CN107405334B - Therapeutic agent for dry eye syndrome accompanying sicca - Google Patents
Therapeutic agent for dry eye syndrome accompanying sicca Download PDFInfo
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- CN107405334B CN107405334B CN201680016835.3A CN201680016835A CN107405334B CN 107405334 B CN107405334 B CN 107405334B CN 201680016835 A CN201680016835 A CN 201680016835A CN 107405334 B CN107405334 B CN 107405334B
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Abstract
The present invention relates to a pharmaceutical composition for treating dry eye syndrome associated with sjogren's syndrome, which contains Ozagrel (Ozagrel) or a pharmacologically acceptable salt thereof as an active ingredient. The pharmaceutical composition of the present invention exhibits an especially excellent therapeutic effect in the treatment of corneal and conjunctival epithelial lesions of dry eye associated with the xerosis syndrome, which is likely to remain after the application of a conventional dry eye therapeutic agent (e.g., artificial tears) thereto. Therefore, the pharmaceutical composition of the present invention is useful as a pharmaceutical composition for treating dry eye accompanied by sjogren's syndrome.
Description
Technical Field
The present invention relates to a pharmaceutical composition useful for the treatment of dry eye accompanied by sjogren's syndrome.
More specifically, the present invention relates to a pharmaceutical composition containing Ozagrel (Ozagrel) or a pharmacologically acceptable salt thereof as an active ingredient, which is useful for the treatment of dry eye associated with sjogren's syndrome.
Background
In recent years, the number of dry eye patients has increased dramatically with the spread of air conditioners, the increase of Visual Display Terminal (VDT) operators, and the like. Therefore, the importance of dry eye treatment is increasing (non-patent document 1).
Sicca syndrome is known as an autoimmune disease accompanied by unknown causes of dry eye. The xerophthalmia associated with the xerosis syndrome is often more severe than other xerophthalmia because of high degree of lymphocyte infiltration in lacrimal gland, salivary gland, and the like (non-patent document 2). In recent years, TXA synthesized by Thromboxane (TX) synthase is mediated2The TXA receptor (TP) of (A) is of interest for the immune control of peripheral lymphoid organs. I.e. prompting through the generated TXA2Act on TP to suppress immune response in vivo (in vivo) (non-patent document 3).
As described above, it is known that corneal and conjunctival epithelium damage is severe in dry eye patients with sicca syndrome. Such epithelial damage tends to remain even after a general dry eye therapeutic agent (e.g., artificial tear) or treatment for increasing the amount of tear fluid on the ocular surface such as punctal embolism is added dropwise. Therefore, more potent steroid eye drops or immunosuppressants are used for the treatment of dry eye accompanied by sjogren's syndrome. However, due to side effects such as increased intraocular pressure and susceptibility to infection, the steroid eye drops must be used for a long period of time with increased attention. In addition, cyclosporin (cyclosporine), which is an immunosuppressant, is the only prescribed drug for dry eye in the united states, but is not recognized by the countries as a therapeutic drug for dry eye. Therefore, there is a need for a dry eye therapeutic agent having a novel mechanism of action without safety risks, which is useful for the treatment of corneal and conjunctival epithelial injuries and the like in a severe dry eye patient such as a dry eye patient with sicca syndrome.
Ozagrel, which is a thromboxane synthase inhibitor, is known to be useful for the treatment of bronchial asthma and the improvement of cerebral vasospasm after subarachnoid hemorrhage surgery and cerebral ischemia symptoms associated therewith. Ozagrel is also known to have a corneal epithelium 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 documents neither describe nor suggest that ozagrel exhibits an especially excellent therapeutic effect in the treatment of dry eye associated with sicca syndrome.
Documents of the prior art
Patent document
Patent document 1: japanese patent No. 4778515 Specification
Non-patent document
Non-patent document 1: "New Ocular" of Ewasaki et al, 2007, Vol.24, No. 2, p.181-184
Non-patent document 2: "treatment" in 2002, Vol.84, No. 3, p.37-41
Non-patent document 3: peri-utero, et al, "Inflammation and Regeneration" (2004, Vol.24, No. 1, p.35-42)
Disclosure of Invention
Problems to be solved by the invention
The present invention addresses the problem of providing a pharmaceutical composition that is useful for the treatment of dry eye associated with sjogren's syndrome.
