JP2008255061A - Soluble cross-linked hyaluronic acid-containing ophthalmic composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an ophthalmic composition more excellent in the protecting effect of epithelial layer of cornea and lasting property (retentivity of the principal agent inter fluid) than those of conventional hyaluronic acid eye drops. <P>SOLUTION: This ophthalmic composition contains a soluble cross-linked hyaluronic acid and a medicinally acceptable carrier. The soluble cross-linked hyaluronic acid is obtained by using hyaluronic acid having ≥5,000 and <100,000 average-molecular weight as a raw material and cross-linking by using 0.01 to 3.0 equivalent cross-linking agent based on the constituting disaccharide unit of the raw material hyaluronic acid. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an ophthalmic composition containing a soluble cross-linked hyaluronic acid, particularly a corneal protective agent.

  With the advent of an aging society and the overuse of eyes accompanying the spread of office automation equipment such as televisions, word processors, and personal computers, it is expected that the number of patients with dry eyes, that is, symptoms or symptoms of dry eyes will increase. . Dry eye is a disease in which the surface of the eye dries out due to a decrease in tears and qualitative changes in its components, resulting in damage such as scratches. The eyes become painful, tired, blinking, and white eyes Is accompanied by symptoms of hyperemia. In addition, bacteria may enter from the wound and be infected, or the wound may become deep and the visual acuity may decrease. Causes of dry eye include various side effects such as Sjogren's syndrome, Stevens-Johnson syndrome, eye burns and trauma, antihypertensive agents, tranquilizers, and eye drops for the treatment of glaucoma. It is. Eye drops are effective for the treatment of dry eye. Currently, eye drops for the treatment of dry eye mainly composed of hyaluronic acid are attracting attention and are often used.

  Hyaluronic acid is a high-molecular substance derived from living organisms, has high physical properties such as high viscosity, viscoelasticity and spinnability, and extremely high water retention, and is used as a moisturizing agent in various skin external preparations. Yes. At present, eye drops mainly composed of hyaluronic acid have attracted attention and are often used. For example, Japanese Patent Application Laid-Open No. Sho 62-64802 (Patent Document 1) discloses a derivative of hyaluronic acid, specifically, hyaluronic acid in which a carboxyl group is partially esterified, which is effective as a drug carrier in ophthalmic drugs. It suggests. However, it has not been confirmed that an ophthalmic drug containing such a carboxyl group-partially esterified hyaluronic acid derivative as a carrier is effective for an ophthalmic composition for dry eye that requires a long-term water retention effect. JP-A-1-238530 (Patent Document 2) discloses a corneal epithelial layer disorder therapeutic agent containing hyaluronic acid. However, since the residence time of hyaluronic acid on the cornea is relatively short, the patient is frequently burdened with frequent eye drops.

  Therefore, an ophthalmic composition that can maintain an effect for a long period of time, and as a result, can reduce the number of instillations and improve a patient's QOL (Quality of Life) is desired. In particular, in the case of dry eye in Sjögren's syndrome, which shows symptoms such as dryness of the whole body, it is effective only for instillation of this hyaluronic acid-containing eye drop for mild symptoms, but when symptoms are severe, hyaluronic acid eye drop of Instillation does not provide a sufficient effect, and treatment such as lacrimal passage closure with a punctal plug may be used in combination.

JP-A-62-64802 JP-A-1-238530

  An object of the present invention is to provide a highly useful ophthalmic composition that is superior in the protective effect of the corneal epithelial layer and its durability (maintenance of the main drug in tears) as compared with conventional hyaluronic acid eye drops.

  Surprisingly, when the present inventor used cross-linked hyaluronic acid as an ophthalmic composition, the soluble cross-linked hyaluronic acid showed an excellent corneal protective effect compared to hyaluronic acid and acetylated hyaluronic acid derivatives, and It was found that the retention after instillation was also excellent.

  Accordingly, the present invention provides an ophthalmic composition, particularly a corneal protectant, comprising a soluble cross-linked hyaluronic acid and a pharmaceutically acceptable carrier. Preferably, the soluble crosslinked hyaluronic acid is made from hyaluronic acid having an average molecular weight of 5,000 or more and less than 100,000, and 0.01 to 3.0 equivalents of a crosslinking agent is used with respect to the constituent disaccharide units of the raw material hyaluronic acid. Or a hyaluronic acid having an average molecular weight of 100,000 or more and 3,000,000 or less as a raw material, and a cross-linking agent is 0.01 or more and 0.5 or more with respect to the constituent disaccharide units of the raw material hyaluronic acid. Cross-linked by using less than equivalent amount. In a preferred embodiment, such an ophthalmic composition is utilized for the treatment or prevention of dry eye, and in a more preferred embodiment it is a dry eye drop.

