WO2016152821A1 - Therapeutic agent for dry eye associated with sjogren's syndrome - Google Patents

Therapeutic agent for dry eye associated with sjogren's syndrome Download PDF

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WO2016152821A1
WO2016152821A1 PCT/JP2016/058882 JP2016058882W WO2016152821A1 WO 2016152821 A1 WO2016152821 A1 WO 2016152821A1 JP 2016058882 W JP2016058882 W JP 2016058882W WO 2016152821 A1 WO2016152821 A1 WO 2016152821A1
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sjogren
syndrome
dry eye
pharmaceutical composition
eye
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PCT/JP2016/058882
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French (fr)
Japanese (ja)
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哲也 浅利
雄治 清野
晃敏 青山
拓允 吉田
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キッセイ薬品工業株式会社
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Priority to JP2016531076A priority Critical patent/JP5997416B1/en
Priority to CN201680016835.3A priority patent/CN107405334B/en
Priority to MYPI2017001388A priority patent/MY184873A/en
Publication of WO2016152821A1 publication Critical patent/WO2016152821A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole

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  • the present invention relates to a pharmaceutical composition useful for the treatment of dry eye associated with Sjogren's syndrome.
  • 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.
  • Non-patent Document 1 Non-patent Document 1
  • Non-patent Document 2 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).
  • TP TXA receptor
  • TX thromboxane
  • Ozagrel a thromboxane synthase inhibitor
  • 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).
  • Patent Document 1 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.
  • An object of the present invention is to provide a pharmaceutical composition useful for the treatment of dry eye associated with Sjogren's syndrome.
  • ozagrel exhibits a particularly excellent therapeutic effect in the treatment of dry eye associated with Sjogren's syndrome.
  • the present invention relates to the following [1] to [4] and the like.
  • a pharmaceutical composition for treating dry eye associated with Sjogren's syndrome comprising ozagrel or a pharmacologically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition according to [1] above containing ozagrel sodium as an active ingredient.
  • the pharmaceutical composition according to the above [2] 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.
  • the present invention relates to “a pharmaceutical composition for improving subjective eye symptoms in dry eye associated with Sjogren's syndrome, comprising ozagrel or a pharmacologically acceptable salt thereof as an active ingredient”.
  • 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 bar graph shows the score of corneal epithelial disorder (mean 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) is 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.
  • the black triangle is the value of the ozagrel sodium ophthalmic solution group at a concentration of 0.5% (w / v)
  • the black square is the value of the ozagrel sodium ophthalmic solution group at the concentration of 1% (w / v)
  • 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 indicates the amount of change ( ⁇ Lissamine green score) of 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.
  • the black triangle is the value of the ozagrel sodium ophthalmic solution group at a concentration of 0.5% (w / v)
  • the black square is the value of the ozagrel sodium ophthalmic solution group at the concentration of 1% (w / v)
  • 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 indicates the amount of change in the total fluorescein corneal staining score ( ⁇ Fluorescein ⁇ 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.
  • the bar graph shows the placebo group (Placebo), ozagrel sodium ophthalmic solution group (0.5% Compound 1) at a concentration of 0.5% (w / v), and ozagrel sodium eye drop at a concentration of 1% (w / v).
  • the responder rate of the liquid administration group (1% Compound 1) is shown.
  • dry eye is a chronic disease of lacrimal fluid and keratoconjunctival epithelium accompanied by eye discomfort or abnormal visual function.
  • NEI National Eye Institute
  • 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.
  • 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,
  • Ozagrel or a pharmacologically acceptable salt thereof of the present invention includes a solvate with a pharmacologically acceptable solvent (for example, water, ethanol, etc.).
  • a pharmacologically acceptable solvent for example, water, ethanol, etc.
  • ozagrel or pharmacologically acceptable salt thereof of the present invention can be produced by a known method.
  • 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.
  • 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.
  • 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, degree of disease and the like.
  • the instillation method in adults is to administer an eye drop at a concentration of 0.25% to 2% (w / v) once per eye, 1 to 6 times a day, Preferably, it is administered twice, four times or six times a day.
  • the ophthalmic method is administration of 1% (w / v) eye drops once per eye, 4 times a day.
  • the administration interval can be determined as appropriate and is usually 3 to 4 hours.
  • Example 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 for 5 days in each eye (13 to 14 patients in each group) .
  • 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.
  • a citrate buffer solution was similarly administered to the normal group by eye drops.
  • the day after the last instillation 1 ⁇ L 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.
  • 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 It was. The scoring was performed blinded. 2. Results Improvement in cornea and conjunctival epithelial disorder was observed in Sjogren's syndrome model mice instilled with 1% (w / v) ozagrel sodium ophthalmic solution (FIG. 1).
  • Example 2 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.
  • Visual 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.
  • 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. Results 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 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
  • 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.
  • 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).
  • Opt subjective symptom 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.
  • 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
  • Chiange in eye subjective symptom (frequency) indicates the average score change in eye subjective symptom (frequency) evaluated at 4 weeks
  • “Change in eye subjective symptom (severity)” indicates an eye evaluated at 4 weeks Shows the average score change of subjective symptoms (severity).
  • 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) as an active ingredient is instilled four times a day. 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.

