JP4870944B2 - Ophthalmic composition - Google Patents

Description

  The present invention relates to an ophthalmic composition such as a dry eye ophthalmic composition effective for prevention, alleviation and healing of dry eye symptoms, and an artificial tear solution composition which is also effective as an artificial tear.

  The surface of the eyeball is properly wetted by the secreted lacrimal fluid under normal conditions, and the appropriate amount of lacrimal fluid prevents the eyeball surface from drying and maintains the health of the eyeball, such as oxygen supply, nutritional supplementation, washing, and sterilization. It is well known that it plays an important physiological role.

  Dry eye generally refers to an abnormal dry state that occurs on the surface of the eyeball and symptoms that are caused by the eyeball. It is considered a disease of the ocular surface including a disease that should not be called a single symptom but also called dry eye syndrome. That is, it refers to a state in which tears are quantitatively or qualitatively abnormal, often accompanied by keratoconjunctival disorder. Symptoms include lacrimation, hypoxia, xerophthalmia, Sjogren's syndrome, dry keratoconjunctivitis, Stevens-Johnson syndrome, ocular pemphigoid, blepharitis, closed eye failure, and sensory nerve palsy. Examples include dry eye related, dry eye related to allergic conjunctivitis, dry eye related to viral conjunctivitis, and dry eye after cataract surgery. In addition, dry eyes that have become particularly problematic in recent years include dry eyes related to contact lens wear, dry eyes related to artificial air conditioning environments, and dry eyes related to long-term gaze on VDT screens of TVs and computers. is there.

  When dry eye is affected, tears decrease, dryness, lack of oxygen, dust adhesion, and the like occur on the surface of the eyeball. As the drying progresses, a defect (tear hole) occurs in the tear film on the eyeball surface. In addition, the eyes may feel burned, dry, persistent irritation, significant fatigue, etc., and the dry eyes may be wounded by adhering dust or the like.

  For example, when the monitor screen is watched for a long time by operating a personal computer, the number of blinks decreases, but the decrease in the number of blinks causes a decrease in tear supply on the eyeball surface and an increase in transpiration. As a result, drying of the eyeball surface, generation of tear holes, lack of oxygen, adhesion of dust, and the like occur, and the eyeball is markedly fatigued and wounded by dust.

  As described above, dry eye symptoms refer to abnormal dry conditions that occur on the surface of the eyeball and the various diseases of the eyeball that accompany it. In this field, various therapeutic agents and treatment methods have been tried (see Patent Documents 1 to 5).

However, therapeutic drugs and treatment methods are still not sufficient, and dry eye symptoms continue as a major problem to be solved for eye diseases.
JP-A-06-271478, JP 09-136932 A, JP-A-10-316574, JP 2003-63964 A, Special Table 2003-528906,

  The present invention provides an ophthalmic composition such as an ophthalmic composition effective for prevention, alleviation, and healing of dry eye symptoms, and an artificial tear composition effective also as an artificial tear.

  It is known that the use of tear fluid substitutes is effective in preventing, alleviating and healing dry eye. However, the conventionally known tear substitutes are temporarily effective, but the effect persists poorly, and they must be repeatedly instilled. Is required. The ophthalmic composition of the present invention is intended to solve such problems.

  Specifically, the present invention provides an ophthalmic composition containing poly-γ-glutamic acid as a component. That is, when the poly-γ-glutamic acid aqueous solution is instilled, it forms a stable aqueous solution film in which moisture hardly evaporates on the surface of the eyeball, such as drying of the eyeball surface, generation of tears, oxygen deficiency, dust adhesion, wounds, etc. It has been found that it has a very good effect on suppressing symptoms. Such characteristics of poly-γ-glutamic acid are far superior to conventionally known hydrophilic substances such as hyaluronic acid. Poly-γ-glutamic acid is uniformly dissolved in a molecularly dispersed state in an aqueous medium. At this time, poly-γ-glutamic acid molecular chains form an association state based on strong hydrogen bonds with a large number of water molecules. A large amount of water molecules can be included. This is synergistically combined with the effect of conformation of the poly-γ-glutamic acid molecular chain in the aqueous medium, and forms a stable aqueous solution film in which moisture hardly evaporates and is formed on the eyeball surface. Further, it has been found that poly-γ-glutamic acid does not cause rejection in the living body, activates living tissue, and has biodegradability and biocompatibility. The high compatibility and safety for the living body can not only be expected to heal the corneal lesions, but if these properties are used as a base for various healing drugs, it will have a synergistic effect complementary to other drugs. Can be planned.

