KR20080005825A - Eye composition with reduced side effects and method of preparing the same - Google Patents

Abstract

An eye composition for treating glaucoma is provided to improve xerophthalmia, a common side effect of conventional glaucoma treating agents significantly, thereby providing increased glaucoma therapeutic effects as well as excellent wound treating effect. An eye composition comprises 0.001-0.1 weight/volume% of a prostaglandin compound having the therapeutic activity on glaucoma and ocular hypertension and at least one polymer material selected from the group consisting of hyaluronic acid, sodium hyaluronate, hydroxypropylmethylcellulose, povidone, sodium chondroitin sulfate and carboxymethylcellulose sodium. The composition further comprises 0.003-5.0 weight/volume% of at least one supplement selected from the group consisting of a preservative, an isotonic agent, a stabilizer, an antioxidant, and a pH adjusting agent. A method for preparing the composition comprises a step of mixing the prostaglandin compound with the polymer material in a mixture ratio of 1:0.1-1,000.

Description

EYE COMPOSITION WITH REDUCED SIDE EFFECTS AND METHOD OF PREPARING THE SAME}

1 is a graph showing the water evaporation amount of the agar medium over time in Experimental Example 1 of the present invention.

FIG. 2 is a graph showing a dry spot generating object over time after wound induction in Experimental Example 2.1 of the present invention.

Figure 3 is a graph showing the area of dry spot generation over time after the wound induction in Experimental Example 2.1 of the present invention (*: control group showing the significance when comparing between groups by time).

Figure 4 is a photograph showing the dry spot area after 48 hours of wound induction in Experimental Example 2.1 of the present invention.

5 is a graph showing corneal erosion-prone individuals over time after wound induction in Experimental Example 2.2 of the present invention.

FIG. 6 is a graph showing corneal sore area over time after wound induction in Experimental Example 2.2 of the present invention (*: control group showing significance in comparison between groups by time).

Figure 7 is a photograph showing the corneal erosion area after 48 hours of wound induction in Experimental Example 2.2 of the present invention.

Figure 8 is a photograph showing the dry spot area after 48 hours after the eye drop administration in Experimental Example 2.3.

The present invention relates to an ophthalmic composition for treating glaucoma with reduced side effects of dry eye syndrome and a method for preparing the same, including a predetermined polymer material together with prostaglandin drugs having therapeutic activity for glaucoma, while maintaining the effect of treating glaucoma as it is. A water-soluble complex ophthalmic composition having a therapeutic effect on the side effects of dry eye and a method for producing the same.

Glaucoma is a disorder that causes various optic groups and causes optic nerve atrophy and visual field defects due to increased intraocular pressure.It is not a single disease, but a group of disorders with various clinical and pathologic findings. It is a general term for the visual field defects caused by glaucoma-specific optic neuropathy and retinal ganglion cells caused by various other risk factors. Such drugs for treating glaucoma and ocular hypertension include pilocarpine hydrochloride, beta-blockers (timolol, maledeol, betaxolol), carbonic anhydrous dehydrogenase inhibitors (dozolamide hydrochloride, brinzolamide), adrenaline receptor blockers ( Brimonidine), a prostaglandin-type compound (unoproston, latanoprost, travoprost, bimatoprost), a combination of a prostaglandin-type (latanoprost) and a beta-blocker (timolol). Of these, prostaglandins have been leading the market since 2000.

Among prostaglandins, latanoprost, which is prescribed as a primary treatment for glaucoma, has been known to have a superior intraocular pressure lowering effect than beta-blocker thymol oleate (Aung, T. et al. Ophthalmol. 107: 1178-1183, 2000 ). Ratanoprost has the chemical name Isopropyl- (Z) -7 [(1R, 2R, 3R, 5S) 3,5-dihydroxy-2-[(3R) -3-hydroxy-5-phenylpentyl] cyclopentyl A prostaglandin-treated glaucoma drug represented by] -5-heptanoate is known as a useful drug for use as a local hypotension drug, and a study of its use is reported in US Pat. No. 5,321,128. It is a prostaglandin F2α receptor agonist and is known to lower intraocular pressure by facilitating the outflow of water from the uveal sclera (Camras, CB et al. Invest.Ophthalmol. Vis. Sci. 28: 463-469, 1987 ). The latanoprost may exhibit continuous intraocular pressure control effect and excellent intraocular pressure drop effect by the above characteristics. In addition, the safety of the patient was demonstrated due to high compliance, excellent ocular tolerability and low congestion expression (Sudesh, S. et al. Arch. Ophthalmol. 117: 539-540, 1999).

