JP2011251932A - Ophthalmic solution and eye wash - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a composition for an ophthalmic solution or eye wash exhibiting excellent antiseptic stability without containing an antiseptic agent with no irritation to eye mucosa that can be used while contact lenses are fitted to a wearer.SOLUTION: The composition is used for ocular instillation or eye washing and contains 1,2-octanediol, desirably contains a boric acid and/or borax. There are also provided an ophthalmic solution and eye wash composed of the composition.

Description

  The present invention relates to a composition used for eye drops or eye wash.

  Generally, preservatives such as benzalkonium chloride and parabens are blended in compositions used for eye drops and eyewashes for the antiseptic stability of products. However, such an antiseptic component may irritate the ocular mucosa, and is particularly prominent in contact lens wearers and dry eye patients.

  Also, contact lens wearers and dry eye patients frequently use eye drops, so they tend to prefer eye drops that do not contain irritating preservatives.

  Therefore, attempts have been made to suppress the antiseptic stability and ocular mucosal irritation of the composition without blending conventional preservatives. In Patent Document 1, an ophthalmic composition in which boric acid and / or a salt thereof and a compound having three or more hydroxyl groups in one molecule is blended with panthenol is reported. Patent Document 2 reports an ophthalmic composition containing trometamol and boric acid in a specific ratio.

  On the other hand, it has been reported that 1,2-octanediol can be used as an antiseptic disinfectant for cosmetics, pharmaceuticals, foods and the like (see Patent Document 3). However, in Patent Document 3, although application to external preparations such as hair styling agents, massage creams, and acne prevention agents is disclosed, it can also be used by contact lens wearers, and the possibility of use as eye drops or eye wash agents is described. Not disclosed.

JP 2002-265357 A JP 2004-2364 A Japanese Patent Laid-Open No. 11-322591

  The present invention has been made in view of the above prior art, and is excellent in antiseptic effect even without containing other antiseptic components, is not irritating to the ocular mucosa, and is used even when a contact lens is worn. An object of the present invention is to provide a composition that can be used for eye drops or eye wash.

That is, the present invention
[1] A composition used for eye drops or eyewash, which contains 1,2-octanediol,
[2] The composition according to [1], further containing boric acid and / or borax,
[3] An eye drop comprising the composition according to [1] or [2], and [4] a composition according to [1] or [2]. Related to eye wash.

  The composition used for eye drops or eyewashes containing 1,2-octanediol is excellent in antiseptic effect even if it does not contain other antiseptic ingredients, has no irritation to the eye mucosa, and has no adsorptivity to contact lenses. There is an effect that it can be used with the contact lens attached.

  Furthermore, the composition used for eye drops or eyewashes containing boric acid and / or borax has the effect of synergistically enhancing the antiseptic effect on fungi such as yeast and mold.

It is a figure which shows an example of the method of determining the effect produced when two types of substances which have antimicrobial property are mix | blended from binary minimum growth inhibitory density | concentration. (A) is a binary minimum growth inhibitory concentration diagram for oral candidiasis in Test Example 2. FIG. (B) is a binary minimum growth inhibitory concentration diagram for black mold of Test Example 2. FIG. It is a figure showing the cell survival rate of the rabbit corneal epithelial cell in each drug density | concentration of Example 4 and Comparative Examples 2-3. It is a figure showing the adsorption amount and discharge | release amount to a soft contact lens in each sample of Examples 5-6 and Comparative Example 4.

  The composition used for the eye drop or eye wash of the present invention contains 1,2-octanediol. The content of 1,2-octanediol is not particularly limited as long as the effects of the present invention are exhibited. However, it may contain 0.05 w / v% or more from the viewpoint of the antiseptic effect, and suppresses irritation to the ocular mucosa and dissolves. From the viewpoint of, it is preferable to contain 0.3 w / v% or less. From these, the content of 1,2-octanediol in the composition is generally 0.05 to 0.3 w / v%.

  The composition used for the eye drop or eye wash of the present invention may further contain boric acid and / or borax. Thereby, antibacterial activity is further synergistically enhanced against fungi such as yeast and mold.

  The content of boric acid and / or borax is not particularly limited as long as the effects of the present invention are exhibited. However, 0.05 w / v% or more may be contained from the viewpoint of the antiseptic effect, and irritation suppression and dissolution to the ocular mucosa is preferable. From the viewpoint of property, it is preferable to contain 1 w / v% or less. From these, the content of boric acid and / or borax in the composition is in principle 0.05 to 1 w / v%.