  Further noteworthy is the complex formation between poly-γ-glutamic acid molecular chains and calcium ions. This complex formation suppresses the binding of calcium and glycoprotein in tear fluid. A contact lens wearer may feel strong pain in the eyeball due to precipitates formed on the eyeball surface. This precipitate is formed by the binding of calcium and glycoprotein in tear fluid, but the complex formation between poly-γ-glutamic acid molecular chain and calcium ion is thought to suppress the formation of precipitate by the above calcium and glycoprotein. . This is a great benefit for contact lens wearers.

  In addition, the use of poly-γ-glutamic acid produced by using natto bacteria that have been edible for many years by Japanese people makes the safety more reliable.

  Here, the molecular weight of poly-γ-glutamic acid will be described. The molecular weight of poly-γ-glutamic acid is 30,000 or more, preferably 50,000 or more. Speaking of the molecular weight, (1) the concentration dependence of osmotic pressure becomes smaller as the molecular weight becomes larger, so the larger molecular weight is preferable. (2) The solution viscosity increases exponentially with respect to the molecular weight, so the larger one is preferable. (3) Since the property of including water molecules in an associated state is larger and more stable as the molecular weight is larger, it is preferably larger. When these various points are comprehensively examined, the above range is preferable.

  In addition, poly-γ-glutamic acid may have a side chain carboxyl group in an acid form, a salt form, or a mixture of an acid form and a salt form. Moreover, the counter ion which forms a salt should just be a cation, for example, sodium, potassium, ammonium, calcium, magnesium, tin, zinc, copper, iron etc. are mentioned. Of course, it goes without saying that the present invention is not limited to those listed here.

  Further, if necessary, poly-γ-glutamic acid may be cross-linked within a range that does not impair its original properties. Moderate crosslinking is effective for controlling water retention, swelling, and solution viscoelasticity. As a crosslinking method, a reagent, radiation, heat, or the like can be used. Further, poly-γ-glutamic acid and crosslinked poly-γ-glutamic acid may be mixed.

  Moreover, poly-γ-glutamic acid may contain fructans. Both components are uniformly dissolved within a practical range. Fractans that exist within a range that does not impair the properties of poly-γ-glutamic acid not only dissolve uniformly, but also increase the affinity between poly-γ-glutamic acid molecular chains and water molecules. Retention is increased.

  Further, poly-γ-glutamic acid may contain hyaluronic acid. Both components are uniformly dissolved within a practical range. Hyaluronic acid present within a range that does not impair the properties of poly-γ-glutamic acid not only dissolves uniformly, but also has the effect of complementarily and synergistically improving the water retention performance of poly-γ-glutamic acid and hyaluronic acid.

  Further, poly-γ-glutamic acid may contain fructans and hyaluronic acid. Fractans and hyaluronic acid that exist within a range that does not impair the properties of poly-γ-glutamic acid not only dissolve uniformly, but also make the effect of poly-γ-glutamic acid more complementary and synergistic. it can.

Another aspect has Oite the presence of poly -γ- glutamic acid and hyaluronic acid, reagent, radiation, poly by means such as heat -γ- glutamic acid and hyaluronic acid chemically covalently coupled to form a substance (e.g., graft polymer) Substitution or partial replacement significantly improves the stability of both components in the solution state and the retention of hyaluronic acid on the corneal surface, and the characteristics of both can be complementarily and synergistically exhibited.

Eye pharmaceutical compositions of the present invention, Oite the extent that the effect of the present invention is not impaired carbohydrate used in ordinary ophthalmic formulations, electrolytes, amino acids, vitamins, lipids, pharmaceutical additives, various drugs, etc. Ingredients may be included. For example, glucose, maltose, oligosaccharide, sodium chloride, calcium chloride, magnesium sulfate, glycine, alanine, thiamine hydrochloride, riboflavin phosphate, nicotinamide, folic acid, biotin, vitamin A, L-ascorbic acid and derivatives thereof. You may combine them.

