JP2022099576A - Eye drop-type eyewash composition - Google Patents

Abstract

To provide an eye drop-type eyewash composition and the like having excellent antiseptic properties.SOLUTION: The eye drop-type eyewash composition contains 0.005-0.03 w/v% of allantoin and does not contain any antiseptic agents selected from quaternary ammonium salt-based antiseptic agents, p-hydroxybenzoic acid esters, chlorobutanol, and sorbic acid.SELECTED DRAWING: None

Description

The present invention relates to an eye drop type eye wash composition.

Conventionally, an eye washing method using an eye washing cup (eye cup) and an eye washing method using eye drops are known. As an example of an eyewashing method using an eyewashing cup, an appropriate amount (for example, about 5 mL) of eyewashing solution is poured into the eyewashing cup, and then the cup is pressed against one side of the eye to press the eyewashing solution and the eye in the cup. A method of washing the eyes by contacting them and blinking them several times is known. Further, as an example of the eye-washing method by eye drops, a method of directly instilling an eye-washing solution into the eye to wash the eyes is known (for example, Patent Document 1).

Compared with the eye-washing method using an eye-washing cup, the eye-dropping method has advantages that it is excellent in portability because it does not require an eye-washing cup and is easy to use even on the go. In this way, the eye-washing method using eye drops is easy to use, but since it is directly instilled and is often used on the go, there is a high risk that the eye-washing solution will be exposed to microbial contamination. In order to reduce the risk of such contamination, it is known to add a preservative such as benzalkonium chloride to the eyewash. However, the addition of such a preservative tends to be unfavorable from the viewpoint of the influence on the cornea and the adsorption to contact lenses. Therefore, there is a demand for an eye drop type eye wash composition having excellent antiseptic properties without adding a preservative such as benzalkonium chloride.

Japanese Unexamined Patent Publication No. 2019-210265

Therefore, it is an object of the present disclosure to provide an eye drop type eye wash composition having excellent antiseptic properties.

The present inventor has made a diligent study in view of the above problems, and found that when a specific amount of allantoin is blended in the eye drop-type eye-washing composition, even though the preservative is not blended, the eye-drop-type eye-washing composition is used. It has been found that the desired antiseptic property can be imparted to the composition. The present invention has been completed by further studies based on such findings. That is, the present disclosure includes the following inventions.
Item 1. For eye-drop type eye wash, which contains allantin at 0.005 to 0.03 w / v% and does not contain preservatives selected from quaternary ammonium salt-based preservatives, paraoxybenzoic acid esters, chlorobutanol and sorbic acids. Composition.
Item 2. Item 2. The eye drop-type eye wash composition according to Item 1, further comprising at least one selected from the group consisting of chlorpheniramine and a salt thereof.
Item 3. Item 2. The eye drop-type eye wash composition according to Item 1 or 2, further comprising tocopherol acetate.

An eye drop-type eye-washing composition containing no preservatives selected from quaternary ammonium salt-based preservatives, paraoxybenzoic acid esters, chlorobutanol and sorbic acids, containing 0.005 to 0.03 w / v% of allantin. By blending in such a manner, an antiseptic effect can be imparted to the eye-washing composition. It is possible to provide an eye drop type eye wash composition containing allantoin having an antiseptic effect at 0.005 to 0.03 w / v% and not containing the preservative.

Hereinafter, embodiments included in the present disclosure will be described in more detail.

The eye drop-type eye wash composition included in the present disclosure contains allantin at 0.005 to 0.03 w / v%, and contains a quaternary ammonium salt-based preservative, paraoxybenzoic acid esters, chlorobutanol and sorbic acid. Contains no preservatives selected from.

Allantoin is a known compound represented by the chemical formula C ₄ H ₆ N ₄ O ₃ . The content of allantoin in the eye drop type eye wash composition is 0.005 to 0.03 w / v%. Although not limited to this limitation, the content of allantoin in the composition is preferably 0.006 to 0.03 w / v%, more preferably 0.01 to 0, from the viewpoint of improving the antiseptic property of the composition. 0.03 w / v%, more preferably 0.015 to 0.03 w / v% is exemplified.