  By using soluble cross-linked hyaluronic acid, it is possible to provide an ophthalmic composition that has an excellent corneal protective effect as compared with hyaluronic acid-containing ones and that remains on the cornea for a longer period of time and exhibits the protective effect.

  The soluble crosslinked hyaluronic acid according to the present invention can be prepared by crosslinking hyaluronic acid, a derivative thereof or a salt thereof with a crosslinking agent. The term “hyaluronic acid” as used in the present invention includes not only its free form but also its salt such as a salt formed with a cation such as sodium ion or potassium ion, or a derivative thereof such as acetylated hyaluronic acid. Include. The cross-linking agent to be used is not particularly limited, but is not particularly limited as long as it has a function of cross-linking hyaluronic acid molecules and can be sufficiently removed by a washing step. For example, an ether, ester or amide bond It is possible to use a difunctional or polyfunctional conventionally known cross-linking agent that yields. As the crosslinking agent, di- or polyfunctional epoxides are preferably used in the present invention. Specific examples of the di- or polyfunctional epoxide include 1,4-butanediol diglycidyl ether, ethylene glycol diglycidyl ether, glycerol diglycidyl ether, glycerol triglycidyl ether, and the like. To 1,4-butanediol diglycidyl ether is preferably used.

  The crosslinked hyaluronic acid according to the present invention is considered to exhibit a cornea protecting effect on the condition that it is “soluble” in an aqueous medium. That is, when the crosslinked hyaluronic acid has low solubility and a precipitate is formed remarkably when it is dissolved / dispersed in an aqueous medium, it is considered that a sufficient corneal protective effect cannot be expected. Therefore, the relationship between the crosslinking agent and the raw material hyaluronic acid molecular weight that affects the solubility of the crosslinked hyaluronic acid is preferably set such that the larger the raw material molecular weight, the smaller the amount of the crosslinking agent, that is, the lower the crosslinking rate. For example, when the average molecular weight of the raw material hyaluronic acid is a relatively high molecular weight of about 100,000 to 3,000,000, the amount of the crosslinking agent used is 0.01 to 0.00 with respect to the constituent disaccharide units of the raw material hyaluronic acid. By setting the amount to about 50 molar equivalents, preferably about 0.01 to 0.10 molar equivalents, it is possible to suppress the formation of precipitates of crosslinked hyaluronic acid, and an excellent corneal protective effect can be expected. When the raw material hyaluronic acid has a relatively low average molecular weight of about 5,000 to 100,000, the amount of the crosslinking agent used is 0.01 to 3.00 mol with respect to the constituent disaccharide units of the raw material hyaluronic acid. By setting the equivalent amount, preferably in the range of about 0.01 to 0.50 molar equivalent, the formation of a crosslinked hyaluronic acid precipitate can be suppressed, and an excellent corneal protective effect can be expected.

FIG. 1 shows the relationship between the amount of the crosslinking agent and the molecular weight of the raw material hyaluronic acid that affects the solubility of the crosslinked hyaluronic acid. The cross-linking agent molar equivalent in the chart of the figure = 616 × (MW) ^−0.639 The conditions belonging to the region below the straight line are the amount of the cross-linking agent and the molecular weight (MW) of the raw material hyaluronic acid (HA). When satisfied (soluble cross-linked HA region), the resulting cross-linked hyaluronic acid is soluble. In short, the obtained crosslinked hyaluronic acid is soluble when the following formula is satisfied.
Cross-linking agent molar equivalent ≦ 616 × (MW) ^-0.639
The molecular weight MW of the raw material hyaluronic acid can be calculated by an intrinsic viscosity measurement method.

