JP6931257B2 - A novel eye drop composition for treating dry eye containing rebamipide and a method for solubilizing and stabilizing it. - Google Patents

Description

The present invention relates to the production of an aqueous eye drop solution for dry eye treatment, which stably solubilizes rebamipide, contains an additive component that is safe for the human body, and has an excellent therapeutic effect, and a composition thereof.

The aqueous solution of the present invention can be used to provide an eye drop composition for the treatment of dry eye. A completely aqueous solution of eye drops has a high bioavailability, is convenient without a feeling of refusal to the user, and is economical and efficient in aseptic production and quality control. Due to the characteristics of the eye drops, there are various storage forms such as refrigeration, room temperature, and high temperature conditions in distribution and use after production. Therefore, under such various conditions, maintaining the solution state, which is the initially set quality state, is the key to ensuring stability. In addition, it is important to ensure safety by long-term use to manufacture using safe additives in the actual eye drop administration route.

Therefore, the present inventors solubilize the poorly soluble rebamipide to a epoch-making sufficiently high concentration level, and physicochemically stabilize it over a long period of time by using a safe additive suitable for the route of administration of eye drops. We have come to manufacture a new aqueous solution of eye drops.

The number of patients with dry eye in Japan is increasing every year, and tends to increase from 1.1 million in 2004 to 2.14 million in 2014. As a result, many patients are inconvenienced in their daily lives, their quality of life deteriorates, and when they are severe, they suffer from loss of eyesight and other pains.
The causes of dry eye are diverse, but therapeutic agents are limited.

Examples of dry eye therapeutic agents include cyclosporine, which is an immunosuppressant, diquafosol and rebamipide, which promote mucous secretion, and hyaluronic acid eye drops, which promote eye dryness prevention and epithelial cell healing.

Among them, rebamipide is known to promote mucin, secrete mucus, and have an effect on dry eye, and is currently sold in Japan as a MUCOSTA (registered trademark) UD 2% suspended eye drop.

This product is a product made of a white suspending agent, and has a problem of causing side effects such as burning sensation, pain, and eye stains generated from the suspending agent.

In addition, since filtration sterilization and steam sterilization are not possible in manufacturing as compared with solution-state preparations, the process design required for sterilization becomes complicated, and quality control and guarantee of sterility are extremely difficult. ..

In order to overcome this, the development of safe and effective new solution-state eye drops is required.

Patent Document 1 for such an eye drop in a solution state describes the production in a solution state, but the pH of the eye drop is 8.3 to 9.3 by using a separate dissolving additive. It is stated that there is a risk of irritation and mucosal damage when administered by eye drops.

The pH of ordinary eye drops preferably does not exceed 8, and the range of pH 7 to pH 8 similar to that of body fluids is compatible with the living body.

Rebamipide is hardly soluble in water, and as the pH becomes more basic, its solubility increases and it becomes easier to dissolve.

However, when the pH of rebamipide, which is basic and solubilized, is lowered to the biological range, precipitation occurs due to a rapid decrease in solubility.

Patent Document 2 discloses a composition using hydropropylmethylcellulose as a viscosity enhancer, glycols as an isotonic agent, and an inorganic salt as a buffer in order to maintain the stability of an aqueous solution containing rebamipide. There is.

However, the composition of Patent Document 2 also has a problem that it is dissolved in a weak alkalinity and a precipitate is formed when left for a long time.

Patent Document 3 describes an eye drop composition in an aqueous solution state produced by using an amino acid, polyvinylpyrrolidone as a solubilizing agent, and macrogol, and the main additive, macrogol, is described. Difficult to use as eye drops.

Macrogol is usually used to solubilize sparingly soluble substances, but when used for eye drops, it may irritate the ocular mucosa, so only a small amount can be used, and it can be used from the aspect of safety. Better to be eliminated.

In particular, it is preferable to eliminate the use of macrogol in formulations such as dry eye that are prone to recurrence and must be used for a long period of time.

In order to minimize such side effects, in Patent Document 4, rebamipide is dissolved together with a base in water at a pH of 8.5 or higher, and then cyclodextrins are used as a recrystallization inhibitor to adsorb rebamipide to make it transparent. A formulation method for solubilizing while maintaining a stable solution state is posted.

