WO2005058932A1

WO2005058932A1 - Tear layer stabilizer

Info

Publication number: WO2005058932A1
Application number: PCT/JP2004/018883
Authority: WO
Inventors: Masatsugu Nakamura; Shin-Ichiro Hirai; Akio Kimura; Kayoko Sakamoto; Yukiko Sugihara
Original assignee: Santen Pharmaceutical Co., Ltd.
Priority date: 2003-12-18
Filing date: 2004-12-17
Publication date: 2005-06-30

Abstract

The invention aims at finding remedies for dry eye or corneal and conjunctival epitheliopathies caused by dry eye. Eye drops containing mannose exert excellent ameliorative effects on dry eye or corneal and conjunctival epitheliopathies caused by dry eye through the stabilization of the tear layer.

Description

Specification

Tear film stabilizer

Technical field

The present invention relates to a tear film stabilizing agent comprising mannose as an active ingredient. In addition, the present invention relates to a therapeutic agent for dry eye or a corneal conjunctival epithelial disorder caused by dry eye, which contains mannose as an active ingredient.

Background art

[0002] The cornea is a transparent avascular tissue with a diameter of about lcm and a thickness of about lmm, and the conjunctiva is a mucous membrane covering the surface of the eyeball behind the limbus and the back of the eyelid. Is known to have a significant effect on visual function.

[0003] By the way, the tear film covering the surface of the eyeball is kept extremely thin and smooth, but when the tear film becomes unstable, the surface becomes less smooth, resulting in a short time before blinking. During this time, a dry area called a dry spot is formed, and a part of the cornea may be exposed. If the tear film on the surface of the eyeball becomes unstable in this way, dryness and discomfort may occur in the eye, and frequent exposure of the cornea may cause symptoms such as dry eye.

[0004] Dry eye is a condition in which the tears decrease or the function of the tears deteriorates, and thus the surface of the eyes can be damaged, resulting in eye fatigue, pain, redness, etc. It also causes keratoconjunctival epithelial damage (Non-Patent Document 1). In recent years, corneal epithelial damage due to dry eye has been increasing with the wearing of contact lenses.

[0005] On the other hand, mannose is widely distributed in the plant kingdom, and is also used as an additive in power drugs known as hydrolysates (monosaccharides) of polysaccharides such as mannan. Safety to the human body has also been confirmed. Patent Document 1 describes an invention relating to a wound treatment agent for severe burns, burns, pressure sores, etc., comprising sugar, potassium and a disinfectant (antibiotic 'antibacterial agent), and glucose, mannose, maltose as sugar. Are listed. Patent Document 2 describes an invention relating to a pharmaceutical composition for treating skin or mucosal diseases such as allergic rhinitis and allergic conjunctivitis, and one of the pharmaceutical compositions is Darco. Sugars such as sugar, galactose and mannose.

[0006] Nevertheless, there is no finding that mannose stabilizes the tear film on the surface of the eyeball, and there is no report examining pharmacological effects on dry eye.

Patent Document 1: JP-A-63-215631

Patent Document 2: Japanese Patent Application Laid-Open No. 2002-308783

Non-Patent Document 1: Rinsei, 46, 738-743 (1992)

Disclosure of the invention

Problems to be solved by the invention

An object of the present invention is to provide a safe eye drop having an excellent therapeutic effect on dry eye and keratoconjunctival epithelial disorder caused by dry eye.

Means for solving the problem

[0008] The present inventor first performed a corneal surface irregularity index change test, instilled a mannose-containing eye drop, and then applied a spherical irregularity on the eyeball surface (the spherical irregularity was caused by the tear film on the corneal surface). When measured over time, it was surprisingly surprising that mannose, which is easily available and has excellent safety for the human body, has a stabilizing effect on the tear film. I found something. Furthermore, the present inventors have found out that mannose exerts an excellent ameliorating effect on corneal epithelial disorder by conducting a test on the effect of curing corneal epithelial disorder on a dry eye model.

That is, the present invention provides a tear film stabilizer containing mannose as an active ingredient.

[0010] The concentration of mannose is preferably 0.01 20% (wZv).

[0011] The present invention also provides a therapeutic agent for dry eye or a corneal conjunctival epithelial disorder caused by dry eye, comprising mannose as an active ingredient.

[0012] Corneal conjunctival epithelial disorders caused by dry eye include, for example, corneal ulcer, keratitis, conjunctivitis, punctate keratopathy, corneal epithelial defect, conjunctival epithelial defect, keratoconjunctivitis sicca, upper limbal keratoconjunctivitis, or filamentous Keratitis.

[0013] A preferred dosage form is an eye drop.

[0014] The present invention provides a tear film on the surface of an eyeball by instilling an eye drop containing mannose. Also provides a system to stabilize.

The ophthalmic solution containing mannose of the present invention is intended to stabilize the tear film and treat keratoconjunctival epithelial disorder caused by dry eye or dry eye. The treatment of corneal epithelial disorders associated with the use of is also included in the object of the present invention. It is presumed that the ophthalmic solution containing mannose of the present invention exerts a therapeutic effect on corneal epithelial damage by the dry eye model based on the stabilization of the tear film by mannose.