  The mixing ratio of 1,2-octanediol and boric acid and / or borax is not particularly limited as long as synergistic antibacterial activity is exhibited, but is preferably 0.1: 1 to 10 by mass ratio. : 1, more preferably 0.2: 1 to 5: 1. When 1,2-octanediol is added in an amount exceeding 10 mass times the boric acid and / or borax content, and less than 0.1 mass times, a sufficient enhancement effect of antibacterial activity is not expected. Absent.

  In addition to the above-described components, components usually used in eye drops and eye wash can be appropriately blended in the composition used for eye drops or eye wash according to the present invention, depending on the purpose of blending. For example, medicinal ingredients, solubilizers, buffers, tonicity agents, stabilizers, suspending agents, surfactants, chelating agents, thickening agents and the like can be mentioned, and these are the effects of the present invention. Ordinary doses can be formulated within a range that does not impair.

  Specifically, examples of the medicinal component include sodium chondroitin sulfate (corneal protection), pyridoxine hydrochloride (metabolism promotion), potassium L-aspartate, neostigmine methylsulfate, chlorpheniramine maleate (antihistamine), diglycyrrhizinate Examples include potassium (anti-inflammatory), pranoprofen (anti-inflammatory), cromoglycate sodium (anti-allergy), tranilast (anti-allergy), ofloxacin (antibacterial) and the like.

  Examples of the solubilizer include polysorbate 80, polyvinyl pyrrolidone, polyethylene glycol, propylene glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 40 stearate, and the like.

  Examples of the buffer include citric acid or a salt thereof, tartaric acid or a salt thereof, gluconic acid or a salt thereof, acetic acid or a salt thereof, phosphoric acid or a salt thereof, and the like. In addition, since the composition of the present invention is for eye drops or eye wash, from the viewpoint of alleviating irritation when instilled or entering the eye, when using a buffer, the pH of the composition is in the range of 4-9. It is preferable to add so that it may become, and it is more preferable to add so that pH may become the range of 5-8.

  The isotonic agent is not particularly limited as long as it is water-soluble and does not show adverse effects such as eye irritation, and examples thereof include sorbitol, glucose, mannitol, glycerin, propylene glycol, sodium chloride, potassium chloride and the like. be able to.

  Examples of the stabilizer include ascorbic acid, sodium edetate, cyclodextrin, condensed phosphoric acid or a salt thereof, sulfite, citric acid or a salt thereof, and the like.

  Examples of the suspending agent include methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyoxyethylene hydrogenated castor oil 60, polyoxyl 40 stearate, polyethylene glycol, sodium carboxymethyl cellulose, polyvinyl alcohol and the like.

  Examples of the surfactant include nonionic surfactants such as polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyoxyl 40 stearate, polyoxyethylene lauryl ether; lauroyl sarcosine sodium, lauroyl-L-glutamate triethanolamine, Anionic surfactants such as sodium myristyl sarcosine; amphoteric surfactants such as lauryldimethylaminoacetic acid betaine, 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, alkyldiaminoglycine hydrochloride; benzethonium chloride, chloride Examples include cationic surfactants such as benzalkonium and cetylpyridinium chloride.

  Examples of the chelating agent include sodium edetate, sodium citrate, condensed phosphoric acid or a salt thereof.

  Examples of the thickener include methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium chondroitin sulfate, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol and the like.

  The composition used for the eye drop or eye wash of the present invention exhibits an excellent antiseptic effect even if it does not contain a conventional preservative, and does not cause irritation even when applied to the eye. Can be used.

  Moreover, since the composition of the present invention has no adsorptivity to contact lenses and is excellent in water-wetting effect and can reduce the feeling of foreign matters when wearing lenses, it can also be instilled and washed while wearing the contact lenses.

  EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is not limited only to this Example. The blending amount is w / v% unless otherwise specified.

Test Example 1: Preservative efficacy test (sample preparation)
According to the composition shown in Table 1, compositions used for eye drop or eye wash of each Example and Comparative Example were prepared by a conventional method. In the table, the “balance” of purified water represents the total amount of 100 mL. Moreover, the “suitable amount” of sodium hydroxide and hydrochloric acid represents an amount necessary for adjusting the pH of the system to 7.0.

(Test bacteria)
Staphylococcus aureus ATCC 6538 (Staphylococcus aureus), Escherichia coli ATCC 8739 (Escherichia coli), Pseudomonas aeruginosa ATCC 9027 (Pseudomonas aeruginosa), Candida albicans ATCC 10231 (oral Candida sp.