However, studies have shown that a combination therapy of artificial tears and prostaglandins is considered in case of such prostaglandin glaucoma treatments, latanoprost, travoprost, and bimatoprost, which can lead to dry eye syndrome (Kozobolis, VP et al. Am. J. Ophthalmol. 139: 742-743, 2005). According to the above literature, when the prostaglandin-type glaucoma treatment was instilled, tear secretion was significantly reduced after 5 minutes, and the tear breakdown time (BUT) was accelerated.

In addition, as a result of prostaglandin's six-month clinical trial report, latanoprost had side effects in 107 patients (26.6%) out of 402 patients, despite the excellent therapeutic effect, and 142 types of adverse reactions . The specific contents of the side effects were conjunctival congestion 71 cases (17.7%), eye irritation symptoms 15 cases (3.7%), pruritus 14 cases (3.5%), iris pigmentation 11 cases (2.7%), eye pain 6 cases (1.5%) ), 8 cases (2.0%), and 3 cases of blepharitis (0.7%) (Jalatan Product Guide, Japanese Pharmacy, 2006).

In addition, clinical trials with travoprost eye drops have reported side effects of ocular hyperemia in 35-50% of patients. Side effects seen in 5-10% of patients include decreased vision, eye discomfort, foreign body, pain and pruritus. Adverse events such as visual acuity, blepharitis, blurred vision, lens clouding, conjunctivitis, dry eye syndrome have been reported in 1-4% of patients (Travata Product Guide, Alcon Laboratories, Inc., Irvine, California, U.S.A.).

In addition, as a result of ginseng test using bimatoprost eye drops, conjunctival hyperemia, eyelash proliferation, and pruritus were reported in 15-45% of patients, and in 3-10% of patients, dry eye, visual disturbance, burning eyes, and foreign body sensation were observed. , Side effects of ocular pain, peri-dermal skin pigmentation, blepharitis, lens clouding, superficial mucositis, eyelid erythema, eye irritation, and eyelash blackening discoloration have been reported (Lumigan product manual, Allergan, Inc., Waco, Texas, USA).

Among these prostaglandin-treated glaucoma drugs, latanoprost has the lowest frequency of adverse events (Reardon, G. Am. J. Ophthalmol. 137 (Suppl. 1): S3-S12, 2004), but other prostaglandins Like the glaucoma treatments of the type, latanoprost also exhibits side effects of dry eye symptoms, and there is a need to develop a method for alleviating dry eye symptoms in the use of prostaglandins glaucoma treatments.

On the other hand, dry eye refers to diseases such as conjunctival dryness, hypotony, and dry keratoconjunctivitis in consultation. As such, dry eye syndrome is thought to be a disease of the surface of the eye, including diseases called dry eye syndrome, rather than a single disease, because the concept is thought to be broad and cause, but in many cases the cause is unknown. will be. Currently, dry eye is defined as an abnormal state of tear quantity and quality regardless of keratoconjunctivitis disorder. By definition, dry eye categories include diseases such as hypotony, tear deficiency, dry eye syndrome, Sjogren's syndrome, dry keratoconjunctivitis, Stevens-Johnson syndrome, ocular swelling, blepharitis, blepharophagia, and perceptual nerve palsy. do.