A method for preparing the crosslinked hyaluronic acid is well known to those skilled in the art and is not particularly limited. For example, the method can be carried out as follows. First, the raw material hyaluronic acid is dissolved in a basic aqueous solution, then a crosslinking agent is added, and stirring is performed for an appropriate time. The cross-linking reaction conditions depend on the molecular weight of the raw material hyaluronic acid and the amount of the cross-linking agent to be used. For example, the reaction is carried out at 25 ° C. for 1 to 5 days, preferably 2 to 3 days. The produced crosslinked hyaluronic acid is taken out and dissolved in physiological saline or the like, and the pH is adjusted to about 6 to 8 if necessary. When the produced crosslinked hyaluronic acid is in a gel form, it is washed with physiological saline or the like to swell the gel, and the pH is adjusted to about 6 to 8 if necessary. The gel-like crosslinked hyaluronic acid can be crushed using a Teflon (registered trademark) homogenizer or the like to form a solution. In this case, soluble cross-linked hyaluronic acid can be obtained by putting the gel into a homogenizer container and treating it in cold water at, for example, 3,000 rpm for 20 minutes.
Confirmation of the solubility of the crosslinked hyaluronic acid can be achieved, for example, by adding an alcian blue aqueous solution to the physiological saline solution of the crosslinked hyaluronic acid at various concentrations or the physiological saline solution of the crosslinked hyaluronic acid prepared under each condition of the amount of the crosslinking agent. After mixing, it can be performed by centrifuging and confirming the presence or absence of the precipitate after separation.

  It is considered that the soluble cross-linked hyaluronic acid of the present invention covers the cornea and exhibits a cornea protecting effect by preventing damage due to drying of the cornea. The ophthalmic composition of the present invention is a corneal epithelial disorder such as keratitis caused by dryness, particularly dry eye treatment / prevention, bacterial corneal infection, corneal fungal evidence, amoeba keratitis, herpes cornea It is effective in the treatment and prevention of corneal herpes, cataract surgery, corneal transplantation, surgical invasion in brain surgery, and the treatment of prolonged corneal defects associated with diabetes. The ophthalmic composition of the present invention is used as dosage forms such as eye drops, eye cleansing agents, eye ointments and the like.

  The content of the crosslinked hyaluronic acid in the ophthalmic composition of the present invention is 0.001 to 10 mass / volume (mass)%, preferably 0.01 to 5 based on the total volume (or total mass) of the protective agent. The mass / volume (mass)%, more preferably 0.03-1 mass / volume (mass)%. The cross-linked hyaluronic acid concentration means mass / volume (w / v)% in the case of liquid eye drops and eye cleansing agents, and mass / mass (w / w) in the case of solid eye ointments. ) Means%.

  The pH of the ophthalmic composition of the present invention is preferably in the vicinity of neutrality, and is usually 6.5 to 7.5. The osmotic pressure is preferably adjusted to about 0.5 to 4.0 pressure ratio with respect to physiological saline, and more preferably 1.0 to 1.5 pressure ratio. Means commonly used for eye drops are used to adjust pH and osmotic pressure.

  The ophthalmic composition of the present invention can be used in combination with a conventional pharmaceutically acceptable carrier depending on the dosage form. The carrier for eye drops and eye cleansing agents may be any carrier used for conventional eye drops and eye cleansing agents, and purified water is preferred.

  The ophthalmic composition of the present invention may optionally contain various components such as carbohydrates other than crosslinked hyaluronic acid, electrolytes, amino acids, vitamins, lipids, pharmaceutical additives, and pharmaceuticals. Examples of such ingredients include, for example, sugars such as glucose, maltose, oligosaccharides, mannitol, sugar alcohols such as sorbitol; electrolytes such as sodium chloride, sodium hydrogen phosphate, potassium chloride, magnesium sulfate, chloride Amino acids such as glycine and alanine; vitamins such as thiamine hydrochloride, sodium riboflavin phosphate, pyridoxine hydrochloride, nicotinamide, folic acid, biotin, vitamin A, L-ascorbic acid, α-glycosyl ascorbic acid and the like These derivatives may be mentioned, and these may be combined in combination as necessary.

  In addition, additives used in normal eye drops and eye cleansing agents, such as preservatives such as methyl parahydroxybenzoate, sodium dehydroacetate, benzalkonium chloride, etc .; stabilizers such as sodium edetate, sodium bisulfite, etc. Buffering agents such as borax, boric acid, sodium hydrogen carbonate, etc .; thickeners such as methyl cellulose, carboxymethyl cellulose, chondroitin sulfate, polyvinyl alcohol, pullulan, etc .; solubilizers such as polysorbate 80 may be added. .

  When the ophthalmic composition of the present invention is an ophthalmic ointment, a conventional pharmaceutically acceptable ointment carrier can be used, and specific examples thereof include ophthalmic white petrolatum, plastibase and the like. As an additive, liquid paraffin or the like may be used. Furthermore, the ophthalmic composition of the present invention includes, as necessary, steroid hormones such as methylprednisolone, anti-inflammatory agents such as tetracycline, antibiotics such as penicillin G, immunosuppressive agents such as cyclosporine, and immunomodulators. Further, pharmaceuticals such as analgesics, autologous serum and hyaluronic acid may be combined in an appropriate combination.