The composition does not contain a preservative selected from quaternary ammonium salt preservatives, paraoxybenzoic acid esters, chlorobutanol and sorbic acids. The preservative is a preservative conventionally known in the fields of eye drops and eye washing. Examples of the quaternary ammonium preservative include benzalkonium chloride and benzethonium chloride. Examples of paraoxybenzoic acid esters include paraoxybenzoic acid esters such as methyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate, and salts of paraoxybenzoic acid esters (alkali metal salts such as sodium salts). Examples of sorbic acids include sorbic acid and salts of sorbic acid (alkali metal salts such as sodium salt and potassium salt, alkaline earth metals such as calcium salt and magnesium salt) and the like.

The composition may further contain at least one selected from the group consisting of chlorpheniramine and salts thereof. Chlorpheniramine and its salts are known as antihistamines, and the salt of chlorpheniramine is not limited, and examples of the salt include chlorpheniramine maleate. These may be used alone or in combination of two or more. When chlorpheniramine and a salt thereof are contained, the content thereof is not limited, but at least selected from the group consisting of chlorpheniramine and a salt thereof in the composition from the viewpoint of improving the antiseptic property of the composition. The total amount of one kind is preferably 0.0002 to 0.005 w / v%, more preferably 0.0003 to 0.004 w / v%, still more preferably 0.005 to 0.003 w / v%, and particularly preferably. Is exemplified by 0.001 to 0.003 w / v%. Further, the content of one selected from the group consisting of chlorpheniramine and a salt thereof is not limited as long as the effects of the present disclosure can be obtained, but the content of allantin in the composition is preferably 1 part by mass. 0.03 to 1.5 parts by mass, more preferably 0.08 to 1.5 parts by mass, still more preferably 0.1 to 1 part by mass are exemplified.

The composition may further contain tocopherol acetate. Tocopherol acetate includes esters of α, γ or δ-tocopherol and acetic acid. Examples of the tocopherol acetate include α-tocopherol and acetic acid esters, dl-α-tocopherol acetate, d-α-tocopherol acetate (natural vitamin E) and the like, and dl-α is preferable. -Tocopherol acetate and the like are exemplified. These may be used alone or in combination of two or more. When tocopherol acetate is contained, its content is not limited, but from the viewpoint of improving the antiseptic property of the composition, it is preferably 0.001 to 0.007 w / v%, more preferably 0 in the composition. It is exemplified by .0015 to 0.006 w / v%, more preferably 0.002 to 0.005 w / v%. The content of tocopherol acetate is not limited as long as the effects of the present disclosure can be obtained, but is preferably 0.01 to 1.5 parts by mass, more preferably 0.01 to 1.5 parts by mass, per 1 part by mass of the allantin content in the composition. Is exemplified by 0.05 to 1 part by mass, more preferably 0.08 to 1 part by mass.

The eye drop-type eye-washing composition of the present disclosure may further contain any other components acceptable for use in eye-dropping and eye-washing. Examples of the other component include, but are not limited to, a buffer, a stabilizer, an tonicity agent, a solvent, a pH adjuster, a thickener, a medicinal component, a cooling agent, and the like. The other components may be appropriately selected depending on the purpose and the like as long as they do not interfere with the effects of the present disclosure, and may be used alone or in combination of two or more. , The blending amount may be appropriately determined.

As an example of the other component, a buffering agent is given, and boric acid, borax and the like are exemplified as the buffering agent. The buffer may be used alone or in combination of two or more. For example, when the composition contains boric acid, the content of boric acid is not limited as long as it does not interfere with the effects of the present disclosure, and is preferably 0.1 to 2.5 w / v% in the composition. It is exemplified, more preferably 0.2 to 1.5 w / v%. Even when the composition contains borax, the content may be appropriately determined. Further, the composition may contain, for example, both boric acid and borax, or may contain only one of them. Further, the composition may or may not contain a buffering agent other than boric acid and borax.