In the case of dry eyes, in many cases, tears are lacking in any of the oily, aqueous and mucin layers, leading to keratoconjunctivitis disorders. In particular, when tears are lacking in the mucin layer, corneal damage is severe, which is caused by corneal epithelial erosion resulting from corneal epithelial cell damage, corneal epithelial disorders, as well as corneal ulcers (eg, ulcers in the corneal stroma) and infectious eye diseases. Cause easily. In some cases, corneal transplantation is required. In addition, there is a cause of evaporative anti-eye dryness called mybom dysfunction. This is caused by the stimulation of periconductal perceptual nerves due to the accumulation of lipids in the Maibom conduit, or by the increase of irritating lipids (fatty acids etc.). Accordingly, when the leakage is reduced, it may be considered that when the thickness of the aqueous layer becomes thin, the lipid cannot be spread while the lipid layer remains on the bleeding margin, thereby increasing the evaporation of the aqueous layer. In addition, soft contact lenses can cause dry eye problems. Although soft contact lenses are water-soluble, it is difficult to distribute a water layer having a sufficient thickness on the lens surface, so that the spreading of the lipid layer deteriorates, and the evaporation of tears on the lens may be a cause of corneal epithelial disorder.

Sodium hyaluronate is widely known and used as a therapeutic agent for keratoconjunctival epithelium accompanying such internal and exogenous diseases. Sodium hyaluronate is a polymer polysaccharide composed of two sugars, N-acetylglucosamine and D-glucuronic acid, and is a biological polymer widely distributed in large quantities in mammalian connective tissue. At the time of injury, it plays a structural and biological role in local level sensing, which is closely related to tension, flavour, and tissue recovery. It is also viscous and attracts water, making it a conservative effect (Comper, W.D., Laurent, T.C. Physiol. Rev. 58: 255-315, 1978). The chemical and physical properties of sodium hyaluronate are polysaccharide biopolymers such as unbranched molecules that polymerize during replacement and form for long periods of time and vary at a maximum molecular weight of 8,000,000 Daltons (Meyer K. Fed. Proc. 17: 1075-1077, 1958; Laurent TC; Chemistry and Molecular Biology of Intracellula Matrix, 703-732, Academic Press NY, 1970). The action of this biopolymer in aqueous solution assures a special viscosity called so-called point-elasticity, which is typical of certain biological fluids, especially synovial fluid and vitreous fluid, and sodium hyaluronate is present at a concentration of 0.12 to 0.24% (Balazs EA et al. Mod. Probl.Ophthal. 10: 3-21, 1972). In addition, human aqueous body fluids were found to contain sodium hyaluronate at an average concentration of 1.14 mcg / g (Laurent U.B. Arch. Ophthalmol. 101: 129-130, 1983).

In particular, the eye constitutes a major component of the vitreous body, and is a biological component whose presence is found even in waterproofing. In addition, basic research to clarify the action of sodium hyaluronate on the corneal epithelial cells showed that sodium hyaluronate, like EGF (epidermal growth factor) and fibronectin, has a wound healing promoting effect in the rabbit corneal epithelial model of rabbits. (Inoue, M., Katakami, C. Invest.Ophthalmol. Vis. Sci. 34: 2313-2315, 1993).

Prostaglandin-type glaucoma therapeutics, which have been commercially available, have been used as single or combination preparations for the purpose of lowering intraocular pressure, but there are no eye drops containing complex forms or additives that can solve the adverse reaction of dry eye.

Conventional treatment of prostaglandin-type glaucoma treatment drugs is topical administration to the eye mucosa, causing dry eye syndrome frequently as a side effect, and therefore, two drugs, glaucoma treatment drugs and artificial eye drops have been prescribed in combination. Therefore, there are problems such as inconvenience of having to use two treatments separately, increase of cost, and troublesomeness such as continuous administration of glaucoma drug and lacrimal fluid, so that the two eye drops and eye drops can be treated at once. There is a need for the development of new combination eye drops that can both increase the effect of preventing dryness.

Therefore, the present invention helps to treat corneal epithelial disorder caused by eye dryness as well as dry eye appearing as a side effect of glaucoma treatment, and the addition of excellent sodium hyaluronate as a reservoir of the main component latanoprost A new composition for ophthalmic glaucoma combination therapeutics.

