JP5997416B1 - A treatment for dry eye associated with Sjogren's syndrome - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the treatment of dry eye associated with Sjogren's syndrome, comprising ozagrel or a pharmacologically acceptable salt thereof as an active ingredient. The pharmaceutical composition of the present invention is a treatment for dry eye cornea and conjunctival epithelial disorder associated with Sjogren's syndrome, which has a strong tendency to remain after instillation of a general dry eye treatment (eg, artificial tears). In particular, it exhibits an excellent therapeutic effect. Therefore, the pharmaceutical composition of the present invention is useful as a pharmaceutical composition for treating dry eye associated with Sjogren's syndrome.

Description

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

  More specifically, the present invention relates to a pharmaceutical composition useful for the treatment of dry eye associated with Sjogren's syndrome, comprising ozagrel or a pharmacologically acceptable salt thereof as an active ingredient.

  In recent years, the number of dry eye patients has increased rapidly due to the widespread use of air conditioning and the increase in the number of VDT (visual display terminals) workers. Therefore, the importance of dry eye treatment is increasing (Non-patent Document 1).

Sjogren's syndrome is known as an autoimmune disease of unknown cause accompanied by dry eye. Since Sjogren's syndrome involves advanced lymphocyte infiltration in the lacrimal gland, salivary gland, etc., dry eye associated with Sjogren's syndrome is often more severe than other dry eyes (Non-patent Document 2). In recent years, immunoregulation in peripheral lymphoid organs via the TXA receptor (TP) of TXA ₂ synthesized by thromboxane (TX) synthase has attracted attention. That is, it has been suggested that the produced TXA ₂ acts on TP to suppress the in vivo immune response (Non-patent Document 3).

  As mentioned above, corneal and conjunctival epithelial disorders in dry eye patients associated with Sjogren's syndrome are known to be severe. Such epithelial disorders tend to remain after treatment for increasing the amount of tears on the surface of the eye, such as eye drops or punctal plugs of common dry eye treatments (eg, artificial tears). . Therefore, more powerful steroid eye drops and immunosuppressants are used to treat dry eye associated with Sjogren's syndrome. However, due to side effects such as increased intraocular pressure and susceptibility to infection, steroid eye drops should be used for a long time. Cyclosporine, an immunosuppressant, is the only dry eye prescription drug in the United States, but in some countries it has not been approved as a dry eye treatment. Therefore, there is a need for a dry eye treatment drug that has a new mechanism of action that is useful and has no safety concerns in the treatment of cornea and conjunctival epithelial disorders in severe dry eye patients such as those with Sjogren's syndrome. ing.

  Ozagrel, a thromboxane synthase inhibitor, is known to be useful in the treatment of bronchial asthma and the improvement of cerebral vasospasm and associated cerebral ischemic symptoms after subarachnoid hemorrhage. It is also known that ozagrel has a corneal epithelial healing effect in corneal diseases and is useful as a therapeutic agent for corneal diseases such as dry eye (Patent Document 1). However, the document does not describe or suggest that ozagrel exerts a particularly excellent therapeutic effect in the treatment of dry eye associated with Sjogren's syndrome.

Japanese Patent No. 4778515

Shimazaki Jun et al., "New Ophthalmology", 2007, Vol. 24, No. 2, p.181-184 Yukihiro Matsumoto, “Treatment”, 2002, Vol. 84, No. 3, p.37-41 Shu Narumiya et al., "Inflammation and Regeneration", 2004, Vol. 24, No. 1, p.35-42

  An object of the present invention is to provide a pharmaceutical composition useful for the treatment of dry eye associated with Sjogren's syndrome.

  As a result of intensive studies to solve the above problems, the present inventors have found that ozagrel unexpectedly exhibits a particularly excellent therapeutic effect in the treatment of dry eye associated with Sjogren's syndrome.

That is, the present invention relates to the following [1] to [4] and the like.
[1] A pharmaceutical composition for treating dry eye associated with Sjogren's syndrome, comprising ozagrel or a pharmacologically acceptable salt thereof as an active ingredient.
[2] The pharmaceutical composition according to [1] above, containing ozagrel sodium as an active ingredient.
[3] The pharmaceutical composition according to [2] above, which contains ozagrel sodium at a concentration of 1% (w / v) as an active ingredient, and is used to be instilled 1 to 6 times a day A pharmaceutical composition characterized.
[4] The pharmaceutical composition according to [3] above, wherein the pharmaceutical composition is used by instilling 4 times a day.