  Similarly, additives such as a buffer, a stabilizer, a tonicity agent, a pH adjuster, a thickener, and a surfactant can be contained. For example, sodium phosphate, sodium acetate, borate, citrate, tartrate, amino acid, etc. as buffering agents, sodium chloride (salts), glycerin, polyethylene glycol, propylene glycol, sorbitol, mannitol as isotonic agents (Polyhydric alcohol), etc., and preservatives and preservatives such as benzalkonium chloride, benzathonium chloride, methyl paraoxybenzoate, ethyl paraoxybenzoate, benzyl alcohol, phenethyl alcohol, thimerosal, chlorobutanol, etc. There are polyvinyl pyrrolidone, polyvinyl alcohol, polysorbate, hydroxyethyl cellulose, hydroxybutyl cellulose, carboxymethyl cellulose and the like as agents, and hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide as pH adjusters. , Potassium hydroxide, there is ammonium hydroxide and the like, there are various surfactants.

  The concentration of the aqueous solution, that is, the ophthalmic composition of the present invention is not particularly limited as long as there is no problem in use, but it is 0.0001% w / v to 10% w / v, preferably 0.001% w / v. To 1.0% w / v. The pH is 4 to 8, preferably 6.5 to 7.5. The osmotic pressure is 0.5 to 4.0 pressure ratio, preferably 0.95 to 1.5 pressure ratio.

  The usage and dose of the ophthalmic composition of the present invention are not particularly limited as long as there is no problem in use. The same applies to eye washing.

  Needless to say, the composition of the present invention is effective as an immersion liquid for the preservation and storage of contact lenses or the maintenance of properties during use. Moreover, it goes without saying that the present invention can be used as an ophthalmic gel or ophthalmic ointment if necessary.

  The ophthalmic composition comprising the poly-γ-glutamic acid of the present invention as a component is a dry eye ophthalmic composition effective for prevention, alleviation and healing of dry eye and / or an artificial long-lasting effect as a tear substitute. A composition for tears can be obtained.

  That is, when the poly-γ-glutamic acid aqueous solution is instilled, it forms a stable aqueous solution film that is less likely to evaporate on the cornea surface, such as drying of the cornea surface, generation of tears, lack of oxygen, dust adhesion, wounds, etc. It has an excellent effect on suppressing symptoms.

  In addition, poly-γ-glutamic acid does not cause a rejection reaction in the living body, has activation of living tissue, biodegradability, and biocompatibility, and can be expected to be a healing action for a damaged corneal part and a solution due to long-term continuous damage. In addition, if poly-γ-glutamic acid having such properties is used as a base for various healing agents, a complementary synergistic effect with the healing agent can be expected.

  It also has the effect of suppressing the formation of precipitates due to the binding of calcium and glycoprotein, which is a causative substance of strong pain in the eyeball affected by contact lens wearers.

  The contents and effects of the present invention will be described below, but it goes without saying that the present invention is not limited to the examples shown here.

<Reference Example 1>
Evaluation of liquid film retention of ophthalmic solution: Liquid film retention on the corneal surface was evaluated by the following method. That is, using a highly hydrogel soft contact lens (SCL) as a model material of the cornea, the transpiration of water is evaluated from the change over time of the amount of ophthalmic solution dropped onto the SCL, and the state change of the droplet film on the SCL surface From the observation, the formability and stability were evaluated under the following conditions.

(1) SCL: Commercially available SCL (for 1 day) was used. Selection was made with attention to water content, oxygen permeation, and affinity with the cornea.

(2) Water retention amount: Set a square Teflon (registered trademark) sheet dish with a square of 25 mm on each side of a precision balance on the top of a precision balance. Place on the pan and immediately weigh. Next, 20 μL of eye drop solution is dropped onto the center of the SCL, and the weight immediately after dropping and after standing for 20 minutes is measured. After repeating this operation 20 μL × 4 times, that is, 80 minutes after the first 20 μL was dropped, the weight change was measured from the weight of the ophthalmic solution after 80 minutes, 120 minutes, 150 minutes, and 180 minutes. The weight of the ophthalmic solution was a value obtained by subtracting the SCL weight when taken out from the stock solution from the total weight at each time passage. The measurement was performed at a temperature of 25 degrees and a humidity of 50%.