The present invention relates to an ophthalmic composition for treating glaucoma with reduced side effects of dry eye syndrome and a method for preparing the same, including a predetermined polymer material together with prostaglandin drugs having therapeutic activity for glaucoma, while maintaining the effect of treating glaucoma as it is. A water-soluble complex ophthalmic composition having a therapeutic effect on the side effects of dry eye and a method for producing the same.

More specifically, the present invention relates to a composite eye drop composition of a glaucoma treatment agent to reduce the side effect of the glaucoma treatment while reducing the side effect of the glaucoma, by adding sodium hyaluronate, which is a polymer material used as artificial lactose to the prostaglandin-type derivative glaucoma treatment In addition to preventing the occurrence of dry eye syndrome, if a patient with dry eye syndrome needs to be treated concurrently with glaucoma, the effect of treating dry eye syndrome and glaucoma can be expected at the same time, and the wound healing effect of sodium hyaluronate can be obtained. The present invention relates to a therapeutic combination eye drop composition. Therefore, the present invention solves the discomfort that should be used in combination with artificial tears for ocular hypertension and glaucoma patients requiring long-term treatment, and can easily prevent and treat glaucoma treatment and dry eye syndrome with one eye drop. Has

The present invention provides an ophthalmic composition for treating glaucoma and / or ocular hypertension with improved dry eye composition containing a prostaglandin compound and a polymer material having dry eye disease treatment activity.

The prostaglandin compound may be any prostaglandin compound having therapeutic activity for glaucoma and / or ocular hypertension, preferably one selected from the group consisting of unoprostone, latanoprost, travoprost, and bimatoprost. It may be more than. In the eye drop composition of the present invention, the content of the prostaglandin compound is preferably 0.001 to 0.1% (w / v) based on the total eye drop composition in consideration of its glaucoma and ocular pressure therapeutic activity.

The polymer material having dry eye treatment activity may be at least one selected from the group consisting of hyaluronic acid, sodium hyaluronate, hydroxypropylmethylcellulose, povidone, sodium chondroitin sulfate, and sodium carboxymethylcellulose. More preferably, the polymer material may be at least one selected from the group consisting of hyaluronic acid and sodium hyaluronate having a molecular weight of 400,000 to 1,500,000. The hyaluronic acid or sodium hyaluronate has a wound treatment effect, it is preferable to obtain a wound treatment effect with the improvement of dry eye syndrome, there is an advantage that can maintain the drug for a long time because of the retention effect of the prostaglandin compounds. Increasing the content of the polymer material increases the dry eye improvement effect, in consideration of the effect of improving the dry eye and glaucoma treatment components, the content of the polymer material is 0.005 to 3.0% (w) based on the total eye drop composition / v), and more preferably 0.05 to 0.5% (w / v).

In addition, the eye drop composition of the present invention may further include one or more adjuvants selected from the group consisting of preservatives, isotonic agents, stabilizers, antioxidants and pH adjusting agents. The amount of the adjuvant is not limited according to each purpose, and is not limited, and considering the effect on the active ingredients, it is preferable to set it to 0.003 to 5.0% (w / v) based on the total eye drop composition. The adjuvant can be any kind commonly used, and there is no limitation in that kind. For example, sodium edetate may be one or more selected from the group consisting of 0.05 to 0.2% (w / v) and ε-aminocaproic acid 0.01 to 0.05% (w / v). In addition, the eye drop composition of the present invention may further contain a component having glaucoma therapeutic activity in addition to the prostaglandin compounds, the component having glaucoma therapeutic activity may be one or more selected from the group consisting of beta-blockers, preferably It may be maleic acid maleol, and the content may be 0.1 to 1.5% (w / v) based on the total composition.

In another aspect, the present invention provides a method for preparing an eye drop composition for treating glaucoma and ocular hypertension with improved dry eye syndrome comprising the step of mixing a prostaglandin compound and a polymer material having a dry eye treatment activity.