  Moreover, as one embodiment, the present invention relates to a “pharmaceutical composition for improving ocular subjective symptoms in dry eye associated with Sjogren's syndrome, comprising ozagrel or a pharmacologically acceptable salt thereof as an active ingredient”.

  Moreover, as one embodiment, the present invention relates to “a pharmaceutical composition for treating conjunctival epithelial disorder in dry eye associated with Sjogren's syndrome, comprising ozagrel or a pharmacologically acceptable salt thereof as an active ingredient”.

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

The improvement effect of the cornea and conjunctival epithelial disorder in a MRL / lpr mouse (Sjogren's syndrome model mouse) is shown. In the figure, the bar graphs from the left are the score of corneal epithelial disorder (average value + standard deviation) of the normal group (Normal), the control group (Control), and the ozagrel sodium ophthalmic solution administration group (Compound 1), and the normal group (Normal) , The score of the conjunctival epithelial disorder (mean value + standard deviation) of the control group (Control) and the ozagrel sodium ophthalmic solution administration group (Compound 1) are shown. The vertical axis represents the epithelial injury score (Lisamine green grade score) using lissamine green. *** indicates p <0.001 in the Wilcoxon test for the normal group, and ### indicates p <0.001 in the Wilcoxon test for the control group. It shows the effect of improving conjunctival epithelial disorder in dry eye patients with Sjogren's syndrome. In the figure, the black triangle is the value of the ozagrel sodium ophthalmic solution group administered at a concentration of 0.5% (w / v), the black square is the value of the ozagrel sodium ophthalmic solution group administered at a concentration of 1% (w / v), and the white circle is the value of the placebo group ( (Average value) is shown respectively. The horizontal axis indicates time (weeks), and EP means an end point. The vertical axis represents the amount of change (ΔLissamine green score) in the total score of Lisamin Green conjunctival staining. * Indicates p <0.05 relative to placebo. It shows the ameliorating action of corneal epithelial disorder in dry eye patients with Sjogren's syndrome. In the figure, the black triangle is the value of the ozagrel sodium ophthalmic solution group administered at a concentration of 0.5% (w / v), the black square is the value of the ozagrel sodium ophthalmic solution group administered at a concentration of 1% (w / v), and the white circle is the value of the placebo group ( (Average value) is shown respectively. The horizontal axis indicates time (weeks), and EP means an end point. A vertical axis | shaft shows the variation | change_quantity ((DELTA) Fluorescein score) of a fluorescein corneal staining total score. * Indicates p <0.05 relative to placebo. The result of the responder analysis in the dry eye patient accompanying Sjogren's syndrome is shown. In the figure, from the left, the bar graphs show placebo (Placebo), 0.5% (w / v) ozagrel sodium ophthalmic solution (0.5% Compound 1), and 1% (w / v) ozagrel sodium ophthalmic solution. The responder rate of the liquid administration group (1% Compound 1) is shown.

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

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

  In the present invention, “dry eye” is a chronic disease of lacrimal fluid and keratoconjunctival epithelium accompanied by ocular discomfort or visual function abnormality. For the evaluation of the diagnosis and therapeutic effect, for example, the definition and diagnostic criteria described in Non-Patent Document 1, the definition of NEI (National Eye Institute) (Lemp et al., “CLAO J”, 1995, Vol. 21, p. 221-232) can also be used.

  In the present invention, “dry eye associated with Sjogren's syndrome” refers to dry eye associated with Sjogren's syndrome among dry eyes, both dry eye associated with primary Sjogren's syndrome and dry eye associated with secondary Sjogren's syndrome Including. Dry eye associated with Sjogren's syndrome is generally classified as 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, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic 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, glutamic acid, aspartic acid, benzoic acid, sebacic acid, pamo Acid addition salts with organic acids such as acids, salts with inorganic bases such as lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, N-methyl-D-glucamine, N, N′-dibenzylethylenediamine And salts with organic bases such as triethylamine, piperidine, morpholine, pyrrolidine, arginine, lysine and choline. Preferably, the salt of ozagrel (sodium ozagrel, hereinafter sometimes abbreviated as “Compound 1”) may be used.

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

  The ozagrel or pharmacologically acceptable salt thereof of the present invention can be produced by a known method. For example, ozagrel of the present invention can also be produced by the method described in JP-A-55-00313 or a method analogous thereto.

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

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

  The content of the active ingredient in the pharmaceutical composition of the present invention may be determined according to the patient's weight, age, sex, degree of disease, and the like. For example, in the case of eye drops, the content of the active ingredient is 0.25% (w / v) to 2% (w / v), preferably 0.5% (w / v), 1% (w / v), The concentration may be 1.5% (w / v) or 2% (w / v), more preferably 1% (w / v). “W / v” represents weight / volume.