[0016] The mannose used in the present invention is not particularly limited, and commercially available mannose may be used as it is. Mannose is a component of glycoproteins of animals and plants and is used as an additive for pharmaceuticals, so that it is highly safe for the human body.

A preferred administration form of the tear film stabilizer or the therapeutic agent for keratoconjunctival epithelial disorder of the present invention includes, for example, eye drops, which can be formulated using a commonly used technique. .

The concentration of mannose in the ophthalmic solution of the present invention is not particularly limited, but from the viewpoint of the properties and effects of the ophthalmic solution, the mannose concentration is 0.01-1% (w / v), Preferably 0.1-15

% (w / v), more preferably 110% (w / v).

[0019] The ophthalmic solution containing mannose of the present invention may contain other drugs as long as the object of the present invention is not impaired. Examples of such drugs include antibacterial agents, anti-inflammatory agents, antihistamines, antiglaucoma agents, antiallergic agents, immunosuppressants, antimetabolites and the like.

[0020] The eye drops of the present invention may appropriately contain isotonic agents, buffers, pH adjusters, solubilizers, stabilizers, preservatives and the like.

[0021] Examples of the tonicity agent include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like.

[0022] Examples of the buffer include phosphoric acid, phosphate, citric acid, acetic acid, ε-aminocaproic acid, trometamol, and the like.

Examples of the pH regulator include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium hydrogen carbonate and the like. [0024] Examples of the solubilizing agent to be added when the drug or other additives are hardly water-soluble are polysonolate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000 and the like. it can.

[0025] Examples of the stabilizer include edetic acid and sodium edetate.

[0026] Examples of the preservative include sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, and the like. These preservatives may be used in combination. You can also.

[0027] It is desirable that the pH of the eye drop of the present invention is set to 4.0 8.0, and the osmotic pressure ratio is 1

It is desirable to set around 0.

[0028] The present invention also relates to a method for treating a disease caused by tear film instability, which comprises administering a therapeutically effective amount of mannose to a patient. Mannose preferably at a concentration of 0.011 20

% (w / v).

[0029] The present invention further relates to a method for treating dry eye or a corneal conjunctival epithelial disorder caused by dry eye, comprising administering a therapeutically effective amount of mannose to a patient. Corneal conjunctival epithelial disorders caused by dry eye include, for example, corneal ulcers, keratitis, conjunctivitis, punctate keratopathy, corneal epithelial defect, conjunctival epithelial defect, keratoconjunctivitis sicca, superior limbal keratoconjunctivitis or filamentous keratitis. is there.

[0030] The number of times of eye drops of the eye drops of the present invention can be appropriately selected depending on symptoms, age, dosage form and the like, but is preferably about six times once a day. The dosage of mannose is preferably 2 μg / day to about 10 Omg.

The invention's effect

[0031] As described in detail in the section of the change test of the corneal surface irregularity index described below, after the eye drops containing mannose of the present invention were instilled, the spherical irregularity of the eyeball surface was measured over time. The eye drops stably retain the tear film on the eyeball surface. In addition, from the results of the healing efficacy test for corneal epithelial disorder, eye drops containing mannose exhibited an excellent healing effect in a dry eye model, and were useful as a therapeutic agent for corneal conjunctival epithelial disorder caused by dry eye It is.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to Examples, but this is for better understanding of the present invention, and does not limit the scope of the present invention.

[0033] [Cornea surface irregularity index change test]

This test measures the tear stabilizing effect of each test ophthalmic solution by measuring the irregularity of the corneal surface (tear layer irregularity) after instillation of the test ophthalmic solution using a corneal shape measuring device. To evaluate.

(Experimental method)

After instilling 20 μl of 5% aqueous mannose (wZv) solution into the eyes of a male Japanese White White Egret under general anesthesia, 0 (immediately after instillation) under forced eyelids and 10 minutes later the corneal surface shape was measured using a corneal shape measurement device. The measurement was carried out using a device (“TMS_2N” manufactured by Tome Kabushiki Kaisha).

[0035] The same operation as above was performed using 20 µl of physiological saline as a control instead of the aqueous mannose solution.

[0036] (Result)

Based on the measured spherical irregularity index (the spherical irregularity index is a value that increases as the shape of the tear film on the corneal surface becomes irregular). The value subtracted from the spherical irregularity index) was calculated. Table 1 shows the results. The change in spherical irregularity index of each test solution indicates the average value of three or five cases.

[table 1]

[0037] (Discussion)

As is clear from Table 1, the aqueous solution containing mannose shows a remarkable tear stabilizing effect as compared with the physiological saline containing no mannose.

[Healing efficacy test for corneal epithelial disorder] Using a male SD rat, a dry eye model was prepared according to the method of Fujihara et al. (Invest. Ophthalmol. Vis. Sci 42 (1): 96_100 (2001)). After the preparation of the dry eye model, the improvement rate of corneal epithelial disorder was determined using a method modified by the method of Miyata et al.

