JP2005200411A - Lacrimal fluid layer stabilizing agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a remedy for dry eye or keratoconjunctive epithelium disorder caused by the dry eye. <P>SOLUTION: An eye lotion contains mannose, so that the lotion stabilizes a lacrimal fluid layer and therefore produces an excellent improving effect on the dry eye or the keratoconjunctive epithelium disorder caused by the dry eye. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a tear film stabilizer comprising mannose as an active ingredient. The present invention also relates to a therapeutic agent for keratoconjunctival epithelial disorder caused by dry eye or dry eye containing mannose as an active ingredient.

  The cornea is a transparent avascular tissue with a diameter of about 1 cm and a thickness of about 1 mm. The conjunctiva is a mucous membrane covering the surface of the eyeball behind the corneal margin and the back of the eyelid. It is known to have a significant impact on

  By the way, the tear film covering the surface of the eyeball is extremely thin and kept smooth, but when the tear film becomes unstable, the surface becomes unsmoothed, and for a short time before blinking. A dry portion called a dry spot may occur, and a part of the cornea may be exposed. As described above, if the tear film on the surface of the eyeball is destabilized, dryness and discomfort may occur in the eye, and if the cornea is frequently exposed, symptoms such as dry eye may be caused.

  Dry eye is a symptom in which the surface of the eye can be damaged due to a decrease in tears or a worsening of the function of the tears, resulting in eye fatigue, pain, hyperemia, etc. It is also a cause of failure (Non-Patent Document 1). In recent years, corneal epithelial disorders caused by dry eye have been increasing with the wearing of contact lenses.

  On the other hand, mannose is known as a hydrolyzate (monosaccharide) of polysaccharides such as mannan that is widely distributed in the plant kingdom, but it is also used as an additive for pharmaceuticals and is safe for the human body. Has also been confirmed. Patent Document 1 describes an invention related to wound treatment agents such as severe burns, burns, and bruises composed of sugar, potassium and a bactericidal disinfectant (antibiotic / antibacterial agent), and glucose, mannose, maltose and the like are listed as sugars. Has been. 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 sugars such as glucose, galactose and mannose are mentioned as one of the pharmaceutical compositions. It has been.

However, there is no knowledge that mannose stabilizes the tear film on the surface of the eyeball, and there is no report examining the pharmacological action on dry eye.
Japanese Unexamined Patent Publication No. 63-215631 JP 2002-308783 A Eyesight, 46, 738-743 (1992)

  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.

  The present inventor first conducted a corneal surface irregularity index change test, and after instilling eye drops containing mannose, the spherical irregularity on the surface of the eyeball (Note that the irregularity of the tear film on the corneal surface is illegal. Surprisingly, it was found that mannose, which is easily available and excellent in safety to the human body, has a stabilizing effect on the tear film. It was. Furthermore, by conducting a healing efficacy test for corneal epithelial disorders using a dry eye model, it was found that mannose exerts an excellent improvement effect on corneal epithelial disorders, and the present invention was achieved.

That is, the present invention
(1) A tear film stabilizer containing mannose as an active ingredient,
(2) The tear film stabilizer according to (1), wherein the concentration of mannose is 0.01 to 20% (w / v),
(3) Dry eye containing mannose as an active ingredient or a therapeutic agent for keratoconjunctival epithelial disorder caused by dry eye,
(4) The keratoconjunctival epithelial disorder caused by dry eye is corneal ulcer, keratitis, conjunctivitis, punctate superficial keratopathy, corneal epithelial defect, conjunctival epithelial defect, dry keratoconjunctivitis, upper ring keratoconjunctivitis or filiform keratitis A therapeutic agent for keratoconjunctival epithelial disorder as described in (3) above,
(5) The tear film stabilizer or the therapeutic agent for keratoconjunctival epithelial disorder according to any one of (1) to (4), wherein the dosage form is an eye drop;
(6) a system for stabilizing the tear film on the surface of the eyeball by instilling an eye drop containing mannose;
About.

 The eye drop 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 is naturally included in the object of the present invention. It is presumed that the eye drop containing the mannose of the present invention exerts a therapeutic effect on the corneal epithelial disorder caused by the dry eye model is based on the stabilizing action of the tear film by mannose.

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

 A preferable dosage form of the tear film stabilizer or keratoconjunctival epithelial disorder therapeutic agent of the present invention is, for example, eye drops, which can be formulated using a widely used technique.

  The concentration of mannose in the eye drop of the present invention is not particularly limited, but from the viewpoint of the characteristics and effects of the eye drop, the concentration of mannose is 0.01 to 20% (w / v), preferably 0.1 to 0.1%. 15% (w / v), more preferably 1 to 10% (w / v).

 The eye drop containing mannose of the present invention can be blended with 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, immunosuppressive agents, antimetabolites and the like.

 In the eye drop of the present invention, an isotonic agent, a buffer, a pH adjuster, a solubilizer, a stabilizer, a preservative and the like can be appropriately blended.

 Examples of isotonic agents include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like.

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

 Examples of the pH adjuster include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium hydrogen carbonate and the like.