Cyclodextrin has been introduced to the USP as a sequestrant. However, cyclodextrins have not been approved by US and South Korean regulatory agencies as eye drop additives and are used in Europe.

Even in the European FDA, cyclodextrin is not known to be safe according to the dose to the eye.

The European FDA-approved Voltaren product uses hydroxypropyl-γ-cyclodextrin with a content of 2%, and the Indomethacin product contains 2-hydroxypropyl-β-cyclodextrin as the main component. It is described that 4.3% of cyclodextrin is used in the case of 25 times the molar ratio, that is, 0.1% of the main component (Patent Document 5).

However, Jansen T's Non-Patent Document 1 clarifies that cyclodextrins are not suitable as ophthalmic preparations because they may induce toxicity to the cornea at 5% or more.

Patent Document 5 describes that cyclodextrin is used 1.5 to 6 times as much as the main component, and 3% to 12% is used. This has the problem that additional toxicity data must be provided as there is no data available as a pharmaceutical excipient for cyclodextrins in 3% or more. Further, it can be seen that even in the examples, the biocompatibility problem still exists by producing at a pH of 8 or more. The invention discloses an eye drop in an aqueous solution state, but it is said that complete stabilization of the solution state was achieved because the stability test in the aqueous solution state was carried out only for a limited period for some conditions. It is difficult to evaluate. Therefore, it can be said that it is necessary to develop a sufficiently safe and stable aqueous solution for eye drops from the invention.

Further, Patent Document 6 also describes an aqueous solution eye drop composition using cyclodextrins and amino acids, but has the same problems as the above-mentioned patent.

The present invention has found that the cellulose derivative can maintain a stable state for a long period of time even if the pH range suitable for the living body is adjusted after solubilizing the poorly soluble rebamipide, and the cellulose derivative is stabilized. Selected as agents to complete the present invention, they are safe and suitable for use with eye drops.

In addition, among various substances used as buffers, aminocaproic acid has been found to have the property of synergistically suppressing the precipitation of the main component with the stabilizer, and by selecting this, the present invention The stability of the formulation was further improved by applying it to.

Aminocaproic acid is a compound having an anti-salt effect, and the minimum amount used as an eye drop is 10 mg / mL of a drug, which is administered in 2 to 3 drops at a time, 5 to 6 times a day.

Aminocaproic acid is known as a buffer for its function as an additive, and if it is used within 1/5 of the minimum amount of eye drops used, there is no concern about its safety, and Korean food and drug safety. Such a fact is known from the agency.

Due to the characteristics of the formulation, eye drops are often stored refrigerated by users, and are exposed to temperature conditions with large temperature differences such as winter and summer. Under these conditions, ensuring its physicochemical safety is very important, especially when the poorly soluble drug is solubilized.

Therefore, in the present invention, we have developed a complete aqueous solution for eye drops, and have invented and disclosed a composition that is stable in all of refrigeration, room temperature, acceleration, and cross-storage.

The pharmaceutical product of the present invention was physicochemically stable under various storage conditions that could be exposed in the actual distribution and use environment, and was able to overcome instability such as precipitation.

Korean Patent No. 10-0281865 Pamphlet of WO2008 / 074853 Korean Patent Publication No. 2011-0027786 Korean Patent No. 10-178733 US08 / 706,268 Korean Published Patent Gazette No. 2017-0039347

Lens Eye Toxic Res. 1990; 7 (3-4): 459-68.

The present invention relates to an eye drop in an aqueous solution state in which side effects caused by administration of a conventional rebamipide suspension and a solution preparation are minimized and the bioavailability is increased, and long-term precipitation occurs even under various storage conditions. It is an object of the present invention to provide an eye drop composition which is stable and can be used as an eye drop, and which exhibits a pH range suitable for a living body, and a method for solubilizing and stabilizing the eye drop composition.

An object of the present invention is to provide an effective formulation for the treatment of dry eye by the formulation technique.

In the present invention, in order to solve the problems of the prior art, the aqueous solution is adjusted to pH 10 to pH 11 by using a basic substance for solubilizing levamipide without using a separate solubilizing agent or solubilizing agent. After adjustment, levamipide was dissolved in an aqueous solution, and the present invention was completed using a stabilizer and a buffer that are harmless to the human body and a nonionic osmoregulator.