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Abstract

The present invention pertains to a pharmaceutical composition that contains ozagrel or a pharmacologically acceptable salt thereof as an active ingredient and that is for treating dry eye associated with Sjogren's syndrome. The pharmaceutical composition of the present invention has a strong tendency to persist even after administration of an eye drop of a general therapeutic agent (e.g., artificial tears, etc.) for dry eye, and exhibits particularly excellent therapeutic effect for treating disorders of the conjunctiva epithelium and the cornea related to dry eye associated with Sjogren's syndrome. Thus, the pharmaceutical composition of the present invention is useful as a pharmaceutical composition for treating dry eye associated with Sjogren's syndrome.

Description

シェーグレン症候群に伴うドライアイの治療剤A treatment for dry eye associated with Sjogren's syndrome
　本発明は、シェーグレン症候群に伴うドライアイの治療に有用な医薬組成物に関する。 The present invention relates to a pharmaceutical composition useful for the treatment of dry eye associated with Sjogren's syndrome.
　さらに詳しくは、本発明は、オザグレル又はその薬理学的に許容される塩を有効成分として含有する、シェーグレン症候群に伴うドライアイの治療に有用な医薬組成物に関する。 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.
　近年、空調の普及、VDT（visual display terminals）作業者の増加等により、ドライアイの患者数は急増している。そのため、ドライアイの治療の重要性が高まっている（非特許文献１）。 In recent years, the number of dry eye patients has increased rapidly due to the widespread use of air conditioning and the increase in VDT (visual display terminals) workers. Therefore, the importance of dry eye treatment is increasing (Non-patent Document 1).
　ドライアイを伴う原因不明の自己免疫疾患として、シェーグレン症候群が知られている。シェーグレン症候群は涙腺・唾液腺などに高度なリンパ球浸潤を伴うため、シェーグレン症候群に伴うドライアイは、他のドライアイに比べて重篤なことが多い（非特許文献２）。近年、トロンボキサン（TX）合成酵素により合成されるTXA2のTXA受容体（TP）を介した、末梢のリンパ臓器における免疫制御が注目されている。すなわち、産生されたTXA2がTPに作用することにより、in vivoにおける免疫反応を抑制していることが示唆されている（非特許文献３）。 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).
　上述のように、シェーグレン症候群に伴うドライアイ患者の角膜及び結膜上皮障害は、重篤であることが知られている。このような上皮障害は、一般的なドライアイ治療薬（例えば、人工涙液等）の点眼や涙点プラグなどの眼表面の涙液量を増加させる治療を行った後も残存する傾向が強い。そのため、シェーグレン症候群に伴うドライアイの治療には、より強力なステロイド点眼薬や免疫抑制剤が使われている。しかしながら、眼圧上昇や易感染性などの副作用のため、ステロイド点眼薬の長期間の使用には注意を要する。また、免疫抑制剤であるシクロスポリンは、米国で唯一のドライアイ処方薬であるが、ドライアイ治療薬として認可されていない国もある。そのため、シェーグレン症候群に伴うドライアイ患者のような重篤なドライアイ患者の角膜及び結膜上皮障害等の治療においても、有用で安全性に懸念のない新しい作用機序のドライアイ治療薬が求められている。 As described above, it is known that the cornea and conjunctival epithelial disorder in dry eye patients associated with Sjogren's syndrome are serious. 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.
　トロンボキサン合成酵素阻害剤であるオザグレルは、気管支喘息の治療、並びにクモ膜下出血術後の脳血管攣縮及びこれに伴う脳虚血症状の改善に有用であることが知られている。また、オザグレルが角膜疾患における角膜上皮治癒効果を有し、ドライアイのような角膜疾患の治療剤として有用であることも知られている（特許文献１）。しかしながら、前記文献には、オザグレルがシェーグレン症候群に伴うドライアイの治療において、特に優れた治療効果を発揮することは、記載も示唆もされていない。 Ozagrel, a thromboxane synthase inhibitor, is known to be useful for the treatment of bronchial asthma and for 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.
