JPH09100233A - Cornea-protective agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a cornea-protective agent having corneal tissue-protective action against corneal lesions developed by various factors. SOLUTION: This cornea-protective agent contains, as active ingredient, a polyoxyethylene sorbitan mono-higher fatty acid ester. The ester is a mono- higher fatty acid ester reacted with 15-25mol of ethylene oxide and may contain small amounts of di- or triester(s). This agent is pref. administered locally, its dose being normally 0.01-100μg/day for ocular administration, or 0.001-500mg/kg a day in two to four portions or in a continuous mode. This agent is effective for treatment of corneal lesions caused by pathological factors based on inflammation, allergy, microbes (e.g. virus, bacteria, fungi), etc., chemical factors based on medicinal's cytotoxicity, corrosion due to acids and alkalies, etc., and physical factors based on external wounds or burn injury due to foreign matter such as dry-eye or contact lens.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a new use of a polyoxyethylene sorbitan mono-higher fatty acid ester, which has been conventionally used as a surfactant, as a corneal protective agent.

[0002]

2. Description of the Related Art The cornea is located in the foremost part of the eyeball and constitutes the anterior wall of the eyeball together with the sclera to maintain its shape, and at the same time, always keeps transparency to allow external light rays to pass therethrough. It is refracted and sent to the pupil area. The cornea is the epithelium and its basement membrane.
It is divided into 5 layers: Bowman's membrane, parenchyma (inherent layer), Descemet's membrane, and endothelium.

Corneal disorders are caused by defects in corneal tissues, but defects in the epithelium generally cause subjective symptoms such as foreign body sensation, ocular pain, differential vision, and tearing. If the corneal tissue defect remains in the epithelium, it is called epithelial exfoliation or erosion, and if it extends from Bowman's membrane to the parenchyma, it is called corneal ulcer. Various factors can be considered as causes of corneal disorders, but for example, disease factors based on inflammation, allergies, microorganisms (viruses, bacteria, fungi, etc.), cytotoxicity of drugs, etc.
Chemical factors such as corrosion by acids and alkalis, and drying
(Dry eyes, etc.)-Physical factors such as external damage and burns caused by foreign substances (contact lenses, etc.) are included. Particularly in recent years, it has been reported that preservatives contained in eye drops such as benzalkonium chloride and chlorobutanol, aminoglycoside antibiotics, non-steroidal anti-inflammatory agents, eye drops such as IDU and pimalysin, etc. damage corneal epithelium. ing.

It is well known that polyoxyethylene sorbitan mono-higher fatty acid ester is used as a surfactant for the purpose of emulsification or dispersion. It is also known that polyoxyethylene sorbitan mono-higher fatty acid ester has an anti-inflammatory effect (JP-A-4-352725). Further, it is also known that polyoxyethylene sorbitan mono higher unsaturated fatty acid ester is used as a component of the eye drop composition (JP-A-4-352725, etc.).

[0005]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a corneal protective agent having a corneal tissue protective action against corneal disorders caused by various factors.

[0006]

As a result of research on the biological activity of polyoxyethylene sorbitan mono-higher fatty acid ester, the present inventor has found that they have a protective effect on the cornea, and completed the present invention. is there. That is, the present invention provides a corneal protective agent containing polyoxyethylene sorbitan mono higher fatty acid ester as an active ingredient.

Corneal protection is intended to protect corneal tissue against corneal damage caused by various factors. Therefore, the corneal protective agent of the present invention is a disease factor due to inflammation / allergy / microorganisms (virus, bacteria, fungi, etc.), a chemical factor due to cytotoxicity of a drug / acid / alkali corrosion, etc. Effective for treatment of corneal disorders (e.g. corneal epithelial exfoliation, corneal erosion, corneal ulcers, etc.) caused by various factors such as physical factors such as dry eye), trauma caused by foreign substances (contact lenses, etc.), burns, etc. . The treatment as referred to herein includes all management such as prevention, treatment, alleviation of symptoms, reduction of symptoms, and stop of progression.

Therefore, the cornea protective agent of the present invention can be used not only for treating corneal disorders caused by various factors, but also when corneal disorders are predicted due to various factors. By applying the agent in advance, it is possible to prevent corneal disorders. Furthermore, the cornea protective agent of the present invention is known to damage the cornea, for example, preservatives such as benzalkonium chloride and chlorobutanol, aminoglycoside antibiotics, non-steroidal anti-inflammatory agents, IDU, pimalysin, etc. It is also possible to prevent the occurrence of corneal disorders by using it together with the ophthalmic drug.

[0009]

The polyoxyethylene sorbitan mono-higher fatty acid ester used in the present invention is usually 15 to
It is a mono-higher fatty acid ester of sorbitan reacted with 25 moles, preferably about 20 moles of ethylene oxide, which may contain small amounts of di- or triesters. Here, the higher fatty acid has 10 to 24 carbon atoms.
And those of 12 to 20 are preferable. The higher fatty acids include saturated fatty acids and unsaturated fatty acids. As the saturated fatty acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid and the like are preferable. Polyoxyethylene (20) sorbitan monolauric acid ester is also called polysorbate 20, and Tween 20
Marketed under the trademark (Tween 20), polyoxyethylene
(20) Sorbitan monopalmitate is also called polysorbate 40, and Tween 40 (Tween 40)
Marketed under the tradename of Polyoxyethylene (20) sorbitan monostearate, also referred to as Polysorbate 60, marketed under the trademark Tween 60. As unsaturated fatty acids, palmitoleic acid,
Oleic acid, gatoleic acid, linoleic acid and the like are preferable.
Polyoxyethylene (20) sorbitan monooleate, also called polysorbate 80,
(Sorlate), Tween 80 (Tween 80), Monitor
(Monitan), Olothorb and the like.