(3) Formability and stability of liquid film: Qualitative characteristics of liquid film formability, stability, and transparency by observing liquid film formation state and surface reflected light and transmitted light states using a reading microscope and a stereomicroscope. Evaluation.

(4) Preparation of ophthalmic solution: poly-γ- in which the ratio of acid type and sodium salt type of the side chain carboxyl group is 80/20 (sample A), 50/50 (sample B), and 0/100 (sample C) Glutamic acid (molecular weight 3 million) was prepared. Using this poly-γ-glutamic acid, aqueous ophthalmic solutions shown in Table 1 were prepared. Comparative sample 1 is a basic solution to which samples A, B, and C are not added.

  Sample A, Sample B, and Sample C were prepared to 100 mL using sterilized purified water. It may be warmed slightly if necessary to ensure complete dissolution. Sample A, Sample B, and Sample C were all transparent and stable. For comparison, commercial dry eye drops were also measured. The molecular weight of poly-γ-glutamic acid was measured by high performance liquid chromatography using polyethylene oxide as a calibration standard. The molecular weights in other examples were also measured by the same method.

有意差検定はｓｔｕｄｅｎｔ ｔ−ｔｅｓｔを行いｐ＜０．０５で有意であった。 Verification of effect: SCL water retention was measured by the method described in “Evaluation of liquid film retention of ophthalmic solution”, and SCL water retention was changed over time by relative ratio with water retention after 80 minutes being 100. Is shown in Table 2. When samples A, B, and C were compared with comparative sample 1 and commercially available dry eye eye drops, transpiration of water was clearly suppressed in the liquid film of the eye drop solution containing poly-γ-glutamic acid, and was observed with a microscope. It has good liquid film formability and stability, and is effective as a long-lasting ophthalmic composition and / or long-lasting artificial tear composition effective in preventing, alleviating and healing dry eye. Is recognized.

The significant difference test was student t-test and was significant at p <0.05.

The aqueous ophthalmic solution was tested for drug intraocular performance. Measurement is conducted under Polymer Chemistry Laboratory Volume 8 under Polymer Chemistry p. 151 (1958) modified for liquid measurement was used. The isolated porcine cornea was attached to the membrane wearing part of the device. The sample solution portion partitioned by the cornea was filled with sample A, sample B, sample C, and comparative sample 1 in Table 1 in which 0.01% w / v of the model drug fluorescein sodium was added to obtain a test ophthalmic solution (6 mL). Fluorescein sodium was uniformly dissolved in all four test eye drops. The receiving solution portion was filled with model intraocular perfusate (glucose 150 mg, sodium chloride 660 mg, potassium chloride 36 mg, calcium chloride 18 mg, magnesium sulfate 30 mg, sodium bicarbonate 210 mg, pH 7.2, osmotic pressure ratio 1.01) (6 mL). . In this state, the amount of sodium fluorescein in the model intraocular perfusate was measured in the receiving solution part after 3 hours. The measurement was performed at 37 ° C. Table 3 shows the amount of sodium fluorescein in the model intraocular perfusate of the receiving solution after 3 hours. It can be confirmed that the drugs A, B, and C have superior intraocular transfer properties compared to Comparative Sample 1.

  In addition, a cross-sectional section of the corneal piece was cut out and the permeation diffusion state of the model drug from the corneal surface to the inner layer direction was observed with a fluorescence microscope. It was confirmed that all model drugs showed intraocular transferability at the site.

  Sample A, sample B, and sample C were dropped on the surface of the porcine cornea and observed with a microscope. This was a qualitative determination, but the liquid film formation and stability were considered to be comparable to those for SCL. It was.

<Reference Example 2>
Preparation of ophthalmic solution: Poly-γ-glutamic acid having a side chain carboxyl group of sodium salt type molecular weight of 30,000 (sample A), 50,000 (sample B), 300,000 (sample C), and 3 million (sample D) The aqueous ophthalmic solution shown in Table 4 was prepared using this solution. Comparative sample 2 is a basic solution to which samples A, B, C, and D are not added.