Means for solving the problems
The present inventors have made extensive studies to solve the above problems, and as a result, have found that ozagrel unexpectedly exerts an especially 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, which comprises ozagrel or a pharmacologically acceptable salt thereof as an active ingredient.
[2] The pharmaceutical composition according to [1] above, which comprises sodium ozagrel as an active ingredient.
[3] A pharmaceutical composition according to the above [2] containing ozagrel sodium as an active ingredient at a concentration of 1% (w/v), characterized in that: the composition is applied by dropping into eye 1-6 times in 1 day.
[4] The pharmaceutical composition according to [3] above, which is administered in the form of eye drops 4 times per 1 day.
In one embodiment, the present invention relates to "a pharmaceutical composition for improving ocular subjective symptoms in dry eye syndrome associated with sjogren's syndrome, which contains ozagrel or a pharmacologically acceptable salt thereof as an active ingredient".
In one embodiment, the present invention relates to "a pharmaceutical composition for treating conjunctival epithelial injury in dry eye syndrome associated with sjogren's syndrome, which contains ozagrel or a pharmacologically acceptable salt thereof as an active ingredient.
Effects of the invention
The pharmaceutical composition of the present invention improves corneal and conjunctival epithelial lesions in a patient with dry eye syndrome. Therefore, the pharmaceutical composition of the present invention is useful as a therapeutic agent for dry eye associated with sjogren's syndrome.
Drawings
FIG. 1 shows the ameliorating effect of corneal and conjunctival epithelial lesions in MRL/Lpr mice (Sjogren syndrome model mice). In the figure, histograms show the scores (mean value + standard deviation) of corneal epithelial lesions in the Normal group (Normal), the Control group (Control), and the ozagrel sodium eye drop administration group (Compound 1), respectively, from the left; and the scores (mean + standard deviation) of conjunctival epithelial lesions in the Normal group (Normal), the Control group (Control), and the ozagrel sodium eye drop administration group (Compound 1). The vertical axis represents the epithelial lesion score (Lissamine green grade score) using Lissamine green (Lissamine green). Indicates p < 0.001 in the rank sum test (Wilcoxon test) relative to the normal group, and # indicates p < 0.001 in the rank sum test relative to the control group.
FIG. 2 shows the ameliorating effect of conjunctival epithelial lesions in dry eye patients with sjogren's syndrome. In the figure, black triangles represent values (average values) of the drug administration set of ozagrel sodium eye drops at a concentration of 0.5% (w/v); black squares represent the values (average values) of the ozagrel sodium eye drop administration set at a concentration of 1% (w/v); white circles represent values (mean) for placebo administered groups. The horizontal axis represents time (weeks), and EP means an end point. The vertical axis represents the change in the total score of the staining degree of Lissamine green conjunctiva (. DELTA.lissamine green score). Denotes p < 0.05 relative to placebo.
FIG. 3 shows the ameliorating effect of corneal epithelial damage in a dry eye patient with sjogren's syndrome. In the figure, black triangles represent values (average values) of the drug administration set of ozagrel sodium eye drops at a concentration of 0.5% (w/v); black squares represent the values (average values) of the ozagrel sodium eye drop administration set at a concentration of 1% (w/v); white circles represent values (mean) for placebo administered groups. The horizontal axis represents time (weeks), and EP means an end point. The vertical axis represents the change in total fraction of Fluorescein staining index (. DELTA.fluoroescein score). Denotes p < 0.05 relative to placebo.
Fig. 4 shows the results of the reaction analysis of dry eye patients accompanied by sjogren's syndrome. In the figure, the histogram shows, from the left, the response rates of the Placebo administration set (Placebo), the ozagrel sodium eye drop administration set (0.5% Compound 1) at a concentration of 0.5% (w/v), and the ozagrel sodium eye drop administration set (1% Compound 1) at a concentration of 1% (w/v), respectively.
Detailed Description
Hereinafter, embodiments of the present invention will be described in detail.
In the present invention, the terms have the following meanings unless otherwise specified.
In the present invention, "dry eye" is a chronic disease of tears and keratoconjunctival epithelium accompanied by eye discomfort, visual dysfunction, and the like. For the diagnosis or evaluation of the therapeutic effect, for example, the definitions and diagnostic criteria described in non-patent document 1, and the definition of the National Eye Institute (NEI) (see (Lemp et al, "CLAO J", 1995, volume 21, p.221-232)) can be used.