  The dosage and administration of the ophthalmic composition of the present invention can be appropriately adjusted according to the patient's symptoms. In the case of eye drops, it is usually sufficient to apply one drop, for example, about 1 to 3 drops, once to several times a day, for example 1 to 6 times, preferably about 1 to 3 times a day. In the case of an eye cleansing agent, it may be washed once to several times a day, for example, 1 to 6 times, preferably about 1 to 3 times a day, using an eye washing container or a washing bottle. In the case of an eye ointment, an appropriate amount may be applied to the conjunctival sac about 1 to 3 times a day.

  The following non-limiting examples of the present invention are provided.

Preparation of Crosslinked Hyaluronic Acid A basic aqueous solution was prepared by adding 0.625 ml of 2N sodium hydroxide solution to 10.875 ml of purified water, and 1 g of hyaluronic acid was added thereto and dissolved. As hyaluronic acid, three types having molecular weights of about 88,000, molecular weights of about 30,000 and about 860,000 were used. A crosslinking agent (1,4-butanediol diglycidyl ether) was added to this hyaluronic acid solution, and the mixture was stirred for about 1 hour. The addition amount of the crosslinking agent was 0.01, 0.03, 0.1, 0.3, 0.5, and 1.0 molar equivalents per 1 mol of the raw material hyaluronic acid. This solution was subjected to a crosslinking reaction at 25 ° C. for 72 hours, and then washed with physiological saline to prepare crosslinked hyaluronic acid.
The gel-like crosslinked hyaluronic acid was crushed using a Teflon (registered trademark) homogenizer (DIGITAL HOMOGENIZER, HOM type, manufactured by Iuchi Seieido). The gel was put into a homogenizer container and treated in cold water at 3000 rpm for 20 minutes to obtain a crosslinked hyaluronic acid crushed gel.

Confirmation of solubility of crosslinked hyaluronic acid About 10 g each of physiological saline solution of crosslinked hyaluronic acid at various concentrations or physiological saline solution containing 0.3% of crosslinked hyaluronic acid prepared under each condition of the crosslinking agent After adding 200 μL of 0.1% alcian blue solution and shaking well, the mixture was centrifuged at 4000 rpm for 2 minutes to confirm the presence of precipitate after separation.
The results are shown in the following table.

この表から明らかなとおり、原料ヒアルロン酸分子量が大きいほど（約８６万）、架橋率を変えることで可溶性の受ける影響は大きいことがわかる。
図１には架橋ヒアルロン酸の可溶性に及ぼす架橋剤量と原料ヒアルロン酸分子量との関係を示す。図の座表中の架橋剤モル当量＝616×（ＭＷ）^-0.639の式で表される直線よりも下方の領域に属する条件を架橋剤量及び原料ヒアルロン酸（ＨＡ）の分子量（ＭＷ）が満たす場合（可溶性架橋ＨＡ領域）、得られる架橋ヒアルロン酸は可溶性である。要するに、以下の式を満たす場合、得られる架橋ヒアルロン酸は可溶性である。
架橋剤モル当量≦616×（ＭＷ）^-0.639
尚、原料ヒアルロン酸の分子量ＭＷは極限粘度測定法により算出することができる。

As is clear from this table, it can be seen that the greater the raw material hyaluronic acid molecular weight (approximately 860,000), the greater the influence of solubility by changing the crosslinking rate.
FIG. 1 shows the relationship between the amount of the crosslinking agent and the molecular weight of the raw material hyaluronic acid that affects the solubility of the crosslinked hyaluronic acid. The cross-linking agent molar equivalent in the chart of the figure = 616 × (MW) ^−0.639 The conditions belonging to the region below the straight line are the amount of the cross-linking agent and the molecular weight (MW) of the raw material hyaluronic acid (HA). When satisfied (soluble cross-linked HA region), the resulting cross-linked hyaluronic acid is soluble. In short, the obtained crosslinked hyaluronic acid is soluble when the following formula is satisfied.
Cross-linking agent molar equivalent ≦ 616 × (MW) ^-0.639
The molecular weight MW of the raw material hyaluronic acid can be calculated by an intrinsic viscosity measurement method.