More specifically, the manufacturing method of the present invention,

Preparing a prostaglandin compound solution,

Preparing a solution of a polymeric material having dry eye treatment activity, and

Mixing the two solutions and then filtering

It may be to include.

The preparation method of the present invention may further comprise the step of adding one or more adjuvants selected from the group consisting of preservatives, isotonic agents, stabilizers, antioxidants and pH adjusting agents.

The amount of the polymer material having the dry eye treatment activity may be 0.1 to 1000 times by weight of the amount of the prostaglandin compounds, preferably 1 to 100 times by weight. As the solvent used in the preparation of the prostaglandin compound solution, all solvents commonly used may be used and there is no particular limitation, and for example, at least one selected from the group consisting of an aqueous sodium chloride solution and an aqueous potassium chloride solution may be used. The solvent used in the preparation of the solution of the polymer material having the dry eye treatment activity is also available, all solvents that can be used conventionally, there is no particular limitation, for example, selected from the group consisting of aqueous sodium edetate solution and aqueous aminocapronic acid solution It is better to use more than one. The concentrations of the two solutions are 0.001 to 0.1% (w / v) of prostaglandin content in the final eye drop composition, and 0.001 to 3.0% (w / v) of polymer material, more preferably 0.05 to 0.5% ( w / v).

Kinds of the prostaglandin compounds and the polymer material and additives having dry eye treatment activity are as described above.

In the following experiment, the preparation of the eye drop composition and the drug efficacy test of the prepared eye drop were performed. In the pharmacologic study, dry eye was induced in rabbits, and when latanoprost and sodium hyaluronate complex eye drops were applied, the quality of precorneal tear film and corneal wound healing were improved compared to latanoprost alone. It proved effective.

[ Example ]

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.

Example  One: With latanofrost Sodium hyaluronate  Preparation of eyedrops containing

In consideration of the fact that prostaglandin drugs are poorly soluble and unstable substances, eye drop compositions were prepared according to the eye drop preparation method.

To 25 mL of sterile purified water, 0.011 g of sodium edetate and 0.2 g of aminocapronic acid were added and dissolved, and then, 0.1 g of sodium hyaluronate was added and fully hydrated. 70 mL of sterile purified water was added to another beaker, and 0.7 g of sodium chloride and 0.15 g of potassium chloride were completely dissolved while maintaining the temperature at 60 ° C., and 0.005 g of latanoprost was added at the same temperature and dissolved at 60 to 70 ° C. After confirming that the latanoprost was completely dissolved, it was quenched, mixed with sodium hyaluronate solution, and then dissolved in 0.003 g of benzalkonium chloride. Then, a proper amount of sodium hydroxide was added to show the following pH. After sterile filtration (0.2 μm, membrane filter), the eye drop composition having the composition of Example 1 in Table 1 below was prepared.

In this case, when the type of buffer is changed or the order of the input in the preparation method step is changed, the aggregation of sodium hyaluronate may occur or a precipitate may be formed. good.

Example  2 and 3: Preparation of eye drop composition containing different kinds of prostaglandins components

By the method described in Example 1, the composition for eye drops containing travoprost (Example 2) and the composition for eye drops containing bimatoprost (Example 3) in a composition as shown in Table 1 below Prepared.

TABLE 1

Example 4  To 8 and Comparative example  One: Of sodium hyaluronate  Preparation of eye drop compositions having different concentrations

According to the preparation method described in Example 1, the concentration of sodium hyaluronate was changed to 0%, 0.02%, 0.1%, 0.15%, 0.2%, 0.5% to prepare a combined eye drop with latanoprost. The components and contents used were as described in Table 2 below.

TABLE 2

Experimental Example  1: Demonstrate the moisturizing effect of the eye drop composition of the present invention

When the eye drop compositions prepared in Examples 5 to 7 and Comparative Example 1 of Table 2 were added dropwise to 1.5% agar plate medium, the reduction of agar weight due to water evaporation was compared. 1.5% agar medium was autoclaved, and then dispensed into a 60 mm diameter glass plate to solidify, followed by dropping 300 uL, the minimum amount that each eye drop composition can be widely distributed in the medium (Masatsugu N. et al. Cornea 12 (5): 433-436, 1993).