In the present invention, "dry eye syndrome accompanied with xerosis" refers to dry eye syndrome accompanied with xerosis among dry eye syndromes, and includes dry eye syndrome accompanied with primary xerosis syndrome and dry eye syndrome accompanied with secondary xerosis syndrome. The aforementioned dry eye syndrome accompanied with xerophthalmia is generally dry eye syndrome of a tear secretion reducing type.
In the present invention, examples of pharmacologically acceptable salts of ozagrel include: acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, and the like; acid addition salts with organic acids such as 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, pamoic acid (pamoic acid), and the like; salts with inorganic bases such as lithium salt, sodium salt, potassium salt, calcium salt, and magnesium salt; and organic bases such as N-methyl-D-reduced glucamine, N' -dibenzylethylenediamine, triethylamine, piperidine, morpholine, pyrrolidine, arginine, lysine, and choline. Preferred examples thereof include sodium salts of ozagrel (sodium ozagrel, hereinafter sometimes referred to simply as "Compound 1(Compound 1)").
The ozagrel or a pharmacologically acceptable salt thereof of the present invention also includes a solvate with a pharmacologically acceptable solvent (e.g., water, ethanol, etc.).
The ozagrel or a pharmacologically acceptable salt thereof of the present invention can be produced by a known method. For example, ozagrel of the present invention can be produced 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 be administered in various forms such as eye drops (eye drops, eye ointment, etc.), injection, oral preparation, etc.
The pharmaceutical composition of the present invention can be prepared by a conventional method using ozagrel or a pharmacologically acceptable salt thereof, and at least 1 pharmaceutical additive. Examples of additives include: buffers, isotonic agents, preservatives, stabilizers, pH adjusters, dissolution aids, surfactants, and the like.
The content of the active ingredient in the pharmaceutical composition of the present invention may be determined according to the body weight, age, sex, disease degree, etc. of the patient. 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), 1.5% (w/v), or 2% (w/v), more preferably 1% (w/v). It should be noted that "w/v" represents weight/volume.
The method of administering the active ingredient of the present invention may be determined appropriately according to the body weight, age, sex, degree of disease, and the like of the patient. For example, in the case of administration as eye drops, the method of eye drops for adults is to administer eye drops at a concentration of 0.25% (w/v) to 2% (w/v) to each eye 1 time by 1 drop, 1 to 6 times per day, preferably 2, 4, or 6 times per 1 day. A more preferable method of eye drop administration is 1 (1) drop and 4 (1/4) doses of 1% (w/v) drop per eye. The dosing interval may be appropriately determined, and is usually 3 to 4 hours.
[ examples ]
The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these.
[ example 1]
Improving effect on MRL/Lpr mice (Sjogren syndrome model mice)
1. Test method
In MRL/Lpr mice known as model animals of Sjogren's syndrome and aged 18 weeks after birth (Jabs DA prenergast RA. Murine models of Sjogren's syndrome. adv Exp Med biol.1994, 350, p.623-30), 1% (w/v) of ozagrel sodium eye drops or a control of citric acid buffer solution was applied to both eyes at 5. mu.L/1 day (3-hour interval) for 14 days (13 to 14 cases in each group). In addition, the american Cancer Institute of Cancer Research (ICR) mice were used as a Normal group (Normal) (15 cases), and the Normal group was similarly administered with a citric acid buffer in the form of eye drops. The day after the last eye drop administration, the degree of corneal and conjunctival damage was scored after 1. mu.L of 1% lissamine green solution per eye was applied to both eyes under pentobarbital anesthesia. Regarding the corneal damage score, a case where a spot-like stain is observed in the whole cornea is defined as 4 points, a case where the stain is 1/2 or more and less than 3/4 with respect to the whole cornea is defined as 3 points, a case where the stain is 1/4 or more and less than 1/2 is defined as 2 points, a case where the stain is less than 1/4 is defined as 1 point, and a case where no stain is observed is defined as 0 point, and the total of the scores of the left and right corneas is defined as the score of corneal epithelial damage of the individual. The conjunctival damage score is calculated on the basis of the same criterion as that of the cornea for each of the upper and lower conjunctivas, and the total of the scores of the upper and lower conjunctivas for the left and right conjunctivas is defined as the conjunctival epithelial damage score of the individual. Note that the above-mentioned differentiation is performed in a blind manner.