(Test method)
The preservation efficacy of each composition of Comparative Example 1 and Examples 1 to 3 was tested for preservation efficacy according to the “Preservation Efficacy Test Method” listed in the Japanese Pharmacopoeia (15th Amendment). Judged. That is, 10 mL of each composition was dispensed into 5 sterilized test tubes with stoppers, and after inoculation so that the test bacteria were 10 ⁵ cells / mL, they were stored in an atmosphere at 20 to 25 ° C. .

  After 14 and 28 days from the start of storage, 1 mL was taken from each test tube, mixed with 9 mL of sterile physiological saline, and diluted 10 times. 1 mL of the diluted solution was dispensed into a sterile petri dish, and the bacteria were diluted with a soybean / casein / digest agar medium supplemented with lecithin 0.1% polysorbate 80 0.7% and cultured at 30 to 35 ° C. for 1 day. For fungi, lecithin 0.1% polysorbate 80 0.7% added Sabouraud glucose agar medium, oral candidiasis bacteria are cultured at 20-25 ° C. for 2 days, black mold is 20-25 ° C. Cultured for 7 days. After each culture, the number of colonies produced was measured. The results are shown in Tables 2-3. In addition, the number in a table | surface represents a viable count.

  From the results shown in Tables 2 and 3, the composition used for eye drops or eyewashes according to the present invention containing 1,2-octanediol is based on the “preservation efficacy test method” listed in the Japanese Pharmacopoeia (15th revision). Thus, it can be seen that it conforms to the category IA standard and exhibits the same antiseptic effect as the conventional antiseptic parabens.

Test Example 2: Synergistic effect test of antibacterial activity (test bacteria)
Candida albicans ATCC 10231 (oral candidiasis) and Aspergillus niger ATCC 16404 (black mold) were used as test bacteria.

(Preparation of bacterial solution for inoculation)
As for the bacterial solution for inoculation, oral candidiasis was cultured on an agar medium at 30 ° C., then transplanted to a bouillon medium and cultured at 30 ° C. A solution obtained by diluting the obtained culture broth with a broth medium to about 10 ⁷ cells / ml was used as an inoculum. As for Aspergillus niger, inoculate those prepared approximately 10 ⁶ cells / mL by suspending spores Tween 80 (polyoxyethylene (20) sorbitan monooleate) 2% added saline after culture at 25 ° C. Bacterial fluid was used.

(Preparation of dilution series of test substance)
5, 4-, 3, 2.5, 2.25, 2, 1.75, 1.5, 1.25, 1 w / v% 1,2-octane using 20 w / w% ethyl cellosolve as a diluent solvent A diol solution was prepared. Moreover, about the borax and an equal amount mixture of 1,2-octanediol and borax, a dilution series was prepared by doubling a 5 w / v% solution.

(Measurement of minimum inhibitory concentration (MIC))
For each 1 mL of the dilution series containing the test substance, 9 mL of each agar medium was placed in a petri dish, and the inoculum for the inoculum was streaked to a length of about 1 cm. The culture was performed at 25 ° C., and the presence or absence of the growth of the bacteria after 3 days was determined. At this time, the minimum concentration at which no growth was observed was determined as MIC. The results are shown in Table 4. The unit of MIC in the table is μg / mL.

  In addition, antibacterial power can be evaluated by MIC. When the test substance concentration is low, there is no effect on microorganisms, but growth increases when the concentration is increased. This degree of growth proceeds depending on the concentration, and finally the growth stops. The concentration at this time is expressed as MIC. Therefore, when the concentration is higher than MIC, the microorganisms are killed.

(Dual minimum inhibitory concentration)
Each MIC of the obtained 1,2-octanediol, borax, and a mixture of 1,2-octanediol and borax was plotted against the blending amount of 1,2-octanediol and borax, and binary A minimum growth inhibitory concentration diagram was determined.

  In addition, the effect at the time of mix | blending two types of substances which have antimicrobial property can be determined with a binary minimum growth inhibitory density | concentration. Specifically, when two types of substances having antibacterial properties are blended, the action produced by the substances is roughly classified into synergistic action, additive action, and antagonism. The synergistic action is an action in which two drugs act synergistically to further enhance the inherent antibacterial power. The additive action is an action in which the antibacterial powers of the respective drugs are combined. Antagonism is an action when one drug counteracts the antibacterial activity of another drug. Then, the method based on the binary minimum growth inhibition concentration diagram is a method of determining from the graph by measuring the MIC for each of the A substance and B substance while changing their ratios, as shown in FIG. According to this, when MIC (point A) in only substance A and MIC (point B) only in substance B are connected, the MIC when both substances are used is on the inner side of this line (point C) is a synergistic effect in which the antibacterial activity is enhanced by the combined use, if it is on the line (point D), if it is an additive action, if it is outside the line (point E), either or both It can be determined that the antagonistic action counteracts the antibacterial activity and decreases the antibacterial activity.

