TW202023601A - Use of short-chain peptide compositions in preventing/treating dry eye disease - Google Patents

Abstract

The present invention relates to the use of a composition comprising short-chain peptide in preventing/treating dry eye syndrome. The composition of present invention comprises short-chain peptides having 5~10 amino acids and exhibiting effects on promoting corneal repair, increasing eye humidity and improving dry eye disease.

Description

Application of short-chain peptide composition for preventing or treating dry eye

The present invention claims domestic priority in accordance with Article 30, Item 1 of the Patent Law. The domestic priority application date is December 20, 107, and the application number is: 107146226. This case is related to a preventive or therapeutic intervention. Short-chain peptide composition for ophthalmopathy. More particularly, the present invention relates to a short-chain peptide composition containing an oligopeptide composed of 5-10 amino acids, which is used to promote corneal repair, increase eye moisture, and improve dry eye.

Dry eye disease (DED), also known as keratoconjunctivitis sicca (KCS), is a state of dry eyes, which is mainly caused by insufficient secretion or uneven distribution of tears or excessive evaporation of tears. Tears are unable to properly keep the surface of the eyeball moist. Common symptoms include dry eyes, easy tiredness, foreign body sensation, burning sensation, tight and heavy eyelids, sticky discharge, fear of wind, and photophobia. In more serious cases, the eyes will be red, swollen, congested, and keratinized. Long-term damage may It will cause keratoconjunctival disease and affect vision.

There is a layer of tear fluid on the surface of normal eyes, covering the cornea and conjunctiva to form a lubricating protective film, which is finally eliminated through the nasolacrimal duct. The tear layer can be divided into three layers from the outside to the inside: Grease layer: secreted by the sebaceous glands of the eyelids, which can delay The water layer fluid evaporates to lubricate the eyelids and the surface of the eyeball; the water layer: secreted by the lacrimal glands, in the middle layer, the main function is to provide corneal oxygen, have sterilization effect, and remove metabolites; mucin layer: from the conjunctiva Secreted by goblet cells, in the innermost layer, the tear water layer can be evenly distributed on the surface of the cornea and conjunctiva.

If there is insufficient secretion or uneven distribution of the three layers of tears, it will cause the symptoms of dry eyes. Insufficient tear secretion of the lacrimal glands in the aqueous layer is the most common cause of dry eyes. Recent medical studies have pointed out that the decline of lacrimal gland function in aging is the main problem. In recent years, computers have become an indispensable tool for people's work and mobile phones that are inseparable from people. Or the problem of air pollution PM2.5 has contributed to the younger generation of dry eye syndrome. According to reports in international journals, there is still a lack of effective treatments for dry eye. The treatment of dry eye in Western medicine is mostly using artificial tear syrup and artificial tear ointment, which are mostly temporary and effective, but many patients are still getting worse.

The present invention then provides a short-chain peptide composition for the prevention or treatment of dry eye. Tests have proved that the short-chain peptide of the present invention has the effects of promoting corneal repair, increasing eye humidity and improving acute and long-term dry eye. .

Therefore, the present invention relates to a short-chain peptide composition for preventing or treating dry eye, which is characterized by comprising a short-chain peptide consisting of 5-10 amino acids, which constitutes the short-chain peptide The amino acid is selected from a combination of serine, lysine and other amino acids, and both serine and lysine must be present in the sequence of the short-chain peptide. Preferably, the short-chain peptide has a molecular weight of 550-1100 Da.

In some embodiments of the present invention, the short-chain peptide has It has the effect of promoting corneal repair. In other embodiments of the present invention, the short-chain peptide has the effect of increasing the humidity of the eye to improve acute and long-term dry eye. In one embodiment of the present invention, the dry eye syndrome is acute dry eye syndrome.

In another aspect of the present invention, it relates to the use of a short-chain peptide consisting of 5-10 amino acids for the preparation of medicines for the prevention or treatment of dry eye, wherein the amino group constituting the short-chain peptide The acid is selected from the combination of serine, lysine and other amino acids, and both serine and lysine must be present in the sequence of the short-chain peptide. Preferably, the short-chain peptide has a molecular weight of 550-1100 Da.