The concentration of rebamipide, which is a pharmacological component of the present invention, is preferably 0.5 to 2.0 w / v%, more preferably 1.0 to 1.5 w / v%. If the concentration is less than 0.5 w / v%, the medicinal effect may decrease, and if it exceeds 2.0 w / v%, crystals may be formed, which lowers the stability and also has the effect of increasing the medicinal effect. small.

The basic substance usually has a strongly basic OH group, and when these are used, solubilization can be effectively achieved with a small amount, and it can be used as an eye drop such as NaOH and KOH. It is a thing.

It contains additives to adjust the pH of solubilized levamipide to the biological level and stabilize it, and among various conventional stabilizers, xanthan gum, povidone, hydroxypropyl methylcellulose, which are harmless to the human body, It is characterized in that at least one of water-soluble to water-swellable substances selected from the group consisting of methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose and the like is used.

Preferably, it may be at least one selected from the cellulose derivatives such as hydroxypropylmethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and carboxymethyl cellulose.

The concentration of the stabilizer used is 0.1 to 1.0 w / v%, preferably 0.4 to 0.6 w / v%. If the concentration is less than 0.1 w / v% , crystals may be formed, and if it exceeds 1.0 w / v%, side effects may occur.

The buffer functions so that rebamipide can be maintained in a solubilized state at a pH range suitable for the living body during storage, and among various buffers, aminocaproic acid alone or a mixture of aminocaproic acid and boric acid may be used. Often, the concentration of the buffer used is 0.1 to 1.0 w / v%, preferably 0.2 to 0.5 w / v%. If the concentration is less than 0.1 w / v%, crystallization may occur, and if it exceeds 1.0 w / v%, side effects may occur on the human body.

By using the stabilizer and the buffer, the present inventors have found that the combination of various stabilizers and the components of the buffer is most effective in stabilizing rebamipide, and the present invention has been developed. It is completed.

The osmotic pressure regulator is used for osmotic pressure regulation of eye drops, and a normal osmotic pressure regulator may be used for osmotic pressure regulation, but in particular, ionic NaCl, KCl, etc. are excluded. In principle, at least one of nonionic osmoregulators including sorbitol, mannitol, dextrose, chloride, glycerin and the like is preferably selected and used.

We found that the use of large amounts of electrolyte osmoregulators such as NaCl and KCl facilitated the formation of salts with rebamipide during storage and eliminated their use.

The concentration of the osmotic pressure regulator is 0.5 to 10.0 w / v%, preferably 1.0 to 4.0 w / v%. When the concentration is less than 0.5 w / v%, the osmotic pressure becomes very low and side effects may occur on the mucous membrane. When the concentration exceeds 10.0 w / v%, the osmotic pressure becomes very high and the drug is absorbed. The force is reduced and there is a risk of side effects occurring on the human body.

Finally, the main component, stabilizer, buffer, osmotic pressure regulator and basic substance are all added to solubilize at pH 10 to pH 11 so that the pH is in the range suitable for the living body, pH 7 to pH 8. Adjust the pH by adding an appropriate amount of acid.

If the pH at the time of solubilization is less than 10, it may be difficult to completely dissolve rebamipide, and if it exceeds pH 11, problems such as neutralization due to overuse of basic substances may occur. In addition, when the pH of the final product is less than 7, it shows weak acidity, which may cause maladaptation with the living body, and when the pH exceeds 8, there is a risk of inducing pain in the mucous membrane or damaging cells.

At this time, the basic substance used is preferably NaOH or KOH, and the acid is a pharmaceutically acceptable inorganic or organic acid such as hydrochloric acid, citric acid, tartaric acid or succinic acid. The acid is a 1M concentration solution and is used in less than 0.5% (v / v).

In the present invention, the combined concentration of the buffer agent and the osmotic pressure regulator is characterized in that the osmotic pressure of the aqueous solution for all eye drops is 100 to 300 mOsm, preferably 130 to 250 mOsm.

By producing according to the above method, the present inventors were able to invent an eye drop composition in an aqueous solution state, which is novel to the human body, has high stability in the human body, is excellent in storage stability, and is suitable for the living body. ..

The production method for solubilization and stabilization of the present invention comprises the following steps.

(A) A step of adding a base to rebamipide or a pharmaceutically acceptable salt and stabilizer thereof, dissolving it in water to obtain it at pH 10 to pH 11; and

(B) The step of adding a buffer and an osmotic pressure regulator, dissolving the mixture, and adjusting the pH to 7 to 8 with an acid;

After that, it may be further added to a step such as filtration for sterilization.