As a control, the amount of water evaporated over time of the 1.5% agar plate medium was used as a control, and the amount of water evaporated according to the sodium hyaluronate concentrations of Comparative Examples 1 and 5-7 was shown in Table 3 and FIG. 1.

Table 3 below shows the relative weight (%) of the agar medium over time after the drop.

TABLE 3

       time 0 0.5 One 2.5 4 6 12 24 Control 100 96.685 95.678 94.493 92.396 91.413 89.417 81.379 Comparative Example 1 100 96.737 95.849 94.853 93.069 92.284 90.276 81.957 Example 5 100 96.792 95.903 94.964 93.229 92.407 90.436 83.061 Example 6 100 96.851 96.004 95.033 93.280 92.462 90.490 83.591 Example 7 100 96.794 95.961 95.030 93.292 92.494 90.477 84.908

As can be seen in Table 3 and Figure 1, when the latanoprost alone administration (Comparative Example 1) increased the amount of sodium hyaluronate added (Example 5-7) it was confirmed that the amount of water evaporation is less, In the case of Example 7 (addition of 0.2% sodium hyaluronate), the moisturizing effect was shown to be the most effective.

Example 9  To 12: according to the type of polymer Ratanofrost  Complex Eye Drop Composition

Different types of polymers were prepared for the eye drop according to the method of Example 1. The polymer type, other components and contents used are as described in Table 4 below.

TABLE 4

Example 13  15: beta to prostaglandins Blocking agent  Preparation of eye drop composition containing a component

By the method described in Example 1, as described in Table 5 below to prepare an eye drop composition further comprising a beta-blocker, a complex eye drop was prepared by varying the sodium hyaluronate concentration. In the present example, the beta-blocker was used as thymol maleate, and the content and type and content of other components are shown in Table 5 below.

TABLE 5

Experimental Example  2: Dry Eye  And corneal wound healing effect

 Inducing the dry eye model and epithelial damage model in rabbits, when applying the eye drops composition of Examples 5 and 7, compared to Comparative Example 1, precorneal tear film (hereinafter referred to as 'PTF') In order to prove the effect of promoting qualitative improvement and healing of corneal wound and to investigate the difference in efficacy according to sodium hyaluronate concentration, three types of animal test models were tested. Statistical analysis was performed using SPSS 12.0 software for windows, one-way ANOVA and post-test Dunkan method to verify the statistical significance between groups (p <0.05).

Experimental Example  2.1: Evaporative  Experimental Evaporative Dry Eye Model

Way:

A total of 30 eyes were selected from 15 (8 males and 7 females) of 3.0 kg and 3.5 kg New Zealand white rabbits. Rabbits were anesthetized by intramuscular injection of 35 mg / kg ketamine hydrochloride and 5 mg / kg xylazine hydrochloride. The eyes of the rabbit treated as described above (lid specular) for 2 hours to artificially prevent the eyes blink of the rabbit, and then observed the occurrence of a dry spot by fluorescein staining to confirm the induction of wounds (Gamache DA, et al. J. Ocul. Pharmacol. Ther. 18 (4): 349-361, 2002).

High group-Example 7 (latanoprost + 0.2% sodium hyaluronate)

Low group-Example 5 (latanoprost + 0.1% sodium hyaluronate)

Control group-comparative example 1 (latanofrost)

The drug administration time was 8 am, 1 pm, 6 pm, and 11 pm, and the test time was 1 hour, 3 hours, 6 hours, 12 hours, 24 hours, 48 hours, and 72 hours before the induction. The extent of wound healing was measured by dividing.