2. Results
In the sicca syndrome model mouse to which 1% (w/v) of ozagrel sodium eye drops were eye-dropped, improvement in corneal and conjunctival epithelial lesions was confirmed (fig. 1).
[ example 2]
Ameliorating effect on xerophthalmia accompanying xerophthalmia
1. Test method
In 65 dry eye patients with sicca syndrome, placebo (21 cases), or 1% (w/v) (22 cases) or 0.5% (w/v) (22 cases) of sodium ozagrel eye drops were repeatedly administered to both eyes 1 time for 1 drop, 1 day for 4 times, for 8 weeks.
The test results were obtained by extracting dry eye patients with xerosis syndrome and analyzing the dry eye patients with xerosis syndrome, with reference to the conditions of the revised diagnostic standard for xerosis syndrome (1999) of the research shift of the japan ministry of health and labor.
2. Evaluation item
Evaluation is performed on the total score of the staining degree of lissamine green conjunctiva (the degree of damage in the 6 regions is scored 0 to 3 minutes, respectively), the total score of the staining degree of fluorescein cornea (the degree of damage in the 5 regions is scored 0 to 3 minutes, respectively), the tear layer destruction time (BUT), the tear secretion test (Schirmer test) I method, the ocular subjective symptoms, and the like. The "subjective eye symptoms" were evaluated on 5-stage criteria for the degree of subjective symptoms (dry sensation, eye fatigue, foreign body sensation, photophobia, ophthalmalgia, blurred vision, and itching) observed from the last arrival to the current arrival. In addition, response analysis was performed to determine the effect of comprehensive treatment on keratoconjunctival epithelial injury and ocular subjective symptom associated with dry eye syndrome. The definition of the response is that the total score of the redness of the conjunctiva of lissamine, the total score of the staining of fluorescein on the cornea and the subjective symptoms of the eye are all improved by 3 or more, and the case is referred to as the response (Responder) and the other cases are referred to as the Non-response (Non-Responder).
3. Results
In dry eye patients with sicca syndrome to whom 1% (w/v) of ozagrel sodium eye drops were administered, significant improvement in corneal epithelial damage and conjunctival epithelial damage was confirmed (fig. 2 and 3). It was confirmed that 1% (w/v) of the ozagrel sodium drug administration group is a safe drug with a low expression rate of ocular side effects. In addition, the response analysis results were as follows, and the response rate of 1% (w/v) ozagrel sodium drug group at the time of final evaluation (45.5%) was statistically higher than that of placebo drug group (4.8%) (Fisher's exact test, p is 0.003) (fig. 4).
The results of examples 1 and 2 show that the pharmaceutical composition of the present invention exerts an especially excellent therapeutic effect (improvement effect) in the treatment (improvement) of corneal or conjunctival epithelial damage and ocular subjective symptoms of severe dry eye such as dry eye associated with sjogren's syndrome.
[ example 3]
Method and dosage study for treating xerophthalmia accompanied with sicca syndrome
1. Analytical method
In the results of the following clinical tests a and B in which dry eye patients were targeted, dry eye patients with sicca syndrome were extracted in the same manner as in example 2. The effect of ozagrel sodium eye drops at a concentration of placebo (10 cases), or 1% (w/v) (7 cases), or 2% (w/v) (13 cases) on dry eye patients with the associated sjogren's syndrome was analyzed.
2. Content of the experiment
Clinical trial a:
1-drop for 1 time, 4 times a day, or a concentration of 0.5% (w/v), 1% (w/v), or 2% (w/v) of ozagrel sodium eye drops for 4 weeks.
Clinical trial B:
to dry eye patients, 1 dose of 1 drop, 4 repeated administrations of placebo for 1 day, or 1% (w/v) or 2% (w/v) concentration of sodium ozagrel eye drops was administered to both eyes for 6 weeks.