The aqueous solution produced by the above step was compared with a typical drug used as a therapeutic agent for dry eye in mice in which dry eye was induced.

An eye drop for treating dry eye solubilized by the present invention is provided.

The present invention minimizes the side effects that occur when the rebamipide solution preparation is administered, and even under various storage conditions, there is no long-term precipitation within the pH range suitable for the living body, and a stable effect is exhibited.

Further, the present invention has an effect that an effective solution preparation for the treatment of dry eye can be easily and economically produced without adding a separate additive.

It is a photograph of the property observation result after 8 weeks lapse under the storage conditions of Comparative Example 3, Comparative Example 8 and Example 10. It is a graph which shows the result of confirming the generation of tears between the present invention and a control group in a dry eye model mouse. It is a figure which is the corneal surface flexibility of the control group with this invention, and shows the shape of the optical fiber ring reflected by the stereomicroscope in the dry stress group as compared with the normal group. It is a graph which shows the corneal surface flexibility confirmation result of this invention and a control group in a dry eye model mouse. It is a figure which shows the mucin-stained shape of this invention and a positive control group in a dry eye model mouse. It is a mucin staining analysis graph figure of this invention and a positive control group in a dry eye model mouse.

Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples.
However, the following Examples and Test Examples are for exemplifying the present invention, and the scope of the present invention is not limited thereto.

[Comparative Examples 1 to 8] Effect of stabilizer on solubilization of rebamipide

* Hypromellose: Hydroxypropylmethylcellulose 1) To 85 mL of distilled water, add the stabilizer corresponding to each Comparative Example, stir to dissolve, then add rebamipide, which is the main component, and stir to suspend.
2) To the solution of 1) above, a 1N NaOH solution, which is a solubilizer corresponding to each Comparative Example, is added dropwise with stirring to adjust the pH to 10 to 11, and all the main components are dissolved.
3) Add a 1N HCl solution, which is a pH adjuster, to the transparent solution obtained in 2) above to adjust the pH to the range of 7 to 8. At this time, the osmotic pressure is 70 mOsmol / kg to 90 mOsmol / kg.
4) Distilled water was added to the transparent solution obtained in 3) above to make the total volume 100 mL.

[Test Example 1] Changes in properties of Comparative Examples 1 to 7 In the cases of Comparative Example 1 and Comparative Example 2 produced, the drug was solubilized during the production, but the main component and the polymer were adjusted while adjusting the pH. Precipitation was formed and solubilization was impossible.
On the other hand, the solutions of Comparative Examples 3 to 7 were produced in a solution state in which the solubility of rebamipide in water (about 0.025 mg / mL) was significantly increased by 600 times or more, and Comparative Example 3 Table 2 shows the changes in the properties of ~ 7.

As shown in Table 2, it can be seen that the cellulose derivative is the most excellent as a stabilizer.

[Comparative Examples 8 to 11 and Examples 1 to 8] Production of 1.5% eye drops by solubilization of rebamipide

1) Add the stabilizer corresponding to the example to 85 mL of distilled water, stir to dissolve, then add rebamipide, which is the main component corresponding to each comparative example and the example, and stir to suspend.
2) Add a 1N NaOH solution as a solubilizer to the solution of 1) with stirring to adjust the pH to 10 to 11, and dissolve all the main components.
3) To the solution of 2) above, the buffer corresponding to each Comparative Example and Example is added, and the mixture is stirred to dissolve all of them.
4) The osmotic pressure regulator corresponding to each Comparative Example and Example is added to the solution of 3) above, and the mixture is stirred to adjust the content to 280 mOsmol / kg to 300 mOsmol / kg to make it isotonic with the body fluid.
5) To the transparent solution obtained in 4) above, a 1N HCl solution, which is a pH adjuster corresponding to each Comparative Example and Example, is added dropwise to adjust the pH to 7 to 8.
6) Distilled water was added to the transparent solution obtained in 5) above to make the total volume 100 mL, and a transparent solution was obtained.
7) The transparent solution obtained in 4) above was filtered through a syringe filter having a pore size of 0.2 μm to produce aseptically.
The solutions of Comparative Examples 8 to 11 and Examples 1 to 8 produced as described above can be produced in a clean and transparent aqueous solution state at the time of production, and can be produced by using a buffer and an osmotic pressure regulator. The pH and osmotic pressure can be adjusted within the range that can be used as an eye drop, and the product was produced in a stable solution state.