  FIG. 2 shows a binary minimum inhibitory concentration diagram regarding 1,2-octanediol and borax. From the results of FIG. 2, it can be seen that the combined use of 1,2-octanediol and borax synergistically enhances the antibacterial activity inherent in 1,2-octanediol.

Test Example 3: Cytotoxicity evaluation test (sample preparation)
Each chemical | medical agent was added to the dilution medium shown in the table | surface in the use concentration range shown in Table 5, and the sample of each Example and the comparative example was prepared by the conventional method. In addition, the culture medium for rabbit corneal epithelial cell proliferation (trade name: RCGM2, Kurabo Industries Co., Ltd.) was used as the medium.

(Cell culture)
After thawing frozen normal rabbit corneal epithelial cells (trade name: NRCE2, Kurabo Industries, Inc.), a cell suspension is prepared according to a conventional method, and the cells are 4 × 10 ³ cells / well / 100 μL in each well of a 96-well plate. Sowing. _{Thereafter, 37 ℃, 5% CO 2} , was cultured to confluence in a humidified.

(Measurement of cell viability)
After removing the culture supernatant, 100 μL of each sample of Examples and Comparative Examples prepared above was added. After the sample addition, the sample was treated at 37 ° C., 5% CO ₂ and humidification for 5 minutes. In addition, the medium was added to the untreated group, and the same treatment was performed for 5 minutes.

  After completion of the culture, the supernatant was removed, and each well was washed with 100 μL of medium. A cell Counting Kit-8 solution (trade name; manufactured by Dojindo Laboratories) was added to each well, and after 2 hours, a microplate reader (trade name: POWER SCAN HT, manufactured by Dainippon Sumitomo Pharma Co., Ltd.) was used, and the wavelength was 450 nm. Absorbance was measured at. The absorbance of the untreated group (the ratio of each well to the untreated group (cell survival rate) with the average value of each cell being 100) was determined, and the average value of the cell survival rate of each drug was calculated. The results are shown in FIG.

  From the results shown in FIG. 3, it can be seen that 1,2-octanediol is less cytotoxic than paraben and benzalkonium chloride, which are common preservatives.

Test Example 4: Evaluation of eye irritation (sample preparation)
0.2 w / v% and 0.6 w / v% 1,2-octanediol solutions were prepared. The base used was D-PBS (product name: Dulbecco's phosphate buffer (Catalog No. 14190144), manufactured by Invitrogen) to which ethanol was added so that the final concentration was 0.1%.

(Test method)
Immediately before administration of the sample, the anterior eye part was observed with the naked eye and a slit lamp, and 6 Japanese male white rabbits were confirmed which were confirmed to have no abnormality in the anterior eye part. Of these, each group was divided into 2 groups of 3 animals, and each rabbit had a 0.2% or 0.6% 1,2-octanediol solution in the right eye and a base (0.1% ethanol-containing D in the left eye). -PBS) was instilled 8 times at a dose interval of 1 hour or more, 100 μL each.

  The anterior ocular segment was observed immediately before administration and about 30 minutes after the completion of the first, second, fourth, and eighth administrations using the naked eye or slit lamp for the conjunctiva, iris and cornea of both eyes, and McDonald-Shadduck. The evaluation was made according to the criteria for judging eye disorders according to the law. However, in the observation for about 30 minutes after the first, second and fourth administration, only the conjunctiva was observed with the naked eye. In addition, immediately before administration and 30 minutes after the eighth administration, corneal staining spots were observed using a slit lamp after 10 μL of 0.1% fluorescein solution was administered.

(result)
As a result of the anterior eye irritation test using 0.2% and 0.6% 1,2-octanediol, no abnormality was observed in the conjunctiva, iris and aqueous humor.

Test Example 5: Evaluation of adsorption / release property to soft contact lens (sample preparation)
According to the composition shown in Table 6, compositions of each Example and Comparative Example were prepared by a conventional method. In the table, the “balance” of purified water represents the total amount of 100 mL. The “appropriate amount” of sodium hydroxide represents an amount necessary to adjust the pH of the system to 7.0.

(Soft contact lens)
Soft contact lenses are trade names Medalist Plus (manufactured by Bochrom Japan; hereinafter abbreviated as “Lens A”), trade names 1D Accuview (manufactured by Johnson &Johnson; hereinafter abbreviated as “Lens B”), Five of each of the trade names O ₂ Optics (manufactured by Ciba Vision Inc .; hereinafter abbreviated as “Lens C”) were used.