  Sample A, Sample B, Sample C, and Sample D were prepared to 100 mL using sterilized purified water. It may be warmed slightly if necessary to ensure complete dissolution. Sample A, Sample B, Sample C, and Sample D were all transparent and stable. For comparison, commercial dry eye drops were also measured.

有意差検定はｓｔｕｄｅｎｔ ｔ−ｔｅｓｔを行いｐ＜０．０５で有意であった。 Verification of effect: SCL water retention was measured by the method described in “Evaluation of liquid film retention of ophthalmic solution”, and SCL water retention was changed over time by relative ratio with water retention after 80 minutes being 100. Is shown in Table 5. When samples A, B, C, and D are compared with comparative sample 2 and commercially available eye drops, the transpiration of water is clearly suppressed in the liquid film of the eye drop solution containing poly-γ-glutamic acid, and the liquid film observed with a microscope is also observed. It has good formability and stability, and it is recognized that it is effective as a long-lasting ophthalmic composition and / or long-lasting artificial tear composition effective in preventing, alleviating, and healing dry eye. .

The significant difference test was student t-test and was significant at p <0.05.

Sansei
<Reference Example 3>
Preparation of ophthalmic solution: Poly-γ-glutamic acid having a molecular weight of 3 million was prepared, wherein the ratio between the acid type and sodium salt type of the carboxyl group of the side chain was 100/0 (sample A) and 20/80 (sample B). Using this poly-γ-glutamic acid, aqueous ophthalmic solutions shown in Table 6 were prepared. Poly-γ-glutamic acid was produced from a commercially available natto bacterium.

Production method of poly-γ-glutamic acid: A sticky material on the surface of commercially available natto was collected with a platinum loop and suspended in sterilized water, placed on an agar medium, and cultured at 37 ° C. for 24 hours. The most stringy colony was collected from these, sporulated, and cultured in a culture solution adjusted to pH mainly composed of sodium glutamate and glucose according to a conventional method. After the culture, purification was performed by alcohol precipitation, dialysis, and lyophilization.

  Sample A and sample B solutions were prepared to 100 mL using sterilized purified water. It may be warmed slightly if necessary to ensure complete dissolution. Each solution of Sample A and Sample B was transparent and stable. For comparison, commercial dry eye drops were also measured.

有意差検定はｓｔｕｄｅｎｔ ｔ−ｔｅｓｔを行いｐ＜０．０５で有意であった。 Verification of effect: The water retention amount of SCL was measured by the method described in “Evaluation of liquid film retention of eye drop solution”, and the stability of the liquid film was observed. Table 7 shows changes with time of the SCL water retention amount in terms of relative ratio, with the water retention amount after 80 minutes from the first drop being 100. When samples A and B are compared with comparative sample 3 and commercially available eye drops, the transpiration of water is clearly suppressed in the liquid film of an eye drop solution containing poly-γ-glutamic acid, and the liquid film formation and stability observed with a microscope It is recognized that the composition is an ophthalmic composition having a long duration and / or a composition for artificial tears having a long duration effective for prevention, alleviation and healing of dry eye.

The significant difference test was student t-test and was significant at p <0.05.

  When this solution was used as a contact lens storage immersion solution or an immersion solution for a detached contact lens, it did not change in long-term storage under normal room temperature conditions, and no deterioration of the contact lens was observed. It was also observed that contact lenses had good affinity and drying of contact lenses was extremely slow.

  Furthermore, it is possible to easily prepare gels and ointments by slightly increasing the concentration of poly-γ-glutamic acid or adding a small amount of thickener, and preparing an ointment by adding a thickener or emulsifier It was also possible to do.

<Reference Example 4>
Preparation of eye drop solution: poly-γ-glutamic acid (molecular weight 2.5 million) is dispersed and dissolved in tetrahydrofuran at a concentration of 5 g / 100 mL. To this was added 1/50 equivalent of carbodiimide per structural unit of poly-γ-glutamic acid to crosslink poly-γ-glutamic acid. After the reaction, tetrahydrofuran was removed, and further washed with an acidic aqueous solution and pure water to completely remove the unreacted reagent from poly-γ-glutamic acid. Poly-γ-glutamic acid was then prepared into the sodium salt. Using this, the aqueous ophthalmic solutions shown in Table 8 were prepared.