[Test Example 2] Changes in properties, pH and content of Comparative Examples 8 to 11 and Examples 1 to 8 Table 4 shows changes in pH and content of Comparative Examples 8 to 11 and Examples 1 to 8.
No significant change in pH was confirmed when all of the aqueous solutions of the examples whose properties were evaluated were stored at 25 ° C. for 4 weeks, which is the test period.
In addition, Examples 1 to 8 maintained a stable state with no significant change in content and no precipitation for 5 weeks.

As shown in Table 4, it can be seen that stability is maintained for a long period of time by using aminocaproic acid as a buffer and a nonionic compound as an osmotic pressure regulator.

[Examples 9 to 18] Production of 1.5% eye drops by solubilization of rebamipide

1) To 85 mL of distilled water, the stabilizer corresponding to each example is added, stirred and dissolved, then rebamipide, which is the main component, is added, and the mixture is stirred and suspended.
2) Add a 1N NaOH solution as a solubilizer to the solution of 1) with stirring to adjust the pH to 10 to 11, and dissolve all the main components.
3) Add the buffer corresponding to each example to the solution of 2) above, and stir to dissolve all of them.
4) The osmotic pressure regulator corresponding to each example is added to the solution of 3) above, and the mixture is stirred to adjust the osmotic pressure to 220 mOsmol / kg to 240 mOsmol / kg, which is a storability within a range that can be used as an eye drop.
5) To the transparent solution obtained in 4) above, a 1N HCl solution, which is a pH adjuster corresponding to each example, is added dropwise to adjust the pH to 7 to 8.
6) Distilled water was added to the transparent solution obtained in 5) above to make the total volume 100 mL, and a transparent solution was obtained.
7) The transparent solution obtained in 4) above was filtered through a syringe filter having a pore size of 0.2 μm to produce aseptically.
The solutions of Examples 9 to 18 produced as described above could be produced in a clean and transparent aqueous solution state at the time of production.
The property evaluation of Examples 9 to 18 recorded the time when the precipitation of the solution was first started through the storage at 4 ° C, 25 ° C, 40 ° C and the cross-storage test.
The cross-storage test observed and recorded precipitation formation twice daily in the morning and afternoon with alternating storage at 4 ° C./room temperature.
As a result, it was confirmed that under the above-mentioned all-tube conditions, there was no precipitation for a minimum of 14 weeks or more, and a stable solution state was maintained.

[Test Example 3] Changes in pH and content of Examples 9 to 18 During storage at 4 ° C, 25 ° C, 40 ° C and cross-storage of Examples 9 to 18, as a result of pH change and property observation, storage at 25 ° C, 40 ° C. Table 6 shows the change in the content of the aqueous solution.
Examples 9-18 had no significant pH and content changes under all storage conditions for 12 weeks. It was also physicochemically stable under all storage conditions for 15 weeks.

As shown in Table 6, the same effect was exhibited even when boric acid and aminocaproic acid were mixed and used as a buffer, and the stability was maintained for a long period of time.

[Examples 19 to 22] Production of 1.5% eye drops by solubilization of rebamipide

1) To 85 mL of distilled water, a stabilizer is added and dissolved while stirring, then rebamipide, which is the main component, is added, and the mixture is stirred and suspended.
2) Add a 1N NaOH solution as a solubilizer to the solution of 1) with stirring to adjust the pH to 10 to 11, and dissolve all the main components.
3) Add the buffer corresponding to each example to the solution of 2) above, and stir to dissolve all of them.
4) The osmotic pressure regulator corresponding to each example is added to the solution of 3) above, and the mixture is stirred to adjust the osmotic pressure to 170 mOsmol / kg to 190 mOsmol / kg, which is storable.
5) To the transparent solution obtained in 4) above, a 1N HCl solution, which is a pH adjuster corresponding to each example, is added dropwise to adjust the pH to 7 to 8.
6) Distilled water was added to the transparent solution obtained in 5) above to make the total volume 100 mL, and a transparent solution was obtained.
7) The transparent solution obtained in 4) above was filtered through a syringe filter having a pore size of 0.2 μm to produce aseptically.
The solutions of Examples 19 to 22 produced as described above could be produced in a clean and transparent aqueous solution state at the time of production.
The property evaluation of Examples 19 to 22 recorded the time when the precipitation of the solution was first started by the storage at 4 ° C., 25 ° C., 40 ° C. and the cross-storage test.
As a result, it was confirmed that there was no precipitation for at least 15 weeks under all the above-mentioned storage conditions, and a stable solution state was maintained.

