TWI716389B - Therapeutic agent for dry eye associated with Schwann's syndrome - Google Patents

Abstract

The present invention relates to a medicinal composition for the treatment of dry eye associated with Schweren’s syndrome containing Ozagrel or its pharmacologically acceptable salt as an active ingredient. The medicinal composition of the present invention is used for the treatment of corneal and conjunctival epithelial damage associated with dry eye of Schweren’s syndrome after instillation of general dry eye treatment drugs (such as artificial tears, etc.) Among them, it exerts particularly excellent therapeutic effects. Therefore, the medical composition of the present invention is useful as a medical composition for the treatment of dry eye associated with Schwann's syndrome.

Description

Therapeutic agent for dry eye associated with Schwann's syndrome

The present invention relates to a medicinal composition useful for the treatment of dry eye associated with Hughlen's syndrome.

In more detail, the present invention relates to a pharmaceutical composition containing Ozagrel or its pharmacologically acceptable salt as an active ingredient, which is useful for the treatment of dry eye accompanied by Schwann's syndrome.

In recent years, with the popularization of air conditioners and the increase of visual display terminals (VDT) operators, the number of patients with dryness has increased rapidly. Therefore, the importance of dry eye treatment has increased (Non-Patent Document 1).

As an unexplained autoimmune disease that accompanies dry eye, Sugron syndrome is known. Because of the high degree of lymphocyte infiltration in the lacrimal glands, salivary glands, etc. of the Hugren's syndrome, the dry eye associated with the Hugren's syndrome is often more serious than other dry eye diseases (Non-Patent Document 2). In recent years, the immune control of TXA ₂ synthesized by thrombin (TX) synthase via TXA receptor (TP) on peripheral lymphatic organs has attracted attention. That is, it has been suggested that the produced TXA ₂ acts on TP to suppress the immune response in vivo (Non-Patent Document 3).

As described above, it is known that the cornea and conjunctival epithelial damage of patients with dry eye accompanied by Schwann's syndrome is more serious. This kind of epithelial injury can increase the amount of tears on the surface of the eye through the use of common dry eye treatment drugs (such as artificial tears, etc.) or punctal plugs. There is also a strong tendency to survive after treatment. Therefore, for the treatment of dry eye that accompanies Hughlen's syndrome, more powerful steroid eye drops or immunosuppressive agents are used. However, due to side effects such as increased intraocular pressure or susceptibility to infection, care must be taken when using steroid eye drops for a long time. In addition, cyclosporin, an immunosuppressant, is the only prescription drug for dry eye in the United States, but some countries do not approve its use as a dry eye treatment. Therefore, in the treatment of corneal and conjunctival epithelial damage in patients with severe dry eye, such as dry eye patients with Hugren’s syndrome, we are also seeking a useful and safe mechanism of novel dry eye. Therapeutic drugs.

Ozagrel, which is known as a thromboplastin synthase inhibitor, is useful for the treatment of bronchial asthma and the improvement of cerebral vasospasm after subarachnoid hemorrhage surgery and the associated cerebral ischemia. It is also known that ozagrel has a corneal epithelial healing effect on corneal diseases and is useful as a therapeutic agent for corneal diseases such as dry eye (Patent Document 1). However, the above-mentioned documents neither record nor suggest that ozagrel exerts a particularly excellent therapeutic effect in the treatment of dry eye associated with Hughlen's syndrome.

[Prior Technical Literature] [Patent Literature]

Patent Document 1: Japanese Patent No. 4778515 Specification

[Non-Patent Literature]

Non-Patent Document 1: Shimazaki Jun et al., "New Ophthalmology", 2007, Vol. 24, No. 2, p.181-184

Non-Patent Document 2: Yukhiro Matsumoto, "Therapy", 2002, Vol. 84, No. 3, p. 37-41

Non-Patent Document 3: Cheng Gong Zhou et al., "Inflammation and Regeneration", 2004, Vol. 24, No. 1, p.35-42

The subject of the present invention is to provide a medicinal composition useful for the treatment of dry eye associated with Schwann's syndrome.