  The administration method of the active ingredient of the present invention may be appropriately determined according to the patient's weight, age, sex, disease severity, and the like. For example, in the case of ophthalmic administration, the ophthalmic method in adults is administration of 1 drop per eye, 1-6 times a day, at a concentration of 0.25% (w / v) to 2% (w / v), Preferably, it is administered twice, four times or six times a day. More preferably, the ophthalmic method is administration of 1% (w / v) eye drops once per eye, 4 times a day. The dosing interval can be determined as appropriate and is usually 3 to 4 hours.

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

[Example 1]
1. Improvement effect in MRL / lpr mice (Sjogren's syndrome model mice) Test method In 18-week-old MRL / lpr mice (Jabs DA, Prendergast RA. Murine models of Sjogren's syndrome. Adv Exp Med Biol. 1994, 350, p.623-30) known as a model animal for Sjogren's syndrome 1% (w / v) ozagrel sodium ophthalmic solution or citrate buffer as a control was administered 4 times a day (3 hours interval) for 14 days, 5 μL each in both eyes (13 to 14 cases in each group) . In addition, ICR mice were set as a normal group (Normal) (15 cases), and a citrate buffer solution was similarly administered to the normal group by eye drops. The day after the last instillation, 1 μL of 1% Lisamin Green solution was instilled into both eyes under pentobarbital anesthesia, and the degree of damage to the cornea and conjunctiva was scored. The corneal damage score is 4 points when punctate staining is observed throughout the cornea, 3 points when it is 1/2 or more and less than 3/4, and 2 points when it is 1/4 or more and less than 1/2. A score of less than 1/4 was assigned 1 point, and a case where no staining was observed was assigned 0 point, and the total score of the left and right corneas was taken as the score of corneal epithelial disorder of the individual. Regarding the conjunctival disorder score, the upper eyeball conjunctiva and the lower eyeball conjunctiva are scored according to the same criteria as the cornea, and the sum of the scores of the upper eyeball conjunctiva and the lower eyeball conjunctiva of the left and right conjunctiva is calculated as the conjunctival epithelial disorder score of the individual. It was. The scoring was performed blinded.
2. result
Improvement in corneal and conjunctival epithelial disorders was observed in Sjogren's syndrome model mice administered with 1% (w / v) ozagrel sodium ophthalmic solution (FIG. 1).

[Example 2]
1. Improvement effect in patients with dry eye associated with Sjogren's syndrome Test Method 65 patients with dry eye associated with Sjogren's syndrome were treated with placebo (21 patients) or ozagrel sodium ophthalmic solution at a concentration of 1% (w / v) (22 patients) or 0.5% (w / v) (22 patients). A single drop was administered to both eyes, 4 times a day for 8 weeks.
The results of this study were obtained by analyzing dry eye patients associated with Sjogren's syndrome in a study conducted for dry eye patients, referring to the conditions of the revised criteria for Sjogren's syndrome (1999) by the Ministry of Health, Labor and Welfare. It is.
2. Evaluation items Lisamin Green Conjunctival Stain Level Score (Scores of disorders in 6 areas scored from 0 to 3 points each), Fluorescein Corneal Stain Level Score (Score levels of disorders in 5 areas scored from 0 to 3 points each) ), Tear film destruction time (BUT), Schirmer test I method, subjective eye symptoms, and the like. “Ocular subjective symptoms” refers to the degree of subjective symptoms (dryness, eye strain, foreign body sensation, sensation of sensation, eye pain, foggy vision, pruritus sensation) observed immediately after the previous visit. Each was evaluated on a five-point scale.
In addition, a responder analysis was performed to determine the overall therapeutic effects on dry eye keratoconjunctival epithelial disorder and subjective eye symptoms associated with Sjogren's syndrome. The responder is defined as a responder when the total score of Lisamin Green Conjunctival Staining, the total score of fluorescein corneal staining and subjective ocular symptoms is improved by 3 points or more, and the other is Non-responder. .
3. result
Significant improvement in corneal epithelial disorder and conjunctival epithelial disorder was observed in dry eye patients with Sjogren's syndrome administered with 1% (w / v) ozagrel sodium ophthalmic solution (FIGS. 2 and 3). The incidence of eye-related side effects in the 1% (w / v) ozagrel sodium administration group was low, and it was also confirmed that the drug is highly safe.
In addition, as a result of responder analysis, the responder rate (45.5%) in the 1% (w / v) ozagrel sodium group at the final evaluation was statistically higher than the responder rate (4.8%) in the placebo group (Fisher's exact test, p = 0.003) (Figure 4).