Experimental Method of Protecting Effect of Crosslinked Hyaluronic Acid on Corneal Epithelial Layer <Experiment 1: Comparative Test Method of Hyaluronic Acid, Acetylated Hyaluronic Acid, and Crosslinked Hyaluronic Acid>
As a specimen, a hybrid pig-extracted eyeball slaughtered for meat on the day of the experiment was purchased from Tokyo Shibaura Organ Co., Ltd. The test solutions were physiological saline, 0.3% hyaluronic acid (HA) solution (molecular weight about 860,000), 0.3% acetylated hyaluronic acid (AcHA) solution (molecular weight about 30,000), and 0.3% cross-linked hyaluronic acid. (Cross-linked HA) (raw material hyaluronic acid: molecular weight of about 860,000, cross-linked 0.1 molar equivalent) was used as test groups. In addition, an air-dried group was set in which the administration solution was not instilled and only dried indoors. The test was conducted in a constant temperature / humidity chamber (25 ° C., relative humidity 50%).

  The extracted eyeball was instilled with 50 μL of the test solution every 60 minutes for a total of 4 times, and air-dried for another 60 minutes from the final instillation. This was instilled with 0.1% methylene blue solution to stain cells damaged by drying, and the eyeball was further washed with physiological saline. Next, the cornea was collected from the eyeball, a dye was extracted by adding 500 μL of a saturated sodium sulfate / acetone (3: 7) solution and immersed for 12 hours, and the absorbance (660 nm) of the extract was measured.

  The result is shown in FIG. As is clear from this figure, it can be seen that cross-linked hyaluronic acid strongly inhibits cell damage due to drying compared to uncross-linked hyaluronic acid and acetylated hyaluronic acid, and thus exhibits an excellent corneal protective effect.

<Experiment 2: Concentration dependency test>
As a test solution, cross-linked hyaluronic acid (raw material hyaluronic acid molecular weight of about 860,000; cross-linking rate 0.1 molar equivalent) was used at concentrations of 0.03%, 0.1%, and 0.3%, and the cornea in the same manner as in Experiment 1. The protective effect was investigated.
The result is shown in FIG. As is clear from this figure, it can be seen that the cornea protective effect of cross-linked hyaluronic acid increases in a concentration-dependent manner within the concentration range examined.

<Experiment 3: Influence of the crosslinking rate>
As a test solution, various cross-linked hyaluronic acids (raw material hyaluronic acid molecular weight of about 860,000) having a cross-linking ratio of 0.01, 0.03, 0.1, 0.3, and 1.0 molar equivalents were used, as in Experiment 1. Thus, the cornea protective effect was examined.

  The result is shown in FIG. As is clear from this figure, in the case of the crosslinked hyaluronic acid having a high molecular weight of about 860,000 as the raw material hyaluronic acid molecular weight, it can be seen that the corneal protective effect decreases as the crosslinking rate increases. As the crosslinking rate increases, the solubility of the crosslinked hyaluronic acid decreases, suggesting that the corneal protective effect of the crosslinked hyaluronic acid depends on its solubility.

<Experiment 5: Effect of raw material hyaluronic acid molecular weight>
Two types of crosslinked hyaluronic acids having a molecular weight of about 30,000 and about 860,000 (crosslinking ratio: 0.1 and 0.5 molar equivalent) were used as test solutions, and the cornea protective effect was obtained in the same manner as in Experiment 1. Examined.
The result is shown in FIG. As is clear from this figure, it is considered that the higher the crosslinking rate, the more the corneal protective effect is lost. It can also be seen that the greater the raw material hyaluronic acid molecular weight (approximately 860,000), the greater the effect of changing the crosslinking rate.

<Experiment 6: Evaluation of retention in rabbit after instillation of hyaluronic acid and cross-linked hyaluronic acid>
JW rabbits (male, 2.5 kg; Kitayama Labes Co., Ltd.) were instilled with 50 μL of 0.3% uncrosslinked hyaluronic acid or crosslinked hyaluronic acid (raw hyaluronic acid molecular weight: 860,000, crosslinking rate 0.1 molar equivalent). After 15 minutes, the conjunctival sac was washed with 1 mL of physiological saline. The amount of the test substance in the washings was measured with a hyaluronic acid measurement ELISA kit (Hyaluronan Assay Kit), and the amount of hyaluronic acid or crosslinked hyaluronic acid in tears was calculated.
The result is shown in FIG. As is clear from the results, crosslinked hyaluronic acid is superior in retention compared to uncrosslinked hyaluronic acid.