The inventors of the present invention made diligent studies to solve the above-mentioned problems, and as a result, they discovered that ozagrel unexpectedly exerts a particularly excellent therapeutic effect in the treatment of dry eye associated with Hugren’s syndrome.

That is, the present invention relates to the following [1] to [4] and the like.

[1] A medicinal composition for the treatment of dry eye associated with Schwann's syndrome, which contains ozagrel or a pharmacologically acceptable salt thereof as an active ingredient.

[2] The pharmaceutical composition as described in [1] above, which contains ozagrel sodium as an active ingredient.

[3] A medicinal composition containing 1% (w/v) of ozagrel sodium as an effective ingredient as the medicinal composition described in [2] above, characterized in that: eye drops for 1 day Use 1~6 times.

[4] The pharmaceutical composition as described in [3] above, which is used by instilling eyes 4 times a day.

In addition, as an embodiment, the present invention relates to a "medical composition containing ozagrel or its pharmacologically acceptable salt as an active ingredient, for improving ocular conscious symptoms associated with dry eye with Hugren’s syndrome" ".

Moreover, as an implementation aspect, the present invention relates to a "containing Oza A medicinal composition for the treatment of conjunctival epithelial injury associated with dry eye of Hugren’s syndrome with gray or its pharmacologically acceptable salt as an active ingredient.”

The pharmaceutical composition of the present invention improves corneal and conjunctival epithelial damage in patients with dry eye accompanied by Schwann's syndrome. Therefore, the pharmaceutical composition of the present invention is useful as a therapeutic agent for dry eye associated with Schwann's syndrome.

Figure 1 shows the ameliorating effect of corneal and conjunctival epithelial damage in MRL/Lpr mice (Suglen’s syndrome model mice). In the figure, the histogram from the left represents the scores of corneal epithelial damage in the normal group (Normal), the control group (Control), and the ozagrel sodium eye drops administration group (Compound 1) (mean + Standard deviation), and the scores (mean + standard deviation) of conjunctival epithelial damage in the normal group (Normal), the control group (Control), and the ozagrel sodium eye drops administration group (Compound 1). The vertical axis represents the epithelial injury score (Lissamine green grade score) using Lissamine green. *** means p<0.001 in the Wilcoxon test relative to the normal group, ### means p<0.001 in the rank sum test relative to the control group.

Figure 2 shows the improvement effect of conjunctival epithelial damage in patients with dry eye accompanied by Hughlen's syndrome. In the figure, the black triangle represents the value (average value) of the 0.5% (w/v) concentration of ozagrel sodium eye drops administration group, and the black square represents the 1% (w/v) concentration of ozagrel sodium The value (average value) of the eye drops administration group and the open circle indicate the value (average value) of the placebo administration group. The horizontal axis represents time (weeks) (Time (weeks)), and EP means end point. The vertical axis represents the change in the total score of lissamine green conjunctival staining (△Lissamine green score). * Indicates p<0.05 relative to placebo.

Fig. 3 shows the improvement effect of corneal epithelial damage in patients with dry eye accompanied by Hugren’s syndrome. In the figure, the black triangle represents the value (average value) of the 0.5% (w/v) concentration of ozagrel sodium eye drops administration group, and the black square represents the 1% (w/v) concentration of ozagrel sodium The value (average value) of the eye drops administration group and the open circle indicate the value (average value) of the placebo administration group. The horizontal axis represents time (weeks) (Time (weeks)), and EP means end point. The vertical axis represents the change in the total score of fluorescein corneal staining (△Fluorescein score). * Indicates p<0.05 relative to placebo.

Figure 4 shows the results of the response analysis of patients with dry eye accompanied by Schwann's syndrome. In the figure, the histogram from the left represents the placebo administration group (Placebo), 0.5% (w/v) concentration of ozagrel sodium eye drops administration group (0.5% Compound 1), and 1%, respectively (w/v) The response rate of the ozagrel sodium eye drops administration group (1% Compound 1).