[Test Example 4] Changes in pH and content of Examples 19 to 22 As a result of pH changes and property observations of Examples 19 to 22 at 4 ° C., 25 ° C., 40 ° C. and cross-storage, 25 ° C. and 40 ° C. are being stored. Table 8 shows the change in the content of the aqueous solution of.
Examples 19 to 22 had no significant change in pH and content under all storage conditions for 4 weeks. It was physicochemically stable under all storage conditions for a minimum of 8 weeks.

Based on the above test results, the composition of the present invention was physicochemically stable even after storage for at least 15 weeks, and the comparative example was not maintained in a solution state for 4 weeks or longer. The results of property observation for this are shown in FIG.

[Test Example 5] Effect of 1,1.5% rebamipide aqueous solution in dry eye model A positive control group was applied to mice in which dry eye was induced by using the 1,1.5% rebamipide aqueous solution produced by the method of Example 2. And the dosage was 1% 6 times a day and 1.5% 4 times a day to confirm the efficacy.
6-8 weeks old NOD. After purchasing B10-H2b mice from Jackson Laboratory, they were bred and subjected to drought stress for 10 days in mice aged 12 weeks or older.
For dry stress, 0.5 mg / 0.2 mL of scopolamine hydrobromide was subcutaneously injected into the thigh four times daily (8 am, 11 pm, 2 pm, 5 pm) and the humidity of the breeding environment was 40% or less. Maintained in.
After 10 days, tear formation and corneal surface flexibility were measured and the following tests were performed only on mouse models with dry eye.
Tear production was significantly reduced in the drought stress group (0.034 ± 0.016 μL) compared to the normal group (0.215 ± 0.028 μL) (see FIG. 2).
After removal of drought stress, vehicle (0.124 ± 0.021 μL), cyclosporin A (0.143 ± 0.044 μL), levamipide 1.5% (4 times; 0.21 ± 0.036 μL), mucosta (0. In the treatment group of 244 ± 0.033 μL), diquafosol (0.249 ± 0.027 μL), and levamipide 1.0% (6 times; 0.251 ± 0.051 μL), tear production was 3.7 on the 10th day, respectively. It increased by a factor of 4.2, 6.2 times, 7.2 times, 7.4 times, and 7.5 times.
Rebamipide 1.0% (6 times) and rebamipide 1.5% (4 times) treatment groups were observed to significantly increase lacrimation than the cyclosporine A treatment group, similar to the Mucosta and diquafosol treatment groups. Increased tear production to levels.
It was also observed that there was no significant difference in lacrimation between the rebamipide 1.0% (6 times) and rebamipide 1.5% (4 times) treatment groups.
As for the corneal surface flexibility, a serious distortion of the photofiber ring shape reflected by the stereomicroscope from the drought stress group was observed as compared with the normal group (see FIG. 3).
After drought stress, in the test group rebamipide 1.0% (6 times), rebamipide 1.5% (4 times) treatment group and the control drug group Mucosta treatment group, the distortion of the photofiber ring was observed on the 10th day. Improvement was observed.
As for the corneal surface flexibility score, each membrane surface flexibility increased in the drought stress group (3.667 ± 0.408 points) as compared with the normal group (0.083 ± 0.204 points) (see FIG. 4). ..
Cyclosporin A (3.417 ± 0.376 points), vehicle (3.25 ± 0.274 points), diquafosol (3.25 ± 0.274 points), rebamipide 1. 5% (4 times; 1.833 ± 0.683 points), Mucosta (1.667 ± 0.516 points), rebamipide 1.0% (6 times; 1.5 ± 0.775 points) treatment group The corneal surface flexibility was improved by 6.8%, 11.4%, 11.4%, 50%, 54.5% and 59.1%, respectively.
In addition, it was observed that the rebamipide 1.0% (6 times) and rebamipide 1.5% (4 times) treatment group improved the corneal surface flexibility as compared with the cyclosporine A and diquafosol treatment group, which was similar to Mucosta. It was improved to the standard.
It was observed that there was no significant difference between the rebamipide 1.0% (6 times) and rebamipide 1.5% (4 times) treatment groups.
After the production of the dry eye model, mucin staining was performed to investigate the mucin distribution of the mouse conjunctiva by drug treatment (see FIG. 5).
It was observed that the conjunctival mucin distribution was even reduced in the drought stress group (6.19 ± 1.155 cells / 0.1 mm2) compared to the normal group (17.429 ± 2.726 cells / 0.1 mm2). rice field.
Vehicles (7.524 ± 1.155 cells / 0.1 mm2), diquafosol (8.571 ± 0.99 cells / 0.1 mm2), cyclosporin A (18.952 ± 1.35 cells /) compared to the drought stress group. 0.1 mm2), Mucosta (19.905 ± 2.163 cells / 0.1 mm2), rebamipide 1.0% (6 times; 21.714 ± 1.784 cells / 0.1 mm2), rebamipide 1.5% ( 4 times; 22.095 ± 1.722 cells / 0.1 mm2) In the treatment group, 1.2 times, 1.4 times, 3.1 times, 3.2 times, 3.5 times, 3.6 times, respectively. It was observed that the mutin distribution in the conjunctiva increased (see FIG. 6).
In addition, the mucin distribution in the conjunctiva was increased in the rebamipide 1.0% (6 times) and rebamipide 1.5% (4 times) treatment groups compared to the diquafosol treatment group, and reached a level similar to that of the mucosta and cyclosporine A treatment groups. Was increased.
However, it was revealed that there was no significant difference between the rebamipide 1.0% (6 times) and rebamipide 1.5% (4 times) treatment groups.