The evaluation items in any test were a total score of the staining degree of lissamine green conjunctiva, a total score of the staining degree of fluorescein cornea, subjective eye symptoms (frequency), subjective eye symptoms (severity), and the like. The "subjective eye symptoms (frequency)" is evaluated on a 5-stage basis for the frequency of subjective symptoms (dry sensation, eye fatigue, foreign body sensation, photophobia sensation, eye pain, blurred vision, and itching sensation) in 1 week before the hospital, and the "subjective eye symptoms (severity)" is evaluated on a 5-stage basis for the degree of subjective symptoms (dry sensation, eye fatigue, foreign body sensation, photophobia sensation, eye pain, blurred vision, and itching sensation) in 1 week before the hospital.
3. Analysis results
Analysis of the 4-week evaluation of dry eye patients with sicca syndrome to whom 1% (w/v) or 2% (w/v) of the ozagrel sodium eye drops were administered revealed that corneal epithelial damage and conjunctival epithelial damage tend to be ameliorated. In addition, the tendency of improvement of ocular subjective symptoms was confirmed in any one of the drug combinations, and analysis of the 4-week evaluation revealed that the tendency of improvement of ocular subjective symptoms was higher in 1% of the drug combinations than in 2% of the drug combinations (table 1).
[ Table 1]
| Amount of change in subjective symptoms (frequency) of eyes | Amount of change in subjective eye symptoms (severity) | |
| Placebo administration group | -1.1 | 0.4 |
| 1% administration group | -3.1 | -3.0 |
| 2% administration group | -2.2 | -2.0 |
In table 1, "1% drug administration group" indicates the result of 1% (w/v) of the ozagrel sodium drug administration group, "2% drug administration group" indicates the result of 2% (w/v) of the ozagrel sodium drug administration group, "change amount of ocular subjective symptom (frequency)" indicates the change amount of average score of ocular subjective symptom (frequency) evaluated at 4 weeks, and "change amount of ocular subjective symptom (severity)" indicates the change amount of average score of ocular subjective symptom (severity) evaluated at 4 weeks.
The results of examples 2 and 3 show that the pharmaceutical composition of the present invention exhibits particularly excellent therapeutic effects on dry eye associated with sjogren's syndrome when used as ozagrel sodium at a concentration of 1% (w/v) as an active ingredient by 4 eye drops on 1 day.
Industrial applicability
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. Use of ozagrel or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition for treating conjunctival epithelial injury associated with dry eye syndrome.
2. The use according to claim 1, which comprises ozagrel sodium as an active ingredient.
3. The use according to claim 2, which comprises ozagrel sodium as an active ingredient at a concentration of 1% w/v and is administered by dropping 1 to 6 times in eye for 1 day.
4. The use according to claim 3, which is administered 4 times eye drop after 1 day.
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| Application Number | Priority Date | Filing Date | Title |
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| JP2015-059685 | 2015-03-23 | ||
| JP2015059685 | 2015-03-23 | ||
| PCT/JP2016/058882 WO2016152821A1 (en) | 2015-03-23 | 2016-03-22 | Therapeutic agent for dry eye associated with sjogren's syndrome |
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| CN107405334A CN107405334A (en) | 2017-11-28 |
| CN107405334B true CN107405334B (en) | 2021-05-25 |
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| JP4791131B2 (en) * | 2004-10-07 | 2011-10-12 | 小野薬品工業株式会社 | Stable premixed injection containing ozagrel sodium |
| ES2377342T3 (en) * | 2005-08-24 | 2012-03-26 | 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 |
| 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 |
| JP2012102029A (en) * | 2010-11-09 | 2012-05-31 | Kissei Pharmaceutical Co Ltd | Therapeutic agent for acetaminophen liver damage |
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Non-Patent Citations (2)
| Title |
|---|
| 干眼症治疗中护理干预对于预后的疗效分析;王新梅;《医学信息》;20111231;第24卷(第2期);1103-1104 * |
| 角结膜干燥症的研究现状;邹留河、张丽云;《眼科》;20021231;第11卷(第6期);324-331 * |
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| MY184873A (en) | 2021-04-28 |
| JP2016193949A (en) | 2016-11-17 |
| WO2016152821A1 (en) | 2016-09-29 |
| TWI716389B (en) | 2021-01-21 |
| JP5997416B1 (en) | 2016-09-28 |
| TW201639565A (en) | 2016-11-16 |
| JPWO2016152821A1 (en) | 2017-04-27 |
| CN107405334A (en) | 2017-11-28 |
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