Examples of the stabilizer include polysorbate (polysorbate 80, polysorbate 60, polysorbate 20, etc.), sodium edetate (including hydrate), and the like as examples of the other components. These may be used alone or in combination of two or more. When the composition contains a stabilizer, the content of the stabilizer is not limited as long as it does not interfere with the effects of the present disclosure, and preferably 0.001 to 0.5 w / v% is exemplified in the composition. , More preferably 0.01 to 0.2 w / v%. When the composition contains a stabilizer, for example, only one selected from polysorbate and sodium edetate, or only two may be contained, and the composition for eye washing is made without these. May be good.

Examples of the medicinal ingredient include amino acids, anti-inflammatory agents (anti-inflammatory agents), corneal surface protective agents, antihistamines and the like. These may be used alone or in combination of two or more.

Although not limiting the present disclosure, examples of amino acids include amino acids such as glutamic acid and salts thereof (sodium glutamate and the like) and salts thereof; amino acid analogs such as taurine and the like. These may be used alone or in combination of two or more. The composition of the present disclosure can be prepared without blending amino acids and / or salts thereof. The amino acid referred to here means an amino acid that can be a constituent unit of a protein having both functional groups of an amino group and a carboxy group, and includes, for example, L-aspartic acid and the like. In addition, the eye wash composition of the present disclosure can also be prepared without blending an amino acid analog.

Although not limiting the present disclosure, examples of the anti-inflammatory agent include zinc sulfate, zinc lactate, epsilon-aminocaproic acid, glycyrrhizic acid and salts thereof (dipotassium glycyrrhizinate, etc.). These may be used alone or in combination of two or more. Although not limiting the present disclosure, the compositions of the present disclosure preferably do not contain zinc sulfate and / or zinc lactate.

Although not limiting the present disclosure, for example, chondroitin sulfate and its salt, hyaluronic acid and its salt and the like are exemplified as the corneal surface protective agent, and alkali metal salts such as sodium salt and the like are preferably exemplified as the salt. These may be used alone or in combination of two or more. When the composition of the present disclosure contains chondroitin sulfate and / or a salt thereof, the composition may be prepared without containing hyaluronic acid and a salt thereof. Further, although not limiting the present disclosure, the molecular weight of chondroitin sulfate or a salt thereof is preferably about 5,000 to 45,000, more preferably about 15,000 to 30,000 by weight average. Illustrated. The weight average molecular weight used in the examples described below is measured by gel filtration chromatography.

When the composition of the present disclosure contains a medicinal ingredient, the content of the medicinal ingredient is not limited as long as the effect of the present disclosure is not impaired, and the content of the medicinal ingredient in the composition is preferably 0.01 to 1w. / V%, more preferably 0.025 to 0.5 w / v%, and even more preferably 0.1 to 0.3 w / v% are exemplified. The above-mentioned allantoin, chlorpheniramine and salts thereof are also known as medicinal ingredients, but these ingredients are not included in the description of the medicinal ingredient in the present disclosure, and therefore, allantoin is included in the content of the medicinal ingredient. , Chlorpheniramine and its salt content are not included.

When the eye drop type eye wash composition of the present disclosure contains a refreshing agent, menthol, camphor, borneol and the like are exemplified as the cooling agent. When d-form, l-form, and dl-form are present in the refreshing agent, it does not matter whether they are present or not. The refreshing agent may be used alone or in combination of two or more. The content of the refreshing agent is not limited as long as it does not interfere with the effects of the present disclosure, and is preferably 0.0001 to 0.05 w / v%, more preferably 0.002 to 0.01 w / v in the composition. % Is exemplified.