特許第4778515号明細書Japanese Patent No. 4778515
　本発明は、シェーグレン症候群に伴うドライアイの治療に有用な医薬組成物を提供することを課題とする。 An object of the present invention is to provide a pharmaceutical composition useful for the treatment of dry eye associated with Sjogren's syndrome.
　本発明者らは、上記課題を解決するために鋭意検討を行った結果、オザグレルが意外にもシェーグレン症候群に伴うドライアイの治療において、特に優れた治療効果を発揮することを見出した。 As a result of intensive studies to solve the above problems, the present inventors have unexpectedly found that ozagrel exhibits a particularly excellent therapeutic effect in the treatment of dry eye associated with Sjogren's syndrome.
　すなわち、本発明は、下記の〔１〕～〔４〕等に関する。
〔１〕オザグレル又はその薬理学的に許容される塩を有効成分として含有する、シェーグレン症候群に伴うドライアイの治療用医薬組成物。
〔２〕オザグレルナトリウムを有効成分として含有する、前記〔１〕に記載の医薬組成物。
〔３〕有効成分として1 ％（w／v）の濃度のオザグレルナトリウムを含有する、前記〔２〕に記載の医薬組成物であって、1日1～6回点眼されるように用いられることを特徴とする医薬組成物。
〔４〕1日4回点眼されるように用いられることを特徴とする、前記〔３〕に記載の医薬組成物。 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 the above [2], 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.
　また、一つの実施態様として、本発明は「オザグレル又はその薬理学的に許容される塩を有効成分として含有する、シェーグレン症候群に伴うドライアイにおける眼自覚症状の改善用の医薬組成物」に関する。 Also, as one embodiment, the present invention relates to “a pharmaceutical composition for improving subjective eye symptoms in dry eye associated with Sjogren's syndrome, comprising ozagrel or a pharmacologically acceptable salt thereof as an active ingredient”.
　また、一つの実施態様として、本発明は「オザグレル又はその薬理学的に許容される塩を有効成分として含有する、シェーグレン症候群に伴うドライアイにおける結膜上皮障害の治療用の医薬組成物」に関する。 Also, 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”.
　本発明の医薬組成物は、シェーグレン症候群に伴うドライアイ患者の角膜及び結膜上皮障害を改善する。したがって、本発明の医薬組成物は、シェーグレン症候群に伴うドライアイの治療薬として有用である。 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.
MRL/lprマウス（シェーグレン症候群モデルマウス）における角膜及び結膜上皮障害の改善作用を示す。図中、棒グラフは、左から正常群（Normal）、対照群（Control）、及びオザグレルナトリウム点眼液投与群（Compound 1）の角膜上皮障害のスコア（平均値＋標準偏差）、並びに正常群（Normal）、対照群（Control）、及びオザグレルナトリウム点眼液投与群（Compound 1）の結膜上皮障害のスコア（平均値＋標準偏差）をそれぞれ示す。縦軸は、リサミングリーンを用いた上皮障害スコア（Lisamine green grade score）を示す。***は正常群に対してWilcoxon testでのp<0.001を示し、###は、対照群に対してWilcoxon testでのp<0.001を示す。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, from the left, the bar graph shows the score of corneal epithelial disorder (mean 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) is 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. シェーグレン症候群に伴うドライアイ患者における結膜上皮障害の改善作用を示す。図中、黒三角は0.5 ％（w／v）の濃度のオザグレルナトリウム点眼液投与群、黒四角は1 ％（w／v）の濃度のオザグレルナトリウム点眼液投与群、及び白丸はプラセボ投与群の値（平均値）をそれぞれ示す。横軸は、時間（週）（Time (weeks)）を示し、EPはエンドポイントを意味する。縦軸は、リサミングリーン結膜染色度合計スコアの変化量（ΔLissamine green score）を示す。＊は、プラセボに対してp<0.05を示す。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 at a concentration of 0.5% (w / v), the black square is the value of the ozagrel sodium ophthalmic solution group at the 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 indicates the amount of change (ΔLissamine green score) of the total score of Lisamin Green conjunctival staining. * Indicates p <0.05 relative to placebo. シェーグレン症候群に伴うドライアイ患者における角膜上皮障害の改善作用を示す。