 14 days of storage was calculated, with the bacterial count at the time of inoculation defined as 100%. The antiseptic power of the eyewash composition was evaluated from the calculated values according to the same criteria as described above.

3. Results The results are shown in Tables 1 and 2.

The Reference Example, which contained the preservative benzalkonium chloride, served as the positive control in this test example. As shown in Table 1, the evaluation result was ◎, indicating excellent preservative power. In contrast, Comparative Example 1, which did not contain benzalkonium chloride but contained propylene glycol, was evaluated as ×, indicating that the desired preservative power was not achieved. Furthermore, Comparative Example 2, which did not contain benzalkonium chloride or propylene glycol but contained 0.01 w/v% sodium hyaluronate, was evaluated as △, indicating that the desired preservative power was not achieved. Furthermore, Comparative Example 3, which did not contain benzalkonium chloride but contained 0.001 w/v% sodium hyaluronate and propylene glycol, was evaluated as △, indicating that the desired preservative power was not achieved.

In contrast, Example 1, which did not contain benzalkonium chloride and contained 0.01 w/v% sodium hyaluronate and propylene glycol, was evaluated as ○, demonstrating improved preservative properties. Example 2, which had a higher sodium hyaluronate content than Example 1, was also evaluated as ○, demonstrating improved preservative properties. Surprisingly, this demonstrates that the preservative properties of an eyewash composition can be improved by combining propylene glycol, which has poor preservative properties, with sodium hyaluronate at 0.01 w/v% or more.

In addition, the evaluation results for Examples 3 to 5, in which sodium edetate was further added to Examples 1 and 2, Example 6, in which sodium chondroitin sulfate was further added to Example 5, and Example 7, in which pyridoxine hydrochloride was further added to Example 6, were also ○ or ◎, demonstrating improved preservative properties. Furthermore, when the pH of Examples 1 to 7 was set to 6.2, improvements in preservative properties similar to those of Examples 1 to 7 were also observed.

From these results, it was confirmed that the antiseptic properties of eyewash compositions can be enhanced by combining propylene glycol, which has poor antiseptic properties, with sodium hyaluronate at 0.01 w/v% or more, and by combining it with sodium edetate, sodium chondroitin sulfate, or pyridoxine hydrochloride. Furthermore, the eyewash compositions of Examples 1 to 7 have enhanced antiseptic properties without using preservatives such as benzalkonium chloride, which may be adsorbed onto contact lenses, making it possible to wash eyes with contact lenses still in place.

Eyewash compositions were prepared according to the blending ratios shown in Formulation Example Table 3, and their preservative properties were evaluated in the same manner as in the test examples. All of the eyewash compositions of Formulation Examples 1 to 7 showed improved preservative properties to the same extent as in Example 7.

Claims (3)

(A) 0.01 w/v% or more of at least one selected from the group consisting of hyaluronic acid and salts thereof ;
( B) propylene glycol , and
(C) 0.05 w/v% or more of at least one selected from the group consisting of edetic acid and its salts
and does not contain a preservative selected from quaternary ammonium salt-based preservatives, parahydroxybenzoic acid esters, chlorobutanol, and sorbic acids. The eyewash composition according to claim 1 , further comprising (D) at least one selected from the group consisting of pyridoxine, chondroitin sulfate, and salts thereof. The eyewash composition according to claim 1 or 2 , which is used while wearing contact lenses.