  Examples of solubilizers added when the drug or other additives are poorly water soluble include polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000, and the like.

 Examples of the stabilizer include edetic acid and sodium edetate.

 Examples of the preservative include sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, and the like, and these preservatives can be used in combination.

 The pH of the eye drop of the present invention is preferably set to 4.0 to 8.0, and the osmotic pressure ratio is preferably set to around 1.0.

 The number of eye drops of the eye drop of the present invention can be appropriately selected depending on symptoms, age, dosage form, etc., but is preferably about 1 to 6 times a day. The dosage of mannose is preferably 2 μg to about 100 mg per day.

  As described in detail in the section of corneal surface irregularity index change test described later, when the spherical irregularity of the eyeball surface was measured over time after instilling the eyedrops containing mannose of the present invention, the eyedrops containing mannose were: Stablely maintains the tear film on the surface of the eyeball. In addition, from the results of a test for the healing efficacy of corneal epithelial disorder, eye drops containing mannose exhibit an excellent healing effect in a dry eye model and are useful as a therapeutic agent for keratoconjunctival epithelial disorder caused by dry eye.

  The present invention will be described in detail below with reference to examples, but this is for better understanding of the present invention and does not limit the scope of the present invention.

[Cornea surface irregular index change test]
This test uses a corneal shape measuring device to measure the tear level stabilization effect of each test eye drop by measuring the degree of irregularity of the corneal surface (the degree of tear layer fraud) after instilling the test eye drop. It is something to evaluate.

(experimental method)
After applying 20 μl of 5% mannose (w / v) aqueous solution to male Japanese white rabbit eyes under general anesthesia, 0 (immediately after instillation) and 10 minutes after corneal shape measurement apparatus (for corneal shape measurement) It was measured using “TMS-2N” manufactured by Tome.

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

(result)
Based on the measured spherical irregularity index (the spherical irregularity index increases as the shape of the tear film on the cornea becomes invalid), the spherical irregularity index changes (the spherical irregularity index immediately after instillation is 10 minutes later) The value subtracted from the index.) Was calculated. These results are shown in Table 1. In addition, the spherical irregularity index change of each test solution shows the average value of 3 cases or 5 cases.

(Discussion)
As is apparent from Table 1, the mannose-containing aqueous solution exhibits a remarkable tear stabilizing effect as compared with physiological saline containing no mannose.

[Healing efficacy test for 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 created, the improvement rate of corneal epithelial disorder was determined by a modification of the method of Miyata et al. (Ophthalmology Clinic 48 (2): 183-188 (1994)).

(experimental method)
Nembutal was administered to male SD rats for general anesthesia. Subsequently, the extraorbital lacrimal gland was removed and corneal epithelial injury was induced over 2 months.

  Next, 5% mannose (w / v) aqueous solution was instilled 6 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 staining with fluorescein for each of the upper, middle and lower parts of the corneal epithelium was scored according to the following criteria, and the improvement rate of corneal epithelial disorder was calculated from the average value of the scores of the respective parts.

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

  Furthermore, the average value of the total score of each part was also obtained for normal 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)
The improvement rate of the 5% mannose (w / v) ophthalmic group was calculated based on the average value of the scores of the respective parts in the physiological saline ophthalmic group (control) as a reference (improvement rate: 0%). This is shown in Table 2. In addition, the average value of a score is an average of 8 cases each. The improvement rate was calculated by the following formula.

Improvement rate (%) = {(control) − (mannose)} / degree of failure × 100
Disability = (control)-(normal eye)

(Discussion)
Mannose significantly improves corneal epithelial disorder, as is apparent from the results of the above-mentioned results of the healing efficacy test for corneal epithelial disorder using rats.

[Formulation example]
A typical formulation example using mannose is shown below.

Formulation example (eye drops)
Mannose 5g in 100ml
Concentrated glycerin 500mg
Polysorbate 80 200mg
Sodium dihydrogen phosphate dihydrate appropriate amount 1N sodium hydroxide appropriate amount hydrochloric acid appropriate amount sterilized purified water appropriate amount

An eye drop containing 100 mg, 1 g, 3 g, and 10 g of mannose in 100 ml can be prepared in the same manner as in the above formulation example.

Claims (6)

A tear film stabilizer containing mannose as an active ingredient. The tear film stabilizer according to claim 1, wherein the concentration of mannose is 0.01 to 20% (w / v). A therapeutic agent for keratoconjunctival epithelial disorder caused by dry eye or dry eye containing mannose as an active ingredient. The keratoconjunctival epithelial disorder caused by dry eye is corneal ulcer, keratitis, conjunctivitis, punctate superficial keratopathy, corneal epithelial defect, conjunctival epithelial defect, dry keratoconjunctivitis, upper limbal keratoconjunctivitis or filiform keratitis 3. The therapeutic agent for keratoconjunctival epithelial disorder according to 3. 5. The tear film stabilizer or the therapeutic agent for keratoconjunctival epithelial disorder according to any one of claims 1 to 4, wherein the dosage form is an eye drop. A system that stabilizes the tear film on the surface of the eyeball by instilling eye drops containing mannose.