Eye Exam Item:

Fluorescent dyeing

0.1 ml of 0.5% fluorescein solution was added dropwise, artificially blinked several times, and applied to the entire cornea, followed by washing with 0.9% sterile saline solution. In the dark room, the cobalt blue light was illuminated to identify the lesion, which was taken with a digital camera. The size of the sores or dry spots was measured using an Uthscsa image tool (R software).

result:

One. Fluorescein  dyeing - Drying point  Object

The results for the fluorescent staining are shown in FIG. 2. As shown in FIG. 2, immediately after the induction, dry spots appeared in all individuals of all groups and decreased with time, and it can be seen that a large number of dry spots recovered in the order of High group, Low group, and Control group. . After 12 hours of induction, the individuals began to recover one by one in the High and Low groups. In the High group, six individuals recovered after 24 hours and all individuals recovered after 36 hours. Even in the low group, three individuals recovered after 24 hours, and after 36 hours, all were recovered except one. In the Control group, however, no individuals recovered after 72 hours. Therefore, it can be seen that as the concentration of sodium hyaluronate in the test eye drops increases, the recovery rate of corneal damage is accelerated.

2. Fluorescein  dyeing - Drying point  area

The dry spot area measurement results at the time of fluorescence staining are shown in FIGS. When comparing the significance between groups at each time, the Ccontrol group was significantly larger than the High and Low groups from 12 hours to 48 hours (p <0.05). Fast in the low group.

In addition, the recovery of corneal damage occurred at 12 hours in the high group, 24 hours in the low group, and 36 hours in the control group, indicating a concentration-dependent healing effect of sodium hyaluronate (p <0.05).

Experimental Example  2.2: Model of hyperosmotic induced corneal epithelial injury

Way:

A total of 30 eyes (15 males, 7 females, 8 females) were selected as the experimental animals, including 3.0 kg and 3.5 kg New Zealand white rabbits. Rabbits were anesthetized by intramuscular injection of 35 mg / kg ketamine hydrochloride and 5 mg / kg xylazine hydrochloride, and the prepared Teflon tape was applied to the eyes, and sugar powder was applied sufficiently, followed by washing with sterile saline solution after 20 minutes. Thereafter, corneal wounds were induced by fluorescence sample staining to identify circular sores, and then divided into three groups and instilled at 4 hour intervals (Katsuyama, I., Arakawa, TJ Ocul. Pharmacol. Ther. 19: 281). -289, 2003).

High group-Example 7 (latanoprost + 0.2% sodium hyaluronate)

Low group-Example 5 (latanoprost + 0.1% sodium hyaluronate)

Control group-comparative example 1 (latanofrost)

The drug administration time was 8 am, 1 pm, 6 pm, and 11 pm, and the test time was 1 hour, 3 hours, 6 hours, 12 hours, 24 hours, 48 hours, and 72 hours before the induction. The extent of wound healing was measured by dividing.

Eye Exam Item :

Fluorescein staining and corneal erosion and corneal erosion area were measured in the same manner as in the dry evaporative dry eye model experiment of Experimental Example 2.1.

result:

One. Fluorescein  dyeing - Corneal erosion  The presence or absence

5 shows the results of measuring corneal erosion by fluorescein staining of the present experimental example. Immediately after induction, corneal sores appeared in all individuals of all groups. Healed individuals appeared after 12 hours in the high group, and 36 hours in the low group and 72 hours in the control group. This can be seen that there is a difference in the healing time of corneal erosion depending on the concentration of sodium hyaluronate.

2. Fluorescein  dyeing - Corneal erosion  area

Results of corneal erosion area by fluorescein staining of the present experimental example are shown in FIGS. 6 and 7. The significance of the corneal erosion was significantly greater in the control group at 72 hours than in the high group (p <0.05). In addition, the high group has a faster healing rate than the other groups.

All groups showed significant increase in corneal erosion at 1 hour after induction and gradually decreased. There was no significant difference from pre-induction at 36 hours in the high group and 48 hours in the low group, and no significant difference at 72 hours in the control group. This suggests that the healing rate of corneal erosion is proportional to the increase in sodium hyaluronate concentration (p <0.05).