The instillation type eye wash composition of the present disclosure can be produced by mixing at least one selected from the group consisting of allantoin, chlorpheniramine and a salt thereof, tocopherol acetate, and other components. can. Here, allantoin is mixed so as to be 0.005 to 0.03 w / v% in the composition. In addition, the composition does not contain a preservative selected from quaternary ammonium salt-based preservatives, paraoxybenzoic acid esters, chlorobutanol and sorbic acids.

Therefore, as one embodiment of the instillation type eye wash composition of the present disclosure, (1) allantin contains 0.005 to 0.03 w / v%, and if necessary, (2) chlorpheniramine and a salt thereof. At least one selected from the group consisting of, if necessary, (3) tocopherol acetate, if necessary (4) buffer, stabilizer, tonicity agent, solvent, pH adjuster, thickener, Contains at least one selected from the group consisting of medicinal properties and cooling agents, and (5) preservatives selected from quaternary ammonium salt-based preservatives, paraoxybenzoic acid esters, chlorobutanol and sorbic acids. Compositions that do not contain are exemplified. Further, as the embodiment, a composition consisting of the component (1) and at least one selected from the group consisting of the components (2) to (4) is exemplified. Further, as shown in Examples described later, as one embodiment, a composition containing no component generally used as a preservative in the fields of eye drops and eye washing is exemplified.

The pH of the eye drop-type eye-washing composition of the present disclosure is not limited as long as it can be used as an eye drop or an eye-washing agent, but the pH is 5 to 8 at room temperature (24 ° C.), from the viewpoint of improving the antiseptic property of the composition. Therefore, it is preferably pH 5.5 to 7, more preferably pH 5.5 to 6.5, further preferably pH 5.5 to 6, particularly preferably pH 5.5 to 5.8, and particularly more preferably pH 5.5 to 5. .7 is exemplified. The pH is measured with a desktop pH meter F-52 (manufactured by HORIBA, Ltd.). The forms of the compositions of the present disclosure are not limited and are usually liquid at room temperature.

As will be described later, the eye drop-type eye-washing composition of the present disclosure is usually contained in an eye-drop container and instilled. From this, the viscosity and osmotic pressure (osmotic pressure ratio) of the composition are not limited as long as they can be used in this way.

The eye drop type eye wash composition of the present disclosure may be used with or without contact lenses. Contact lenses may be hard contact lenses or soft contact lenses.

The composition for eye drop type eye wash of the present disclosure is not limited as long as it can be used by eye drops, but from the viewpoint of ease of use and the like, the composition is usually contained in an eye drop container and used.

The eye drop container is not limited as much as possible by accommodating the composition and instilling the composition. , Including caps) are exemplified. The instillation container is a type in which the container body, the inner plug (nozzle) and the cap are independent, a type in which at least two of the container main body, the inner plug (nozzle) and the cap are integrated, and the inner plug (nozzle). It may be either a type having a hole in the inner plug (nozzle), a type having no hole in the inner plug (nozzle), and a type in which a hole is made in the inner plug (nozzle) by winding a cap at the time of use.

The capacity of the eye drop container is not limited, but from the viewpoint of ease of use and the like, the capacity is exemplified by 8 to 20 mL, preferably 10 to 15 mL, and more preferably 12 to 14 mL. The capacity may be appropriately determined in consideration of the distinction between the multi-dose type and the unit-dose type.

The instillation type eye wash composition of the present disclosure is used by instilling 3 to 8 drops per eye at a time. Although not limited to this limitation, the composition is preferably instilled at 4 to 8 drops per eye, more preferably 4 to 6 drops from the viewpoint of more efficient eye washing. The amount of drops per drop is also not limited, but 30 to 50 μL per drop is exemplified, preferably 35 to 40 μL, and more preferably 35 to 37 μL. The number of times the composition is used per day is not particularly limited, and may be, for example, 1 to 12 times, 2 to 8 times, 3 to 6 times, or the like per eye. In this way, according to the eye drop type eye wash composition of the present disclosure, the eyes can be washed.