  From the results of Examples 1 and 2, the pharmaceutical composition of the present invention is particularly useful in the treatment (improvement) of corneal or conjunctival epithelial disorders in severe dry eye such as dry eye associated with Sjogren's syndrome, and ocular subjective symptoms. It was shown that it exhibits an excellent therapeutic effect (improvement effect).

Example 3
Study of dosage and administration in the treatment of dry eye associated with Sjogren's syndrome Analysis Method In the results of the following clinical trials A and B for patients with dry eye, dry eye patients with Sjogren's syndrome were extracted according to the same criteria as in Example 2. Effects of placebo (10 patients) or ozagrel sodium ophthalmic solution at a concentration of 1% (w / v) (7 patients) or 2% (w / v) (13 patients) in patients with dry eye associated with their Sjogren's syndrome Was analyzed.
2. Study Contents Clinical Trial A:
For patients with dry eye, placebo or ozagrel sodium ophthalmic solution at a concentration of 0.5% (w / v), 1% (w / v), or 2% (w / v) once per day for both eyes Repeated administration 4 times for 4 weeks.
Clinical trial B:
For patients with dry eye, placebo or 1% (w / v) or 2% (w / v) ozagrel sodium ophthalmic solution once in each eye, 4 times a day, repeated for 6 weeks did.
Evaluation items include the total score of lissamine green conjunctival staining, the total score of fluorescein corneal staining, the subjective eye symptoms (frequency), and the subjective eye symptoms (severity). “Ocular subjective symptom (frequency)” refers to the frequency of subjective symptoms (dryness, eye strain, foreign body sensation, sensation of sensation, eye pain, fog vision, pruritus) for one week before the visit. Evaluated according to the criteria, “eye subjective symptoms (severity)” indicates the degree of subjective symptoms (dryness, eye strain, foreign body sensation, dullness, eye pain, foggy vision, pruritus sensation) for 1 week before the visit. Each was evaluated on a five-point scale.
3. Analysis result
Analysis of 4-week evaluation of dry eye patients with Sjogren's syndrome administered with 1% (w / v) and 2% (w / v) ozagrel sodium ophthalmic solution showed a tendency to improve corneal epithelial disorder and conjunctival epithelial disorder It was. In addition, there was a tendency for improvement in the subjective symptoms of the eye in any of the administration groups, and in the 4-week evaluation analysis, there was a tendency for improvement in the subjective symptoms of the eye in the 1% administration group compared to the 2% administration group (Table 1).

表１において、「1％投与群」は1 ％（w／v）のオザグレルナトリウム投与群の結果を示し、「2％投与群」は2 ％（w／v）のオザグレルナトリウム投与群の結果を示し、「眼自覚症状（頻度）の変化量」は４週時評価の眼自覚症状（頻度）の平均スコア変化量を示し、「眼自覚症状（重症度）の変化量」は４週時評価の眼自覚症状（重症度）の平均スコア変化量を示す。

In Table 1, “1% administration group” indicates the result of the 1% (w / v) ozagrel sodium administration group, “2% administration group” indicates the result of the 2% (w / v) ozagrel sodium administration group, “Change in eye subjective symptom (frequency)” indicates the average score change in eye subjective symptom (frequency) evaluated at 4 weeks, and “Change in eye subjective symptom (severity)” indicates an eye evaluated at 4 weeks Shows the average score change of subjective symptoms (severity).

  From the results of Examples 2 and 3, the pharmaceutical composition of the present invention is a particularly excellent sjogren when it is used so that ozagrel sodium at a concentration of 1% (w / v) is instilled four times a day as an active ingredient. It was suggested that the therapeutic effect of dry eye associated with the syndrome is demonstrated.

  The pharmaceutical composition of the present invention is extremely useful as a pharmaceutical composition for treating dry eye associated with Sjogren's syndrome.

Claims (4)

A pharmaceutical composition for the treatment of dry eye associated with Sjogren's syndrome, comprising ozagrel or a pharmacologically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to claim 1, comprising ozagrel sodium as an active ingredient. The pharmaceutical composition according to claim 2, comprising ozagrel sodium at a concentration of 1% (w / v) as an active ingredient, wherein the pharmaceutical composition is used to be instilled 1 to 6 times a day. Composition. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is used by instilling four times a day.

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