According to the present invention, the polyoxyethylene sorbitan mono-higher fatty acid ester has a corneal protective action and therefore can be used as a pharmaceutical for animals or humans. Suitable administration methods are mainly topical administration,
It is not limited to this and can be administered by various administration methods. The dose varies depending on the type of subject such as animal or human, age, body weight, condition to be treated, desired therapeutic effect, administration method, treatment period, etc.
In the case of (ocular) administration, a dose of 0.01 to 100 μg / eye or a dose of 2 to 4 divided doses per day or a dose of 0.001 to 500 mg / kg when administered in a connected form usually gives a sufficient effect.

The corneal protective agent of the present invention is usually administered in the form of a composition. Such a composition may contain various components other than the active ingredient, for example, carriers, auxiliary agents, preservatives and the like. The composition can take the form of a liquid, such as a solution, emulsion or suspension, or a semisolid form such as a gel, eye ointment. Distilled water, physiological saline, etc. are contained as an aqueous solution and a diluent for suspensions. Non-aqueous solutions and diluents for suspensions include vegetable oil, liquid paraffin, mineral oil, propylene glycol, p-octyldodecanol and the like. Also, for the purpose of making it isotonic with tear fluid,
Tonicity agents such as sodium chloride, boric acid and sodium citrate, and buffer agents such as borate buffer solution and phosphate buffer solution for the purpose of keeping the pH constant at, for example, about 5.0 to 8.0. You can In addition, sodium sulfite,
It may contain a stabilizer such as propylene glycol, a chelating agent such as sodium edetate, and a thickener such as glycerin, carboxymethyl cellulose and carboxyvinyl polymer. These are sterilized by filtration through a bacteria-retaining filter, heat sterilization, and the like. The ophthalmic ointment is based on Vaseline, Zelen 50, Plastibase, Macrogol, etc., and a surfactant can be added for the purpose of enhancing hydrophobicity. It may also contain a jelly agent such as carboxymethyl cellulose, methyl cellulose, carboxy vinyl polymer and the like.

Further, the composition of the present invention comprises a drug known to damage the cornea, for example, a preservative such as benzalkonium chloride or chlorobutanol, an aminoglycoside antibiotic, a nonsteroidal anti-inflammatory agent, Ophthalmic drugs such as IDU and pimalysin may be included. Hereinafter, the present invention will be specifically described with reference to formulation examples and test examples, and the effects thereof will be clarified. However, the present invention is not limited to these.

Formulation Example 1 Polyoxyethylene (20) sorbitan monooleate (Polysorbate 80) 1.0 g Salt 0.8 g Distilled water Appropriate amount The above amount is adjusted to 100 ml.

Test Example 1 (Method) A rabbit was held on a fixture so that the eyeballs face upward,
250 μl of the used drug was instilled into the conjunctival sac, and the drug solution was brought into contact with the entire surface of the keratoconjunctiva. Immediately after 2 minutes, the total amount of the mixed solution of the drug solution and the tear fluid was collected from the eyelid margin using a glass capillary tube. The following three types of chemicals were used. Solution A: Saline solution Solution B: Saline solution containing 0.01% benzalkonium chloride Agent C: 0.01% benzalkonium chloride and polyoxyethylene sorbitan monooleate (polysorbate 80) 1.0% Saline containing

The amount of glutathione (GSH) was determined by adding 50 μl of 0.5% sodium acetate-hydrochloric acid buffer solution to 70 μl of the collected mixed solution, and adding N- (9-acridinyl) maleimide (N
AM) (0.4 mg / ml) and coumarin 3-carboxylic acid (internal standard) (0.8 mg / ml) in acetonitrile 20 μm
l, react at 40 ° C. for 1 hour, then place at 4 ° C.,
Used for GSH measurement. The GSH amount was measured by a high performance liquid chromatography (HPLC) method. Lactate dehydrogenase
The (LDH) was quantified by measuring the collected mixed solution using an automatic analyzer (AU-550 manufactured by Olympus). The results are shown in Tables 1 and 2.

[0016]

[Table 1]

[0017]

[Table 2]

Glutathione (GSH) and lactate dehydrogenase
It is known that (LDH) is not secreted from the lacrimal gland and is strongly derived from corneal tissue. Therefore, in the drug solution B containing only benzalkonium chloride, which is a corneal lesion substance,
The dramatic increase in GSH and LDH levels indicates that benzalkonium chloride caused corneal damage and was effused from corneal tissues. On the other hand, in the chemical solution C containing polyoxyethylene sorbitan monooleate with benzalkonium chloride, GSH
The amount and the amount of LDH are suppressed to the same extent as the control drug solution A.

Therefore, from the above results, the corneal protective agent of the present invention containing polyoxyethylene sorbitan monooleic acid ester and other polyoxyethylene sorbitan mono higher fatty acid ester as an active ingredient is effective for treating corneal tissue against corneal injury. It has been found to have a protective effect.

Claims (5)

[Claims] 1. A corneal protective agent comprising polyoxyethylene sorbitan mono higher fatty acid ester as an active ingredient. 2. The agent according to claim 1, wherein the higher fatty acid has 10 to 24 carbon atoms. 3. The higher fatty acid is a higher unsaturated fatty acid,
The agent according to claim 1. 4. The agent according to claim 1, wherein the polyoxyethylene sorbitan mono-higher fatty acid ester is polyoxyethylene sorbitan monooleate. 5. The agent according to claim 1, which is for topical administration.