図中、黒三角は0.5 ％（w／v）の濃度のオザグレルナトリウム点眼液投与群、黒四角は1 ％（w／v）の濃度のオザグレルナトリウム点眼液投与群、及び白丸はプラセボ投与群の値（平均値）をそれぞれ示す。横軸は、時間（週）（Time (weeks)）を示し、EPはエンドポイントを意味する。縦軸は、フルオレセイン角膜染色度合計スコアの変化量（ΔFluorescein score）を示す。＊は、プラセボに対してp<0.05を示す。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 at a concentration of 0.5% (w / v), the black square is the value of the ozagrel sodium ophthalmic solution group at the 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 indicates the amount of change in the total fluorescein corneal staining score (ΔFluorescein の score). * Indicates p <0.05 relative to placebo. シェーグレン症候群に伴うドライアイ患者におけるレスポンダー解析の結果を示す。図中、棒グラフは、左からプラセボ投与群（Placebo）、0.5 ％（w／v）の濃度のオザグレルナトリウム点眼液投与群（0.5% Compound 1）、及び1 ％（w／v）の濃度のオザグレルナトリウム点眼液投与群（1% Compound 1）のレスポンダー率をそれぞれ示す。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 graph shows the placebo group (Placebo), ozagrel sodium ophthalmic solution group (0.5% Compound 1) at a concentration of 0.5% (w / v), and ozagrel sodium eye drop at a concentration of 1% (w / v). The responder rate of the liquid administration group (1% Compound 1) is shown.
　以下、本発明の実施の形態についてより詳細に説明する。 Hereinafter, embodiments of the present invention will be described in more detail.
　本発明において、各用語は、特に断らない限り、以下の意味を有する。 In the present invention, each term has the following meaning unless otherwise specified.
　本発明において、「ドライアイ」は、眼不快感や視機能異常等を伴う、涙液及び角結膜上皮の慢性疾患である。その診断や治療効果の評価には、例えば、非特許文献1に記載の定義及び診断基準、NEI（National Eye Institute）の定義（Lempら、「CLAO J」、1995年、第21巻、p.221-232参照）等を用いることもできる。 In the present invention, “dry eye” is a chronic disease of lacrimal fluid and keratoconjunctival epithelium accompanied by eye discomfort or abnormal visual function. 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.
　本発明において、「シェーグレン症候群に伴うドライアイ」とは、ドライアイのうち、シェーグレン症候群に伴うドライアイをいい、原発性シェーグレン症候群に伴うドライアイ、及び続発性シェーグレン症候群に伴うドライアイのいずれも含む。前記シェーグレン症候群に伴うドライアイは、一般的に涙液分泌減少型ドライアイに分類される。 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.
　本発明において、オザグレルの薬理学的に許容される塩としては、塩酸、臭化水素酸、硝酸、リン酸などの鉱酸との酸付加塩、ギ酸、酢酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、プロピオン酸、クエン酸、コハク酸、酒石酸、フマル酸、酪酸、シュウ酸、マロン酸、マレイン酸、乳酸、リンゴ酸、炭酸、グルタミン酸、アスパラギン酸、安息香酸、セバシン酸、パモ酸等の有機酸との酸付加塩等、リチウム塩、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩等の無機塩基との塩、Ｎ－メチル－Ｄ－グルカミン、Ｎ，Ｎ’－ジベンジルエチレンジアミン、トリエチルアミン、ピペリジン、モルホリン、ピロリジン、アルギニン、リジン、コリン等の有機塩基との塩を挙げることができる。好ましくは、オザグレルのナトリウム塩（オザグレルナトリウム、以下、「化合物１（Compound 1）」と略称する場合がある）が挙げられる。 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 may be abbreviated as “Compound 1 (Compound 1)”).
　本発明のオザグレル又はその薬理学的に許容される塩には、薬理学的に許容される溶媒（例えば、水、エタノール等）との溶媒和物も含まれる。 Ozagrel or a pharmacologically acceptable salt thereof of the present invention includes a solvate with a pharmacologically acceptable solvent (for example, water, ethanol, etc.).
　本発明のオザグレル又はその薬理学的に許容される塩は、公知の方法で製造することができる。例えば、本発明のオザグレルは、特開昭５５－００３１３号公報に記載の方法又はそれに準じた方法で製造することもできる。 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.