As described above, although the eye drop type eye wash composition of the present disclosure does not contain a preservative selected from a quaternary ammonium salt-based preservative, paraoxybenzoic acid esters, chlorobutanol and sorbic acid. By blending allantin in an amount of 0.005 to 0.03 w / v%, an antiseptic effect can be imparted to the eye drop type eye wash composition. Further, when the composition further contains the above-mentioned medicinal ingredient or the like, it is possible to provide a useful action based on the medicinal ingredient or the like.

Hereinafter, the present disclosure will be described in more detail with reference to examples, but the present disclosure is not limited thereto.

Test Example 1
1. 1. Preparation of Eye Drop Type Eye Washing Composition and Evaluation of Antiseptic Action Each component was mixed according to the blending ratio shown in Table 1 below to prepare each composition (Examples 1 to 8, Comparative Examples 1 to 2 and Reference Example). 10 mL of the obtained composition was poured into a general eye drop type eye drop container (capacity: 13 mL, polyethylene terephthalate resin, multidose type, manufactured by Shinko Chemical Co., Ltd.). Next, a solution (bacterial solution) in which Candida albicans was suspended in sterilized physiological saline was inoculated into each container at 1 × 10 ⁷ cfu / mL, and stored at 30 ° C. in the dark for 21 days. did. After storage, 0.1 mL of each composition inoculated with Candida bacteria is taken out from the container, and this is applied to a commercially available GPLP agar medium (GPLP agar medium "Daigo", manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) with a spreader. After culturing at 30 ° C. for 48 hours, the number of colonies was visually counted, and the value obtained by multiplying the counted value by 100 was used as the number of bacteria in each composition 21 days after storage. The ratio (survival rate) of the number of bacteria in each composition after storage for 21 days was calculated with the number of bacteria at the time of inoculation as 100%. From the calculated values, the antiseptic power of the eye drop type eye wash composition was evaluated according to the following criteria.
[Evaluation criteria]
⊚: Survival rate decreased to 0.05% or less of the inoculation amount ○: Survival rate decreased to 0.1% or less of the inoculation amount △: Survival rate decreased to 3% or less of the inoculation amount ×: Based on the criteria of △ above Not satisfied

In addition, the pH of each composition immediately after preparation was measured. The pH was measured at room temperature (24 ° C.) using a desktop pH meter F-52 (manufactured by HORIBA, Ltd.).

2. 2. Results The results are shown in Table 1.

The reference example to which benzalkonium chloride, which is a typical preservative, was added means positive control in this test example, and as shown in Table 1, the evaluation result was ⊚, and the antiseptic power was excellent. In the reference example, the survival rate of Candida in the composition after storage was 0.001%. On the other hand, Comparative Example 1 prepared in the same manner as in Reference Example except that benzalkonium chloride was not added, and Comparative Example prepared in the same manner by adding chlorpheniramine maleate instead of adding benzalkonium chloride. In No. 2, the evaluation result was ×, and the desired antiseptic power could not be obtained.

On the other hand, in Example 1 in which allantoin was contained at 0.006 w / v% instead of benzalkonium chloride, the evaluation result was ◯, and the desired antiseptic power was obtained. In Example 1, the survival rate was 0.100%, that is, the survival rate was reduced to 0.1% or less of the inoculation dose. Further, in Example 2 in which the content of allantoin was increased in Example 1, the evaluation result was ⊚, and higher antiseptic power was obtained. In addition, the evaluation results were ⊚ in Examples 3 to 6 in which allantoin and chlorpheniramine maleate were used in combination, and high antiseptic activity was obtained. In Examples 4 to 6 in which the pH of the composition of Example 3 was lowered, the antiseptic property was further improved. The survival rates in Examples 2 to 6 were 0.050%, 0.010%, 0.008%, 0.005%, and 0.004%, respectively. Furthermore, the evaluation results of Examples 7 to 8 in which allantoin, chlorpheniramine maleate and dl-α-tocopherol acetate were used in combination were ⊚, and the survival rates in Examples 7 to 8 were 0.001% and 0%, respectively. The antiseptic property was significantly improved. Therefore, by adding allantoin to the eyewash composition containing no preservative, or by adding allantoin and chlorpheniramine maleate, allantoin, chlorpheniramine maleate, and dl are further added. It was confirmed that by blending with -α-tocopherol acetate, the desired antiseptic effect can be imparted or enhanced to the eyewash composition.