Experimental Example  2.3: Teardrop  Lack of dry eyeballs ( Lacrimal  insufficiency dry eye model

Way:

A total of 40 eyes (10 males, 10 females) were selected from 20 kg (10 males and 10 females) of 3.0 kg and 3.5 kg New Zealand white rabbits. A 1% atropine sulfate eye drop was applied for 40 days at 9 am, 4 pm, and 11 pm with a Hamilton microliter syringe, and then a Schirmer tear test was performed to confirm the reduction of tear amount (Burgalassi, S. et. al.Ophthalmic.Res. 31: 229-235, 1999).

High group-Example 7 (latanoprost + 0.2% sodium hyaluronate)

Low group-Example 5 (latanoprost + 0.1% sodium hyaluronate)

Control group-comparative example 1 (latanofrost)

Blank group-no eye drops

Eye Exam Item:

The dry spot area was observed by fluorescein staining in the same manner as the evaporative dry eye model experiment of Experimental Example 2.1.

result:

Fluorescein  dyeing - Drying point  area

Results of the dry point area by fluorescein staining of the present experimental example are shown in FIG. As shown in Figure 8, when comparing the area of the drying point after the induction, the area stained in the high group appeared the smallest compared to the other groups, followed by the low group, followed by the control group. As a result, it can be seen that in the high group of high concentration of sodium hyaluronate, the healing rate for dry damage is the fastest.

As described above, the present invention provides an eye drop composition for treating glaucoma in which dry eye syndrome, which is a common side effect of the existing glaucoma treatment agent, is remarkably improved, and the eye drop composition of the present invention is elevated by improved dry eye syndrome. Not only can a therapeutic effect be obtained, but also an excellent wound healing effect.

Claims (11)

Prostaglandin compounds having therapeutic activity against glaucoma, ocular hypertension, or both; And At least one polymeric material selected from the group consisting of hyaluronic acid, sodium hyaluronate, hydroxypropylmethylcellulose, povidone, sodium chondroitin sulfate and sodium carboxymethylcellulose An ophthalmic composition containing the same. The composition of claim 1, wherein the prostaglandin compound is at least one selected from the group consisting of unoprostone, latanoprost, travoprost, and bimatoprost. The eye drop composition according to claim 1, wherein the content of the prostaglandin compound is 0.001 to 0.1% (w / v) based on the total eye drop composition. The eye drop composition according to claim 1, wherein the polymer material is at least one selected from the group consisting of hyaluronic acid and sodium hyaluronate having a molecular weight of 400,000 to 1,500,000. The eye drop composition according to claim 1, wherein the content of the polymer material is 0.001 to 3.0% (w / v) based on the total eye drop composition. The method according to any one of claims 1 to 5, wherein one or more adjuvants selected from the group consisting of preservatives, isotonic agents, stabilizers, antioxidants, pH adjusters and the like is 0.003 to 5.0% (w / v) based on the composition. The composition for eye drops further containing in quantity. The eye drop according to claim 6, wherein the adjuvant contains at least one selected from the group consisting of 0.05 to 0.2% (w / v) of sodium edetate and 0.01 to 0.05% (w / v) of ε-aminocaproic acid. Composition. The eye drop composition of claim 1 further comprising at least one glaucoma therapeutic ingredient. Prostaglandin compounds having therapeutic activity against glaucoma, ocular hypertension, or both, at least one polymer material selected from the group consisting of hyaluronic acid, sodium hyaluronate, hydroxypropylmethylcellulose, povidone, sodium chondroitin sulfate, and sodium carboxymethylcellulose To a mixing ratio of 1: 0.1 to 1000 (prostaglandin compound weight: polymer material weight), The content of the prostaglandin compound in the mixture obtained above is 0.001 to 3.0% (w / v), the content of the polymer material is 0.01 to 1.0% (w / v), Method for producing the eye drop composition The method of claim 9, Preparing a prostaglandin compound solution, Preparing a solution of a polymeric material having dry eye treatment activity, and Mixing the two solutions and then filtering It includes, a manufacturing method. The production method according to claim 9 or 10, wherein the prostaglandin compound is at least one selected from the group consisting of unoprostone, latanoprost, travoprost, and bimatoprost.

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