　本発明の医薬組成物は、例えば、点眼剤（点眼液、眼軟膏等）、注射剤、経口剤等の種々の形態で投与することもできる。 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.
　本発明の医薬組成物は、常法により、オザグレル又はその薬理学的に許容される塩、並びに少なくとも1つの医薬品添加剤を用いて調整することができる。添加剤としては、例えば、緩衝剤、等張化剤、防腐剤、安定化剤、pH調整剤、溶解補助剤、界面活性剤等が挙げられる。 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.
　本発明の医薬組成物における有効成分の含有量は、患者の体重、年齢、性別、疾患の程度等に応じて定めればよい。例えば点眼剤の場合、有効成分の含有量は、0.25 ％（w／v）～2 ％（w／v）であり、好ましくは、0.5％（w／v）、1％（w／v）、1.5％（w／v）又は2％（w／v）の濃度であってもよく、1％（w／v）がより好ましい。なお、「w／v」は、重量／容量を表す。 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.
　本発明の有効成分の投与方法は、患者の体重、年齢、性別、疾患の程度等に応じて適宜定めればよい。例えば点眼投与の場合、成人における点眼方法は、0.25 ％（w／v）～2 ％（w／v）の濃度の点眼剤を片目あたり1回1滴、1日1～6回投与であり、好ましくは、1日2回、4回又は6回投与である。より好ましくは、点眼方法は1％（w／v）の点眼剤を片目あたり1回1滴、1日4回投与である。なお、投与間隔は、適宜定めることができ、通常、3～4時間である。 The administration method of the active ingredient of the present invention may be appropriately determined according to the patient's weight, age, sex, degree of disease and the like. For example, in the case of ophthalmic administration, the instillation method in adults is to administer an eye drop at a concentration of 0.25% to 2% (w / v) once per eye, 1 to 6 times a day, 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 administration interval can be determined as appropriate and is usually 3 to 4 hours.
　以下に、本発明を実施例にもとづいてさらに詳細に説明するが、本発明はその内容に限定されるものではない。 Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to the contents thereof.
〔実施例１〕
MRL/lprマウス（シェーグレン症候群モデルマウス）における改善作用
１．試験方法
　シェーグレン症候群のモデル動物として知られている生後18週齢のMRL/lprマウス（Jabs DA、Prendergast RA. Murine models of Sjogren's syndrome. Adv Exp Med Biol. 1994、350、p.623-30)に、1 ％（w／v）のオザグレルナトリウム点眼液又はcontrolとしてクエン酸緩衝液を1日4回（3時間間隔）で14日間、両眼に5 μLずつ点眼投与した（各群13～14例）。また、ICRマウスを正常群（Normal）（15例）とし、正常群にクエン酸緩衝液を同様に点眼投与した。最終点眼投与の翌日に、ペントバルビタール麻酔下にて1 ％リサミングリーン溶液を両眼に1 μLずつ点眼後、角膜及び結膜の障害の程度をスコア化した。角膜障害スコアは、角膜全体に点状染色が認められる場合を4点、角膜全体に対して1/2以上3/4未満の場合を3点、1/4以上1/2未満の場合を2点、1/4未満の場合を1点及び染色が認められない場合を0点とし、左右角膜のスコアの合計をその個体の角膜上皮障害のスコアとした。また、結膜障害スコアに関しては、上眼球結膜及び下眼球結膜のそれぞれにおいて、角膜と同様な基準でスコア化し、左右結膜の上眼球結膜及び下眼球結膜のスコアの合計をその個体の結膜上皮障害スコアとした。なお、上記スコア化は盲検化して行った。
２．結果
　1 ％（w／v）のオザグレルナトリウム点眼液を点眼投与したシェーグレン症候群モデルマウスにおいて、角膜及び結膜上皮障害の改善が認められた（図１）。 [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 for 5 days in each eye (13 to 14 patients 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 It was. The scoring was performed blinded.
2. Results Improvement in cornea and conjunctival epithelial disorder was observed in Sjogren's syndrome model mice instilled with 1% (w / v) ozagrel sodium ophthalmic solution (FIG. 1).
〔実施例２〕
シェーグレン症候群に伴うドライアイ患者における改善作用
１．試験方法
　シェーグレン症候群に伴うドライアイ患者65例に、プラセボ（21例）、又は1 ％（w／v）（22例）若しくは0.5％（w／v）（22例）の濃度のオザグレルナトリウム点眼液を両眼に1回1滴、1日4回、8週間、反復投与した。
　なお、本試験結果は、ドライアイ患者を対象として実施した試験において、厚生労働省研究班によるシェーグレン症候群改訂診断基準（1999年）の条件を参考にシェーグレン症候群に伴うドライアイ患者を抽出し解析したものである。
２．評価項目
　リサミングリーン結膜染色度合計スコア（6領域の障害の程度をそれぞれ0～3点でスコア化）、フルオレセイン角膜染色度合計スコア（5領域の障害の程度をそれぞれ0～3点でスコア化）、涙液層破壊時間（BUT）、シルマーテストＩ法、及び眼自覚症状等を評価した。なお、「眼自覚症状」は、前回来院直後から今回来院時までに認められた自覚症状（乾燥感、眼精疲労、異物感、羞明感、眼痛、霧視、そう痒感）の程度をそれぞれ5段階の基準で評価した。