  The sample A solution was prepared to 100 mL using sterilized purified water. It may be warmed slightly if necessary to ensure complete dissolution. Sample A solution was clear and stable. For comparison, commercial dry eye drops were also measured.

有意差検定はｓｔｕｄｅｎｔ ｔ−ｔｅｓｔを行いｐ＜０．０５で有意であった。 Verification of effect: The water retention amount of SCL was measured by the method described in “Evaluation of liquid film retention of eye drop solution”, and the stability of the liquid film was observed. Table 9 shows the time variation of the SCL water retention amount as a relative ratio, with the water retention amount after 80 minutes from the first drop being 100. When sample A is compared with comparative sample 4 and commercially available eye drops, the transpiration of water is clearly suppressed in the liquid film of the eye drop solution containing poly-γ-glutamic acid, and the formation and stability of the observed liquid film are good. It is recognized that the composition is an ophthalmic composition having a long duration and / or a composition for artificial tears having a long duration effective for prevention, alleviation and healing of dry eye.

The significant difference test was student t-test and was significant at p <0.05.

Preparation of aqueous ophthalmic solution composed of poly-γ-glutamic acid containing fructan: 90% by mass of sodium poly-γ-glutamate (molecular weight 3 million) purified by alcohol precipitation, dialysis and freeze-drying from the culture solution and 10% by mass of purified fructan A 0.1 g / 100 mL solution was prepared in the same manner as in Reference Examples 1 to 4 using sterilized purified water as a solvent. Poly-γ-sodium glutamate and fructan were compatible with each other, and a stable homogeneous solution was obtained. This was designated as Sample A shown in Table 10.

Preparation of aqueous ophthalmic solution composed of poly-γ-glutamic acid containing hyaluronic acid: 90% by mass of sodium poly-γ-glutamate (molecular weight 3 million) purified by alcohol precipitation, dialysis and freeze-drying from the culture solution and purified sodium hyaluronate 10 A 0.1 g / 100 mL solution was prepared in the same manner as in Reference Examples 1 to 4 by mixing mass% and using sterile purified water as a solvent. Poly-γ-sodium glutamate and sodium hyaluronate were compatible and stable homogeneous solutions were obtained. This was designated as Sample B shown in Table 10.

Preparation of aqueous ophthalmic solution containing a cross-linked polymer in which poly-γ-glutamic acid and hyaluronic acid are covalently bonded: (1) Cross-linking reaction of poly-γ-glutamic acid / hyaluronic acid: purified from the culture solution by alcohol precipitation, dialysis, and freeze-drying 80% by weight of poly-γ-glutamate sodium (molecular weight: 3 million) and 20% by weight of purified sodium hyaluronate were mixed, and 0.5 g / 100 mL of solution was prepared in the same manner as in Reference Examples 1 to 4 using sterile purified water as a solvent. Prepared. Poly-γ-sodium glutamate and sodium hyaluronate were compatible and stable homogeneous solutions were obtained. This solution was freeze-dried and then pulverized at liquid nitrogen temperature to prepare a powdered solid. 1 g of this poly-γ-glutamic acid / hyaluronic acid mixture was sealed in a glass ampoule and irradiated with 5 Mrad of gamma rays. Cobalt 60 was used as the radiation source. Here, it goes without saying that it is possible to directly irradiate a mixed solution of sodium poly-γ-glutamate and sodium hyaluronate with gamma rays. This gamma-irradiated solid was dissolved in sterilized purified water, and then a volume of dimethyl sulfoxide equal to that of purified water was added. This solution was homogeneous and the concentration was 0.3 g / 100 mL. Furthermore, the total amount of purified water and dimethyl sulfoxide and twice the volume of ethanol were added to this solution to make 0.1 g / 100 mL. Free poly-γ-glutamate sodium precipitated by addition of ethanol. The precipitate was collected by filtration and the solution was freeze-dried to obtain a solid sample. The same purification operation was repeated until no precipitation occurred, and poly-γ-glutamic acid not bound to hyaluronic acid was separated. Although it is difficult to accurately determine the amount of cross-linking reaction between poly-γ-glutamic acid and hyaluronic acid, the infrared spectrum of poly-γ-glutamic acid together with hyaluronic acid (NH stretching vibration, amide I, II, III) Absorption) and both substances are thought to be crosslinked by covalent bonds.