Test Example 2
1. 1. Preparation of Eye Drop Type Eye Washing Composition and Evaluation of Antiseptic Action Each component was mixed according to the blending ratio shown in Table 2 below to prepare each composition (Examples 9 and 10, Comparative Example 3). In the table, as the sodium chondroitin sulfate, sodium chondroitin sulfate (manufactured by Seikagaku Corporation, weight average molecular weight 20000) was used. The pH of each composition immediately after preparation was measured in the same manner as in Test Example 1.

After passing 10 mL of each obtained composition through a sterilizing filter, each of them was placed in a sterilized general eye drop type eye drop container (same as Test Example 1). Ten panelists were asked to instill 4 drops of each composition from the eye drop container into both eyes 3 times a day for 5 days, and a general bacterial count test was performed on each composition remaining in the container. ..

The general bacterial count test was performed according to the following procedure. 1 mL of the composition remaining in the container was recovered. All 1 mL of each composition recovered from 10 bottles was mixed to obtain a mixed solution of 10 mL. 1 mL is recovered from the obtained mixed solution, diluted 10-fold with sterile water, and the entire amount is applied to a standard agar medium (standard agar medium (granule) "Nissui", manufactured by Nissui Pharmaceutical Co., Ltd.) at 35 ° C. Was cultured for 48 hours. After culturing, the number of colonies was visually counted, and the value obtained by multiplying the counted number by 10 was taken as the general bacterial count (cfu / mL) (detection limit value 10 cfu / mL).

2. 2. Results The results are shown in Table 2.

As shown in Table 2, the general bacterial count of Comparative Example 3 containing no allantoin was 100 cfu / mL. On the other hand, in Examples 9 and 10 to which allantoin, chlorpheniramine maleate and dl-α-tocopherol acetate were added, the number of general bacteria could be suppressed to non-detection (below the detection limit). In the eye drop type detergent, it is considered that bacteria are likely to be mixed in the composition in the container due to the high contact frequency of the eyelashes. In this way, in the eye drop type detergent which is easily contaminated with bacteria, Examples 9 and At 10, the increase in the number of bacteria could be suppressed. Further, when the compositions of Examples 9 and 10 were changed so as not to contain only allantoin and evaluated in the same manner, the number of general bacteria could not be suppressed undetectably. For this reason as well, by blending allantin, chlorpheniramine maleate, and dl-α-tocopherol acetate in the eye drop type eye drop composition containing no preservative, the desired antiseptic composition can be obtained. It was confirmed that the action was imparted or enhanced.

Prescription Example Table 3 shows a prescription example of the eye drop type eye wash composition of the present invention. When the antiseptic properties of the formulation examples shown in Table 3 were evaluated in the same manner as in Test Examples 1 and 2, any of Formulation Examples 1 to 8 was compared with the case where the compositions of Formulation Examples 1 to 8 did not contain allantoin. It was confirmed that the composition of No. 1 was also excellent in antiseptic property.

Claims (3)

For eye-drop type eye wash, which contains allantin at 0.005 to 0.03 w / v% and does not contain preservatives selected from quaternary ammonium salt-based preservatives, paraoxybenzoic acid esters, chlorobutanol and sorbic acids. Composition. The eye drop type eye wash composition according to claim 1, further comprising at least one selected from the group consisting of chlorpheniramine and a salt thereof. The eye drop-type eye wash composition according to claim 1 or 2, further comprising a tocopherol acetate.