In some embodiments of the present invention, the dry eye syndrome is acute dry eye syndrome. In other embodiments of the present invention, the dry eye syndrome is chronic dry eye syndrome.

Figure 1 shows the results of eye humidity measurement in a 14-day experiment using hydrochloric acid to cause acute dry eye in rabbits. Among them, the control group (◇) are normal eyes without hydrochloric acid treatment; the control group (■) are damaged eyes treated with hydrochloric acid; the AE250 group (▲) is a combination of hydrochloric acid treatment and short-chain peptides AE250 medication eye.

Figure 2 is a photograph of an eye taken using rose bengal sodium to stain dead corneal cells to evaluate the repair effect of AE 250 on corneal cells. A. is the observation results on the third and seventh days after the administration of 0.12N hydrochloric acid treatment and AE250 drops; B. is the observation results on the third and tenth days after stopping the hydrochloric acid treatment and drops the AE250 treatment.

The short-chain peptide used in the present invention is composed of 5-10 amino acids, and the molecular weight is preferably 550-1100 Da. The amino acids constituting the short-chain peptide structure of the present invention must include serine and lysine. Serine is a polar, uncharged amino acid with a hydroxyl group. It is a compound that mainly contributes one carbon in the biosynthetic reaction. It can promote the metabolism of fats and fatty acids, promote muscle growth, and assist in the production of antibodies in the body. For maintenance, it helps nerve fibers to form myelin sheath; Lysine is an essential amino acid for the human body. The hydroxyl lysine contained in collagen is hydroxylated by lysine and is often used for protein repair. Patients and athletes who need additional muscle mass.

For the embodiment of the present invention, the short-chain peptide Ala-Asn-Ser-Ile-Lys (SEQ ID No. 1) was dissolved in physiological saline to prepare a short-chain peptide solution with a concentration of 250 μg/ml ( Hereinafter referred to as AE250), and then aseptically treated with a filter membrane for later use.

Other features and advantages of the present invention will be further exemplified and illustrated in the following embodiment examples, and the embodiment examples are only used as an auxiliary explanation and are not used to limit the scope of the present invention.

Example 1: Short-chain peptide composition promotes corneal repair

In this example, 500 μl of hydrochloric acid (0.12N, pH=2) was used to corrode the rabbit’s cornea, resulting in a decrease in eye humidity. A 14-day rabbit dry eye experiment was conducted to evaluate the efficacy of AE 250 in the protection of dry eye. The drug is AE250 dripped 4 times a day, 200 μl/time only drip for 7 days, stop dripping AE250 on the 8th day; do eye humidity test for left/right eye. The result is shown in Figure 1.

The results in Figure 1 show that after the rabbit eyes stop dripping AE250 on the 8th day, compared with the injury group, an increase in eye humidity of 40-50% can indeed improve dry eye. After the rabbit eyes stopped dripping AE250 on the 8th day, compared with the injury group, AE250 did last for 7 days, which significantly improved the rabbit’s acute dry eye syndrome. It is confirmed that AE250 can improve dry eye for a long time.

Corneal repair test: Use 500μl of hydrochloric acid (0.12N, pH=2) to corrode the cornea once, then use 1% Rose Bengal sodium salt (500μl), instill it from the upper eyelid, 2 minutes later, 10ml of mercury-free physiological buffer solution washes off the excess dye, the dead corneal cells are stained red, and the area of dead corneal cells is calculated by photographing and scanning to evaluate the effect of AE 250 on corneal cell repair.

The results in Fig. 2 show that on the third day of treatment, hydrochloric acid (pH 2.0) will cause secondary (slight to moderate) damage to the rabbit’s eyes, which are red (epithelial cell death) and dry after staining. In the treatment group of AE250 (4 times/day), observed 8 hours after the last application of the drug, it still showed a good corneal state, even better than the control group, indicating that the short-chain peptide composition of the present invention has obvious The corneal cell repairing effect, and it does have a moisturizing effect from the eye moisturization degree, which can produce a protective effect in the acute stage of dry eye. Observed on the seventh day of treatment, it was found that the hydrochloric acid treatment group had the most severe damage, while the treatment group with continuous application of AE250 still showed a good corneal repair effect.