Hereinafter, embodiments of the present invention will be described in detail.

In the present invention, each term has the following meanings unless otherwise specified.

In the present invention, "dry eye syndrome" is a chronic disease of tears and corneal and conjunctival epithelium accompanied by eye discomfort or abnormal visual function. In the evaluation of its diagnosis or treatment effect, for example, the definition and diagnostic criteria described in Non-Patent Document 1 and the definition of the National Eye Institute (NEI) (refer to (Lemp et al., "CLAO J ", 1995, Volume 21, p.221-232)) etc.

In the present invention, the so-called "dry eye accompanied by Hugren’s syndrome" refers to the dry eye accompanied by Hugren’s syndrome in dry eye, including the Any of the dry eye of Glenn’s syndrome and the dry eye that accompanies the recurring Schweren’s syndrome. The above-mentioned dry eye associated with Schwann's syndrome is generally a type of dry eye with reduced tear secretion.

In the present invention, pharmacologically acceptable salts of ozagrel include: acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, and phosphoric acid; and formic acid, acetic acid, methanesulfonic acid, and benzenesulfonic acid. Acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamine, Acid addition salts of organic acids such as aspartic acid, benzoic acid, sebacic acid, pamoic acid, pamoic acid, etc.; and inorganic bases such as lithium salt, sodium salt, potassium salt, calcium salt, and magnesium salt The salt; with N-methyl-D-reduced glucosamine, N,N'-dibenzylethylenediamine, triethylamine, piperidine, morpholine, pyrrolidine, arginine, lysine, Salts of organic bases such as choline. Preferably, the sodium salt of ozagrel (sodium ozagrel, hereinafter sometimes referred to as "Compound 1") is preferred.

Ozagrel or its pharmacologically acceptable salt of the present invention also includes a solvate with a pharmacologically acceptable solvent (for example, water, ethanol, etc.).

The ozagrel of the present invention or its pharmacologically acceptable salt can be produced by a known method. For example, the ozagrel of the present invention can also be manufactured by the method described in Japanese Patent Laid-Open No. 55-00313 or a method according to the method.

The pharmaceutical composition of the present invention can also be administered in various forms such as eye drops (eye drops, eye ointment, etc.), injections, and oral preparations.

The pharmaceutical composition of the present invention can be prepared by a conventional method using ozagrel or its pharmacologically acceptable salt, and at least one pharmaceutical additive. Examples of additives include buffers, isotonic agents, preservatives, stabilizers, pH adjusters, dissolution aids, and surfactants.

The content of the active ingredients in the pharmaceutical composition of the present invention can be determined according to the patient's weight, age, sex, and disease severity. For example, in the case of eye drops, the content of the active ingredient is 0.25%(w/v)~2%(w/v), preferably 0.5%(w/v), 1%(w/v), 1.5 The concentration of %(w/v) or 2%(w/v), more preferably 1%(w/v). Furthermore, "w/v" means weight/volume.

The method of administration of the active ingredient of the present invention may be appropriately determined according to the patient's weight, age, sex, and disease severity. For example, in the case of eye drop administration, the eye drop method for adults is to give each eye 1 drop, 1 to 6 times a day, at a concentration of 0.25% (w/v) to 2% (w/v) Eye drops are preferably administered twice, 4 times or 6 times a day. A better method of eye drops is to administer 1% (w/v) eye drops to each eye once, 4 times a day. Furthermore, the interval of administration can be determined appropriately, usually 3 to 4 hours.

[Example]

Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to this content.