[0039] (Experimental method)

Nembutal was administered to male SD rats to perform general anesthesia. The extraorbital lacrimal gland was excised and induced corneal epithelial damage over 2 months.

Next, a 5% aqueous solution of mannose (w / v) was instilled six times a day for 7 days.

Seven days after the start of instillation, the damaged part of the corneal epithelium was stained with fluorescein. The degree of fluorescein staining was determined for each of the upper, middle and lower parts of the corneal epithelium according to the following criteria, and the amelioration rate of corneal epithelial disorder was calculated from the average of the sum of the scores of each part.

[0042] The same operation as above was performed using physiological saline as a control instead of the aqueous mannose solution.

Further, for the normal eye, the average value of the sum of the scores of the above-described parts was determined.

(Judgment criteria)

0: Not stained.

1: Staining is sparse, and each dot-like stained part is separated.

2: Staining is moderate, and a part of the dot-like stained portion is adjacent.

3: Dyeing is dense, and each dot-like stained portion is adjacent.

[0048] (Result)

The improvement rate of the 5% mannose (w / v) eye drop group was calculated based on the average value of the scores of the respective parts in the physiological saline eye drop group (control) (the improvement rate: 0%). This is shown in Table 2. The average of the scores is the average of eight cases. The improvement rate was calculated by the following formula.

[0049] Improvement rate (%) = {(control) — (mannose)} / disability X 100

Disability = (control) — (normal eye)

[Table 2] Average of total group scores Improvement rate (%) Normal eyes 3.2

Physiological saline 5.60

5% mannose aqueous solution 4.3 5 4.2

[0050] (Discussion)

As is clear from the results of the above-mentioned corneal epithelial disorder healing efficacy test using rats, mannose significantly improves corneal epithelial disorder.

[Formulation Examples]

Representative preparation examples using mannose are shown below.

[0052] Formulation example (eye drops)

In 100ml

Mannose 5g

Concentrated glycerin 500mg

Polysorbate 80 200mg

Sodium dihydrogen phosphate dihydrate qs

1N sodium hydroxide

Hydrochloric acid

Appropriate amount of sterilized purified water

[0053] In the same manner as in the above-mentioned formulation examples, eye drops containing 100 mg, lg, 3 g, and 10 g of mannose in 100 ml can be prepared.

Industrial applicability

[0054] An ophthalmic solution containing mannose stably retains the tear film on the eyeball surface. In addition, the ophthalmic solution containing mannose exhibits an excellent healing effect similar to a dry eye model, and is useful as a therapeutic agent for corneal conjunctival epithelial disorder caused by dry eye.

Claims

The scope of the claims

[1] A tear film stabilizer containing mannose as an active ingredient.

[2] The stabilizer for a tear film according to [1], wherein the concentration of mannose is 0.01 to 20% (w / v).

[3] A therapeutic agent for dry eye or keratoconjunctival epidermal disorder caused by dry eye, which contains mannose as an active ingredient.

[4] Corneal conjunctival epithelial disorder caused by dry eye is corneal ulcer, keratitis, conjunctivitis, punctate keratopathy, corneal epithelial defect, conjunctival epithelial defect, keratoconjunctivitis sicca, superior limbal keratoconjunctivitis or filamentous keratitis 4. The therapeutic agent for keratoconjunctival epithelial disorder according to claim 3, which is:

[5] The agent for stabilizing a tear film or a therapeutic agent for corneal conjunctival epithelial disorder according to any one of [14] to [14], wherein the dosage form is an eye drop.

[6] A system that stabilizes the tear film on the eyeball surface by applying eye drops containing mannose.

[7] A method for treating a disease caused by tear film instability comprising administering a therapeutically effective amount of mannose to a patient.

[8] The method according to claim 7, wherein the mannose is administered at a concentration of 0.01 20% (wZv).

[9] A method for treating corneal conjunctival epithelial disorder caused by dry eye or dry eye, comprising administering a therapeutically effective amount of mannose to a patient.

[10] Corneal conjunctival epithelial disorders caused by dry eye include corneal ulcers, keratitis, conjunctivitis, punctate keratopathy, corneal epithelial defect, conjunctival epithelial defect, keratoconjunctivitis sicca, superior limbal keratoconjunctivitis or filamentous keratitis 10. The method according to claim 9, wherein

[11] A method for stabilizing a tear film on an eyeball surface by instilling an eye drop containing mannose.

[12] Use of mannose for the manufacture of a tear film stabilizer.

[13] The use according to claim 12, wherein the concentration of mannose is 0.01-1% (w / v).

[14] Use of mannose for the manufacture of dry eye or a therapeutic agent for corneal conjunctival epithelial disorder caused by dry eye.

[15] Corneal conjunctival epithelial disorders caused by dry eye include corneal ulcers, keratitis, conjunctivitis, punctate superficial horns 15. The use according to claim 14, which is keratopathy, corneal epithelial defect, conjunctival epithelial defect, keratoconjunctivitis sicca, upper limbus keratoconjunctivitis, or filamentous keratitis.

The use according to (12) to (15), wherein the dosage form is an eye drop.