　また、シェーグレン症候群に伴うドライアイの角結膜上皮障害及び眼自覚症状に対する総合的な治療効果を判断するため、レスポンダー解析を行った。なお、レスポンダーの定義は、リサミングリーン結膜染色度合計スコア、フルオレセイン角膜染色度合計スコア及び眼自覚症状がいずれも3点以上改善した症例をレスポンダー（Responder）とし、それ以外をNon-responderとした。
３．結果
　1 ％（w／v）のオザグレルナトリウム点眼液を投与したシェーグレン症候群に伴うドライアイ患者において、角膜上皮障害及び結膜上皮障害の有意な改善が認められた（図２及び図３）。1 ％（w／v）のオザグレルナトリウム投与群の眼関連副作用の発現率は低く、安全性が高い薬剤であることも確認された。
　また、レスポンダー解析の結果、最終評価時における1 ％（w／v）のオザグレルナトリウム投与群のレスポンダー率（45.5％）は、プラセボ投与群のレスポンダー率（4.8％）を統計学的に上回った（Fisher's exact test、p=0.003）（図4）。 [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 (Scoring the degree of disability in 6 areas with 0 to 3 points each), Fluorescein Corneal Staining Level Score (Scoring degree of damage in 5 areas with 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. Results 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).
　実施例１及び２の結果から、本発明の医薬組成物は、シェーグレン症候群に伴うドライアイのような重篤なドライアイにおける角膜若しくは結膜上皮障害、及び眼自覚症状の治療（改善）において、特に優れた治療効果（改善効果）を発揮することが示された。 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).
〔実施例３〕
シェーグレン症候群に伴うドライアイの治療における用法・用量検討
１．解析方法
　ドライアイの患者を対象とした下記臨床試験A及びBの結果において、実施例２と同様の基準によりシェーグレン症候群に伴うドライアイの患者を抽出した。それらのシェーグレン症候群に伴うドライアイの患者における、プラセボ（10例）、又は1 ％（w／v）（7例）若しくは2％（w／v）（13例）の濃度のオザグレルナトリウム点眼液の効果を解析した。
２．試験内容
臨床試験A：
　ドライアイ患者を対象に、プラセボ、又は0.5 ％（w／v）、1 ％（w／v）若しくは2％（w／v）の濃度のオザグレルナトリウム点眼液を両眼に1回1滴、1日4回、4週間、反復投与した。
臨床試験B：
　ドライアイ患者を対象に、プラセボ、又は1 ％（w／v）若しくは2％（w／v）の濃度のオザグレルナトリウム点眼液を両眼に1回1滴、1日4回、6週間、反復投与した。
　評価項目は、いずれの試験においてもリサミングリーン結膜染色度合計スコア、フルオレセイン角膜染色度合計スコア、眼自覚症状（頻度）、眼自覚症状（重症度）等である。なお、「眼自覚症状（頻度）」は、来院前1 週間の自覚症状（乾燥感、眼精疲労、異物感、羞明感、眼痛、霧視、そう痒感）の頻度をそれぞれ5段階の基準で評価し、「眼自覚症状（重症度）」は、来院前1 週間の自覚症状（乾燥感、眼精疲労、異物感、羞明感、眼痛、霧視、そう痒感）の程度をそれぞれ5段階の基準で評価した。
３．解析結果
　1 ％（w／v）及び2％（w／v）のオザグレルナトリウム点眼液を投与したシェーグレン症候群に伴うドライアイ患者の4週時評価の解析において、角膜上皮障害及び結膜上皮障害の改善傾向が認められた。また、いずれの投与群においても眼自覚症状の改善傾向が認められ、４週時評価の解析において、2％投与群に比べ1％投与群において高い眼自覚症状の改善傾向が認められた（表１）。 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. Results of analysis In the 4-week evaluation analysis of dry eye patients with Sjogren's syndrome administered with 1% (w / v) and 2% (w / v) ozagrel sodium ophthalmic solution, improvement tendency of corneal epithelial disorder and conjunctival epithelial disorder Was recognized. 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).
Figure JPOXMLDOC01-appb-T000001
 　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。
Figure JPOXMLDOC01-appb-T000001
 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).
　実施例2及び3の結果から、本発明の医薬組成物は、有効成分として1 ％（w／v）の濃度のオザグレルナトリウムが1日4回点眼されるように用いられる場合において、特に優れたシェーグレン症候群に伴うドライアイの治療効果を発揮することが示唆された。 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) as an active ingredient is instilled four times a day. It was suggested that the therapeutic effect of dry eye associated with the syndrome is demonstrated.
　本発明の医薬組成物は、シェーグレン症候群に伴うドライアイの治療用医薬組成物として極めて有用である。 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)