[Example 1]

Improved effect on MRL/Lpr mice (Suglen’s syndrome model mice)

1. Test method

For MRL/Lpr mice at the age of 18 weeks after birth, which are known as model animals of Sjogren’s syndrome (Jabs DA, Prendergast RA. Murine models of Sjogren's syndrome. Adv Exp Med Biol. 1994, 350, p. 623- 30). To both eyes, administer 1% (w/v) ozagrel sodium eye drops or a control citrate buffer eye drops with 5μL per eye 4 times a day (3 hour intervals) for 14 days (each Group 13~14 cases). In addition, the Institute of Cancer Research (ICR, Institute of Cancer Research) mice are regarded as a normal group (Normal) (15 cases), citrate buffer was administered to the normal group in the same way. The day after the last eye drop administration, under pentobarbital anesthesia, 1 μL of 1% lissamine green solution per eye was dropped into both eyes, and the degree of cornea and conjunctival damage was scored. Regarding the corneal damage score, the case where punctate staining can be seen in the entire cornea is set to 4 points, the case where the cornea is more than 1/2 and less than 3/4 is set to 3 points, and the case is 1/4 or more And the case of less than 1/2 is set to 2 points, the case of less than 1/4 is set to 1 point and the case where staining is not confirmed is set to 0 point, and the total of the scores of the left and right corneas is set to the individual's cornea The score of epithelial damage. Regarding the conjunctival injury scores, the upper and lower conjunctiva were scored on the same basis as the cornea, and the total of the scores of the upper and lower conjunctiva of the left and right conjunctiva was set as the individual’s conjunctival epithelial injury fraction. Furthermore, the above-mentioned scoring system is carried out in a blind test method.

2. Results

The improvement of corneal and conjunctival epithelial damage can be confirmed in mice with Hugren’s syndrome in which 1% (w/v) sodium ozagrel eye drops are administered by eye drops (Figure 1).

[Example 2]

Improving effect on patients with dry eye associated with Hughlen's syndrome

1. Test method

For 65 patients with dry eye with Schwann’s syndrome, placebo (21 cases), or 1% (w/v) (22 cases) or 1 drop, 4 times a day, was repeatedly administered to both eyes. 0.5% (w/v) (22 cases) sodium ozagrel eye drops for 8 weeks.

In addition, the results of this test are based on a test conducted on patients with dry eye, referring to the conditions of the Hugren’s Syndrome revised diagnostic criteria (1999) of the Ministry of Health, Labour and Welfare’s research class and extracting the concomitant Hugren’s syndrome Those who have analyzed the patients with dry eye.

2. Evaluation items

The total score of lissamine green conjunctival staining degree (the degree of damage in 6 areas is divided into 0~3 points), the total score of luciferin corneal staining degree (the degree of damage in 5 areas is divided into 0~3 It is divided into points), tear layer destruction time (BUT), tear secretion test (Schirmer test) I method, and eye symptoms are evaluated. In addition, the "eye conscious symptoms" refers to the conscious symptoms (dryness, eye fatigue, foreign body sensation, photophobia, eye pain, blurred vision, itching) that have been confirmed since the last time I arrived at the hospital. The levels are evaluated on a 5-stage basis. In addition, in order to determine the comprehensive treatment effect on corneal and conjunctival epithelial damage and ocular conscious symptoms associated with dry eye with Hughlen's syndrome, response analysis was performed. Furthermore, the definition of response is defined as the case where the total score of lissamine green conjunctival staining, the total score of luciferin corneal staining, and the ocular symptoms are improved by 3 points or more, as the response (Responder), and the other as none Reaction (Non-responder).

3. Results

In patients with dry eye associated with Schweren’s syndrome who administered 1% (w/v) ozagrel sodium eye drops, it was confirmed that corneal epithelial damage and conjunctival epithelial damage were significantly improved (Figure 2 and Figure 3) . It can also be confirmed that the 1% (w/v) ozagrel sodium administration group has a lower incidence of eye-related side effects and is a safer drug. In addition, the results of the response analysis are as follows. At the time of the final evaluation, the response rate (45.5%) of the ozagrel sodium administration group of 1% (w/v) statistically exceeded the response rate of the placebo group (4.8%) ) (Fisher's exact test, p=0.003) (Figure 4).