<Experiment 7: Curative efficacy test of corneal epithelial disorder>
A dry eye model was prepared using male SD rats according to the method of Fujihara et al. (Invest. Ophthalmol. Vis. Sci 42 (1): 96-100 (2001)). After the dry eye model was prepared, an improvement effect of corneal epithelial disorder was determined by a method in which the method of Miyata et al. (Ophthalmology Clinicians 48 (2): 183-188 (1994)) was modified.

(experimental method)
Male SD rats (Nippon Charles River Co., Ltd.) were anesthetized by administration of pentobarbital. Subsequently, the extraorbital lacrimal gland was removed and corneal epithelial injury was induced over 12 weeks. Next, physiological saline, 0.3% uncrosslinked hyaluronic acid or crosslinked hyaluronic acid (raw material hyaluronic acid molecular weight: 860,000, cross-linking ratio 0.1 molar equivalent) 20 μL each, 6 times a day, 1.5 times Instilled at time intervals.

  Before the start of instillation, 1, 2, and 3 weeks after the start of instillation, the damaged part of the corneal epithelium was stained with fluorescein. The degree of staining with fluorescein was scored according to the following criteria for each of the upper part, middle part and lower part of the corneal epithelium, and the total score of each part was calculated. The same operation as described above was performed using physiological saline as a control. Furthermore, the average value of the total score of each of the above-mentioned parts was also obtained for normal eyes that had not caused corneal epithelial disorder (non-treated) and those that had not been instilled (astigmatic eyes).

(Criteria)
0: Not dyed.
1: Dyeing is sparse and each dot-like dyeing part is separated.
2: The dyeing is moderate, and some of the dotted dyed portions are adjacent.
3: Dyeing is dense and each dot-like dyeing part is adjacent.

(result)
FIG. 7 shows the total score of each part in each group. In addition, the average value of a score is an average of 10 examples each. The cross-linked hyaluronic acid ophthalmic group has a significantly lower score than the no-ophthalmic group, the physiological saline ophthalmic group, or the hyaluronic acid ophthalmic group.

Formulation example Cross-linked hyaluronic acid 0.3 g
(Raw material hyaluronic acid molecular weight about 860,000; cross-linking rate 0.1 molar equivalent)
Methyl paraoxybenzoate 0.002g
Isotonic phosphate buffer appropriate volume total volume 100 mL

The relationship between the amount of the crosslinking agent and the molecular weight of the raw material hyaluronic acid on the solubility of the crosslinked hyaluronic acid is shown. The comparative test result of the corneal epithelial layer protective effect of hyaluronic acid, acetylated hyaluronic acid, and crosslinked hyaluronic acid is shown. The relationship between the density | concentration of bridge | crosslinking hyaluronic acid and a cornea protective effect is shown. The relationship between the crosslinking rate of crosslinked hyaluronic acid and the cornea protective effect is shown. The relationship between the molecular weight of the crosslinked hyaluronic acid raw material hyaluronic acid and the corneal protective effect is shown. The retention property evaluation result after hyaluronic acid and bridge | crosslinking hyaluronic acid instillation in a rabbit is shown. The healing effect of the corneal epithelial disorder by cross-linked hyaluronic acid is shown.

Claims (7)

  An ophthalmic composition comprising a soluble cross-linked hyaluronic acid and a pharmaceutically acceptable carrier.   The soluble cross-linked hyaluronic acid is a hyaluronic acid having an average molecular weight of 5,000 or more and less than 100,000, and the cross-linking agent is used in an amount of 0.01 to 3.0 equivalents per constituent disaccharide unit of the raw material hyaluronic acid. The ophthalmic composition according to claim 1.   The soluble crosslinked hyaluronic acid is made from hyaluronic acid having an average molecular weight of 100,000 or more and 3,000,000 or less, and a crosslinking agent is used in an amount of 0.01 or more and less than 0.5 equivalent to the constituent disaccharide units of the raw material hyaluronic acid. The ophthalmic composition according to claim 1, which has been cross-linked by doing so.   The ophthalmic composition according to any one of claims 1 to 3, wherein the soluble crosslinked hyaluronic acid is crosslinked using a di- or polyfunctional group oxide as a crosslinking agent.   The ophthalmic composition according to claim 4, wherein the cross-linking agent is selected from the group consisting of 1,4-butanediol diglycidyl ether, ethylene glycol diglycidyl ether, glycerol diglycidyl ether and glycerol triglycidyl ether.   The ophthalmic composition according to any one of claims 1 to 5, which is used for treatment or prevention of dry eye.   The ophthalmic composition according to claim 6, which is a dry eye eye drop.

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