After seven days of hydrochloric acid treatment, the administration of hydrochloric acid and AE250 point medicine was stopped, and the observation continued for ten days. On the 3rd day after stopping the hydrochloric acid treatment, it was found that the hydrochloric acid treatment group originally The damaged cornea produces self-healing repair, which slightly alleviates the symptoms of dry eye. However, after stopping AE250 for 3 days, although the moisturizing effect is eliminated, it still has a good corneal repair effect. Observed on the 10th day after stopping the hydrochloric acid treatment, the cornea of the eyes corroded by hydrochloric acid has gradually healed on its own, while the cornea of the AE250 spot treatment group showed the least epithelial dead cells, indicating that the short-chain peptide composition of the present invention can slow down and normal The long-term protective effect of epithelial metabolism and apoptosis can produce preventive effects for dry eye.

Example 2: Short-chain peptide composition improves acute dry eye

Rabbit eyes are the most sensitive among animals, so rabbits are used in this example to perform acute dry eye experiments. Tropicamide is a short-acting ciliary muscle relaxant that can inhibit the physiological activity of the parasympathetic nerve of the eye. Tears are controlled by the parasympathetic nerve, so inhibiting the parasympathetic nerve inhibits tear secretion, which can be used to cause acute dry eye in rabbits. Establishment of dry eye animal test model: use Tropicamide (0.4% solution dissolved in physiological saline to antagonize the parasympathetic muscarinic M3 receptor) given 5 drops of rabbit eyes in 12 hours , 1 hour after the last drop of rabbit eyes, drop the test drug: Toppincarbamide group, dropwise add physiological saline without short-chain peptides; Toppincarbamide+AE250 group, dropwise add short-chain AE250 Saline with peptides. One hour after the test drug was dropped, the eye humidity of the left/right eyes of the rabbit was tested (mm, the distance extended by the water on the test paper). The results are shown in Table 1.

After artificial tears were dripped into the eyes of normal rabbits, compared with the eyes of the saline dripping group (control group), the eye humidity increased by 42~44%, indicating that artificial tears can improve dry eye syndrome. Therefore, the rabbit model used in this example is indeed It can be used to evaluate the dry eye improvement ability of the test drug.

Using topincarbamide to drip rabbit eyes, compared with the saline drip group, the eye humidity is reduced by 36~62%, indicating that toppincarbamide in this animal model can indeed cause acute dry eye in rabbits. However, when AE250 was used to drip rabbit eyes, compared with the rabbit eyes of the toppincarbamide drip group, the eye humidity increased by 71~213%, indicating that the short-chain peptide composition of the present invention can significantly improve the acute dry eye of rabbits.

<110> Sanfan Biotechnology R&D Co., Ltd.

<120> Application of short-chain peptide composition in preventing or treating dry eye

<160> 1

<170> PatentIn version 3.3

<210> 1

<211> 5

<212> PRT

<213> Artificial sequence

<400> 1

Claims (10)

A short-chain peptide composition for preventing or treating dry eye, which is characterized by comprising a short-chain peptide composed of 5-10 amino acids and capable of promoting corneal repair, wherein the amino acid is selected from The combination of serine, lysine and other amino acids, provided that both serine and lysine must exist in the sequence of the short-chain peptide. The composition according to claim 1, wherein the short-chain peptide has a molecular weight of 550 to 1100 Da. The composition according to claim 1, wherein the short-chain peptide is a pentapeptide having an amino acid sequence of Ala-Asn-Ser-Ile-Lys. The composition according to claim 1, wherein the short-chain peptide has the effect of increasing eye moisture to improve acute and long-term dry eye. A short-chain peptide composed of 5 to 10 amino acids is used for the preparation of medicines for the prevention or treatment of dry eye, wherein the amino acid is selected from serine, lysine and other amino acids The condition is that serine and lysine must exist in the sequence of the short-chain peptide at the same time. The use according to claim 5, wherein the short-chain peptide has a molecular weight of 550-1100 Da. The use according to claim 5, wherein the short-chain peptide is a pentapeptide having an amino acid sequence of Ala-Asn-Ser-Ile-Lys. The use according to claim 5, wherein the dry eye syndrome is acute dry eye syndrome. The use according to claim 5, wherein the dry eye syndrome is a long-term dry eye condition. The use according to claim 5, wherein the short-chain peptide is used to promote corneal repair.

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