The results of Examples 1 and 2 show that the pharmaceutical composition of the present invention is useful in the treatment (improvement) of corneal or conjunctival epithelial damage, and eye symptoms associated with dry eye such as dry eye associated with Hughlen's syndrome , Play a particularly excellent therapeutic effect (modified Good effect).

[Example 3]

Study on the usage and dosage for the treatment of dry eye with Schwann's syndrome

1. Analysis method

From the results of the following clinical trials A and B in which patients with dry eye are the subjects, the patients with dry eye with Hugren's syndrome are selected on the same basis as in Example 2. For placebo (10 cases), or 1% (w/v) (7 cases) or 2% (w/v) (13 cases) of ozagrel sodium eye drops for these concomitant Hugren’s To analyze the effect of patients with dry eye syndrome.

2. Test content

Clinical trial A:

For patients with dry eye, placebo, or 0.5% (w/v), 1% (w/v), or 2% (w/v) are administered repeatedly to both eyes with 1 drop once, 4 times a day The concentration of Ozagrel Sodium Eye Drops for 4 weeks.

Clinical trial B:

For patients with dry eye, placebo or 1% (w/v) or 2% (w/v) sodium ozagrel drops are administered repeatedly to both eyes with 1 drop once, 4 times a day Eye drops for 6 weeks.

The evaluation items in any test are the total score of lissamine green conjunctival staining, the total score of luciferin corneal staining, ocular symptoms (frequency), and ocular symptoms (severe severity). Furthermore, the "eye conscious symptoms (frequency)" refers to the conscious symptoms (dryness, eye fatigue, foreign body sensation, photophobia, eye pain, blurred vision, itching sensation) 1 week before the hospital. Evaluation based on the standard, "eye symptoms (severe degree)" are the symptoms (dryness, eye fatigue, foreign body sensation, photophobia, eye pain, The degree of blurred vision and pruritus were evaluated on a 5-level basis.

3. Analyze the results

Analyze the 4-week evaluation of patients with dry eye accompanied by Hughren’s syndrome after the administration of 1% (w/v) and 2% (w/v) of ozagrel sodium eye drops, and the corneal epithelial damage can be confirmed And conjunctival epithelial injury has a tendency to improve. In addition, the improvement tendency of eye symptoms can be confirmed in any administration group, and the evaluation at 4 weeks can confirm that the improvement tendency of eye symptoms in 1% of the administration group is higher than that of the 2% administration group (Table 1).

In Table 1, "1% administration group" means the result of 1% (w/v) ozagrel sodium administration group, and "2% administration group" means 2% (w/v) ozagrel In the results of the sodium administration group, "the amount of change in ocular symptoms (frequency)" means the average score change of ocular symptoms (frequency) evaluated at 4 weeks, and "the amount of change in ocular symptoms (severity)" means 4 The change in the average score of eye symptoms (severity) evaluated at the time of the week.

The results of Examples 2 and 3 show that when the pharmaceutical composition of the present invention is used in the form of ozagrel sodium at a concentration of 1% (w/v) as the active ingredient 4 times a day, it is effective against concomitant rest. The dry eye of Glenn's syndrome exerts a particularly excellent therapeutic effect.

(Industrial availability)

The medicinal composition of the present invention is used as the stem that accompanies the Schwann syndrome The medical composition for the treatment of ophthalmopathy is extremely useful.

Claims (4)

A medicinal composition for the treatment of dry eye accompanied by Schwann's syndrome, which contains Ozagrel or a pharmacologically acceptable salt thereof as an active ingredient. The pharmaceutical composition of claim 1, wherein the above-mentioned effective ingredient is ozagrel sodium. A use of a medical composition, which is the use of ozagrel sodium in the manufacture of a medical composition for dry eye associated with Hugren’s syndrome. The characteristic is that the above-mentioned medical composition contains 1% (w/v) The above-mentioned ozagrel sodium is used as the effective ingredient, and the above-mentioned pharmaceutical composition is instilled 1 to 6 times a day. Such as the use of the medical composition of claim 3, wherein the above-mentioned medical composition is instilled 4 times a day.

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