As described above, the aqueous solution-made preparation of the present invention exhibits improved medicinal properties as compared with the conventional eye drops, and is useful because it is easy to manufacture and can provide an eye drop having excellent stability. Invention.

The detailed description of the present invention is merely exemplary of the present invention, which is merely used for the purpose of explaining the present invention, and is described in the meaning limitation and the claims. It was not used to limit the scope of the invention. Therefore, any person with ordinary knowledge in the art may be able to make various variations and equal other examples from these. Therefore, the true technical protection scope of the present invention is determined by the technical idea of the attached claims.

Claims (7)

A method for producing an eye drop composition containing rebamipide as an active ingredient.
(A) A base is added to levamipide or a pharmaceutically acceptable salt thereof, and at least one stabilizer selected from the group consisting of hydroxypropylmethyl cellulose, methyl cellulose, hydroxypropyl cellulose, and hydroxyethyl cellulose, and dissolved in water. To obtain an aqueous ophthalmic solution having a pH of 10 to 11;
(B) Non-ionic eye drops obtained in step (a) containing any one buffer selected from aminocaproic acid, aminocaproic acid and boric acid, and sorbitol, mannitol, dextrose, sucrose and glycerin. The step of adding at least one osmoregulator selected from the osmoregulators, dissolving and adjusting to pH 7 to pH 8 with acid;
(C) A step of filtering the transparent solution obtained in the step (b) with a syringe filter to aseptically produce the solution;
A method for producing a rebamipide eye drop composition for treating dry eye , which comprises. The method for producing a rebamipide eye drop composition for dry eye treatment according to claim 1, wherein rebamipide is solubilized colorless and transparent at a concentration of 0.5 to 2.0 w / v%. The method for producing a rebamipide eye drop composition for dry eye treatment according to claim 1, wherein the concentration of the stabilizer is 0.2 to 0.9 w / v%. The method for producing a rebamipide eye drop composition for treating dry eye according to claim 1, wherein the concentration of the buffer is 0.1 to 0.5 w / v%. The method for producing a rebamipide eye drop composition for treating dry eye according to claim 4, wherein the concentration of the buffer is 0.2 to 0.4 w / v%. The method for producing a rebamipide eye drop composition for dry eye treatment according to claim 1, wherein the osmotic pressure of the solution obtained in the step (b) is 100 to 300 mOsm. The method for producing a rebamipide eye drop composition for dry eye treatment according to claim 6, wherein the osmotic pressure of the solution obtained in the step (b) is 130 to 250 mOsm.

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