(2) Preparation of aqueous ophthalmic solution containing poly-γ-glutamic acid / hyaluronic acid cross-linked polymer: 0.1 g / in the same manner as in Reference Examples 1 to 4 using the above-mentioned gamma-irradiated solid powder as a solvent and sterilized purified water as a solvent. A 100 mL solution was prepared. The solution was stable and uniform. This was designated as Sample C shown in Table 10. Here, poly-γ-glutamic acid, fructan, hyaluronic acid ternary component and poly-γ-glutamic acid, fructan, hyaluronic acid, poly-γ-glutamic acid / hyaluronic acid crosslinked polymer four components are mixed and mixed as necessary. It is possible to obtain a stable and homogeneous solution.

  Sample A, Sample B, and Sample C were prepared to 100 mL using sterilized purified water. It may be warmed slightly if necessary to ensure complete dissolution. Sample A, Sample B, and Sample C were all transparent and stable. For comparison, commercial dry eye drops were also measured.

  Verification of effect: The water retention amount of SCL was measured by the method described in “Evaluation of liquid film retention of eye drop solution”, and the stability of the liquid film was observed. The water retention amount after 80 minutes from the first addition is defined as 100, and the relative ratio is shown in Table 10. In the liquid film of the ophthalmic solution containing poly-γ-glutamic acid on the SCL surface, the transpiration of water is suppressed and the observed liquid film stability is good and the duration is long, as is clear when compared with the control. It is recognized that the composition is an eye drop composition and / or an artificial tear composition that is effective in preventing, alleviating, and healing dry eye as a tear substitute.

有意差検定はｓｔｕｄｅｎｔ ｔ−ｔｅｓｔを行いｐ＜０．０５で有意であった。 Verification of effect: The water retention amount of SCL was measured by the method described in “Evaluation of liquid film retention of eye drop solution”, and the stability of the liquid film was observed. Table 11 shows the time variation of the SCL water retention amount as a relative ratio with the water retention amount after 80 minutes from the first drop being 100. When samples A, B, and C are compared with comparative sample 5 and commercially available eye drops, transpiration of water is clearly suppressed in the liquid film of the eye drop solution containing poly-γ-glutamic acid, and the formation and stability of the observed liquid film It is recognized that the composition is an ophthalmic composition having a long duration and / or a composition for artificial tears having a long duration effective for prevention, alleviation and healing of dry eye.

The significant difference test was student t-test and was significant at p <0.05.

Claims (9)

An ophthalmic composition comprising poly-γ-glutamic acid as a component , wherein the ophthalmic composition comprises fructan . The ophthalmic composition according to claim 1, wherein the poly-γ-glutamic acid comprises poly-γ-glutamic acid, which is an acid form, a salt form, a mixed form of acid and salt, a cross-linked product or a mixture thereof, as a component. The ophthalmic composition according to claim 1 or 2, comprising hyaluronic acid . The ophthalmic composition according to any one of claims 1 to 3, wherein the molecular weight of poly-γ-glutamic acid is 30,000 or more . The ophthalmic composition according to any one of claims 1 to 4, wherein the poly-γ-glutamic acid comprises poly-γ-glutamic acid obtained by culture of Bacillus natto . The ophthalmic composition according to any one of claims 1 to 5, comprising poly-γ-glutamic acid hyaluronic acid in which poly-γ-glutamic acid and hyaluronic acid are bound . A contact lens immersion liquid comprising the ophthalmic composition according to any one of claims 1 to 6 . An ophthalmic gel comprising the ophthalmic composition according to any one of claims 1 to 6 . An ophthalmic ointment comprising the ophthalmic composition according to any one of claims 1 to 6 .