  1. オザグレル又はその薬理学的に許容される塩を有効成分として含有する、シェーグレン症候群に伴うドライアイの治療用医薬組成物。 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.
  2. オザグレルナトリウムを有効成分として含有する、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, comprising ozagrel sodium as an active ingredient.
  3. 有効成分として1 ％（w／v）の濃度のオザグレルナトリウムを含有する、請求項２に記載の医薬組成物であって、1日1～6回点眼されるように用いられることを特徴とする医薬組成物。 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.
  4. 1日4回点眼されるように用いられることを特徴とする、請求項３に記載の医薬組成物。 The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is used by instilling four times a day.
PCT/JP2016/058882 2015-03-23 2016-03-22 Therapeutic agent for dry eye associated with sjogren's syndrome WO2016152821A1 (en)

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Citations (4)

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JP2006131624A (en) * 2004-10-07 2006-05-25 Ono Pharmaceut Co Ltd Stable, premixed injectable preparation containing sodium ozagrel
WO2007023877A1 (en) * 2005-08-24 2007-03-01 Teika Pharmaceutical Co., Ltd. Remedy for corneal diseases
JP2008081427A (en) * 2006-09-27 2008-04-10 R&R Inc Medicine for prevention and/or treatment of deficient secretion disease
JP2012102029A (en) * 2010-11-09 2012-05-31 Kissei Pharmaceutical Co Ltd Therapeutic agent for acetaminophen liver damage

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WO2009007679A2 (en) * 2007-07-11 2009-01-15 Cardoz Ab Combination for use in the treatment of atherosclerosis comprising a mast cell inhibitor and a thromboxane a2 antagonist

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JP2006131624A (en) * 2004-10-07 2006-05-25 Ono Pharmaceut Co Ltd Stable, premixed injectable preparation containing sodium ozagrel
WO2007023877A1 (en) * 2005-08-24 2007-03-01 Teika Pharmaceutical Co., Ltd. Remedy for corneal diseases
JP2008081427A (en) * 2006-09-27 2008-04-10 R&R Inc Medicine for prevention and/or treatment of deficient secretion disease
JP2012102029A (en) * 2010-11-09 2012-05-31 Kissei Pharmaceutical Co Ltd Therapeutic agent for acetaminophen liver damage

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