(Quantification of adsorption amount)
2 mL of each sample of Examples and Comparative Examples was weighed into a vial, immersed in one soft contact lens, and shaken at 25 ° C. overnight. Similarly, a solution in which the soft contact lens was not immersed was similarly shaken overnight at 25 ° C. to serve as a control test solution. After shaking overnight, 1 mL of each test solution is collected, the amounts of 1,2-octanediol and benzalkonium chloride are quantified by liquid chromatography, and the residual rate and the amount adsorbed on the soft lens are calculated from the following formulas. The average value of 5 sheets was adopted. The results are shown in Table 7 and FIG.

(Quantification of released amount)
2 mL of physiological saline was weighed into a vial, immersed in each of the soft contact lenses after the test, and shaken at 25 ° C. overnight. After shaking, 1 mL of the immersion liquid is collected, the amounts of 1,2-octanediol and benzalkonium chloride are quantified by liquid chromatography, and the release amount and release rate from the soft contact lens are calculated from the following formula. The average value of the sheets was adopted. The results are shown in Table 7 and FIG.

  From the results of Table 7 and FIG. 4, it can be seen that 1,2-octanediol (Examples 5 and 6) is adsorbed to the soft contact lens, but is quickly released and does not accumulate in the lens. On the other hand, benzalkonium chloride (Comparative Example 4), which is a general preservative, has a high adsorption rate of about 10 to 20% in the residual rate, and is almost released once adsorbed to the lens. It can be seen that the accumulation in the lens is high.

Test Example 6: Evaluation of swellability of soft contact lens According to the composition shown in Table 8, the composition of each example was prepared by a conventional method. In the table, the “balance” of purified water represents the total amount of 100 mL. In addition, “appropriate amount” of sodium hydroxide and hydrochloric acid means an amount necessary to adjust the system so as to be equivalent to ISO-PBS (phosphate buffered saline; pH 7.4, osmotic pressure 300 mOsm). To express.

(Before immersion in test solution)
Soft contact lens (trade name One Day Accuview (manufactured by Johnson & Johnson)) was rinsed lightly with ISO-PBS, then immersed in ISO-PBS for 2 hours, and the diameter and curvature of the soft contact lens in ISO-PBS. The radius was measured with a soft contact lens analyzer and the results are shown in Table 9.

(After immersion in test solution)
The soft contact lens after immersion in ISO-PBS is lightly rinsed with the test solution of each example and then immersed in each test solution for 2 hours. The diameter and the radius of curvature of the soft contact lens are determined in the test solution. It measured similarly. The results are shown in Table 9.

From the results of Table 9, it can be seen that even in the test solutions of each Example, the expansion ratio of the contact lens is 0.2 mm or less, which does not affect the contact lens. For this reason, it can be seen that even when instilled with the contact lens attached, the contact lens does not feel uncomfortable and the contact lens has a good fit and there is no risk of shifting or coming off.
The Japan Contact Lens Association has established “Voluntary Safety Standards for Contact Lens Cleaning Agents, Preservatives, Cleaning Preservatives, etc.”. The difference is specified within ± 0.2 mm.

Test Example 7: Evaluation of water wettability of hard contact lens According to the composition shown in Table 10, compositions of Examples and Comparative Examples were prepared by a conventional method. In the table, the “balance” of purified water represents the total amount of 100 mL. The “appropriate amount” of sodium hydroxide represents an amount necessary to adjust the pH of the system to 7.0.

(Hard contact lens)
As the hard contact lens, a trade name Bochromu EX-O ₂ (manufactured by Bochrom Japan) was used.

(Measurement of contact angle)
1 microliter of each sample of an Example and a comparative example was dripped on the contact lens, the contact angle was measured 6 times each using the contact angle meter (CA-X type, Kyowa Interface Science company make), and the t test was performed. As a result, Examples 9 and 10 showed a significant difference at a risk rate of 0.1%. The results are shown in Table 11.

  From the results of Table 11, it can be seen that the contact angle is significantly lowered and the wettability with respect to the contact lens is improved only by containing a small amount of 1,2-octanediol of 0.02%. Thereby, the foreign material feeling at the time of wearing a contact lens can be reduced.

Claims (4)

  A composition for use in eye drops or eyewashes, which comprises 1,2-octanediol.   Furthermore, boric acid and / or borax are contained, The composition of Claim 1 characterized by the above-mentioned.   An ophthalmic solution comprising the composition according to claim 1 or 2.   An eye wash comprising the composition according to claim 1 or 2.

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