JP2017137307A - Drug for improvement/treatment of sleep disorder and mood disorder of patients with dry eye - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a drug for improving sleep disorders and mood disorders of patients with dry eye.SOLUTION: A method in which both sleep disorders and mood disorders are improved by eye drops for eye treatment or eye ointment in patients with dry eye, especially in new patient groups diagnosed with dry eye for the first time. In addition, sleep disorders and mood disorders for patients with symptoms other than eye diseases can be treated with eye drops and/or eye ointment without using internal medicine. The drug for treating/improving sleep disorders and/or mood disorders of patients with dry eye is an eye drop and/or eye ointment comprising as an active ingredient at least one of an artificial tear composition or cyclosporine, hyaluronic acid, diquafosol, rebamipide, fluorometholone, betamethasone, chondroitin sulfate, levofloxacin, flavin adenine dinucleotide, dexamethasone, methylbrednisolone, fradiomycin, or ofloxacin or a salt or solvate thereof.SELECTED DRAWING: Figure 1

Description

  The present invention relates to improvement of sleep disorder and mood disorder. In particular, it relates to the improvement of sleep disorders and mood disorders in dry eye patients.

  Even though sleep is an important physiological activity that accounts for about one third of daily life, it is said that about one out of every five Japanese people suffers from some kind of sleep disorder. Problems such as falling asleep and not being able to sleep well after going to sleep are said to contribute not only to excessive sleepiness during the day, but also to lifestyle-related diseases and depression over the long term.

  In order to get rid of sleep disorders, non-pharmacotherapy includes improvement of sleep hygiene. Examine whether there is room for improvement in bedroom environment such as noise, lighting, temperature and humidity, intake of luxury items such as drinking, smoking and caffeine, and sleeping habits when falling asleep such as bedtime and wake-up time And these need to be improved. In the United States and the United Kingdom, from the viewpoint of mental illness, the treatment guideline is that cognitive behavioral therapy is the first option prior to drug treatment.

  However, in Japan, many people actually rely on drug treatment. Diphedohydramine, which is an antihistamine that does not require a prescription, and benzodiazepine drugs represented by Halcyon (registered trademark) and non-benzodiazepine drugs are used as typical sleeping pills as prescription drugs.

  It is clear from the current situation that many people rely on drug therapy, non-drug therapy has not been effective enough. However, the problem with pharmacotherapy is its side effects and high dependence. For example, in the case of a benzodiazepine-based drug, withdrawal symptoms may be exhibited if the drug is stopped after long-term use. In addition, side effects appear in cognitive, physical and mental aspects, cloudy emotions, nausea, headache, dizziness, irritability, lethargy, memory impairment, personality changes, aggression, depression, agoraphobia, social ability It has been reported that various problems occur, such as a decrease in the number.

  The Pittsburgh Sleep Questionnaire (Pittsburgh Sleep Quality Index, sometimes referred to as PSQI) is an assessment of sleep quality and is based on a study of thousands of patients. . According to our recent study using the Pittsburgh Sleep Questionnaire, patients with dry eye symptoms are not only significantly impaired in sleep compared to the control group, but also have mood disorders. It became clear (Non-Patent Document 1).

  Dry eye disease (hereinafter sometimes referred to as DED) is the ability to moisturize the surface of the eye by reducing the amount of tear secretion or reducing the quality of tears even if the amount is sufficient. Refers to the state of reduced. Dry eye is a chronic disease of tears and keratoconjunctival epithelium due to various factors, and is a disease accompanied by eye discomfort and abnormal visual function. Dry eye patients not only have dry eyes but also various symptoms such as foreign body sensation, eye pain, glare, and eye fatigue. In addition, continuing to use the eyes also causes a reduction in visual acuity.

  As described above, studies by the present inventors have revealed that many dry eye patients feel sleep disorders and mood disorders as well as dry eyes and foreign body sensations. However, for both patients and doctors, dry eye is an eye disease, sleep disorders and mood disorders are neuropsychiatric disorders, so dry eye treatment is ophthalmology, sleep improvement, mood disorder treatment is neurology, etc. In fact, it is actually done using internal medicine.

Ayaki, M. et al., 2015, Neuropsychiatr. Dis. Treat., Vol. 11, p.889-894. Brody, B.L. etal., 2001, Ophthalmololgy, Vol.108, p.1893-1900. Mabuchi, F. et al., 2012, Br. J. Ophthalmol., Vol. 96 (6), p.821-825. Kong, X.M. et al., 2014, BMJ Open., Vol.4 (5), e004632. Ishii, K. et al., 2008, Am. J. Ophthalmol., Vol.146, p.404-409. Labbe, A. et al., 2013, Br. J. Ophthalmol., Vol.97, p.1399-1403. Wen, W. et al. 2012, Cornea., Vol.31, p.686-692. Buysee, D.J. et al., 1989, Psychiatry Res., Vol.28, p.193-213. Zigmond, A. S. & Snaith, R. P. 1983, Psychiatr. Scand., Vol. 67, p.361-370. Suzukamo, Y. et al., 2005, Health Qual. Life Outcomes, Vol.3, p.65. Horne, J. A. & Ostberg, O., 1976, Int. J. Chronobiol., Vol. 4, p. 97-110.

  When dry eye patients have symptoms such as sleep disorder and mood disorder, benzodiapine sleep induction drugs and anxiolytic drugs have been conventionally prescribed. However, these internal medicines can affect the lives of patients, and there has been a demand for therapeutic drugs that have no side effects.

  The present inventors have found that administration of eye drops and eye ointments to dry eye patients not only improves dry eye, but also improves sleep disorders and mood disorders, and the present invention has been completed.

  The present invention relates to a therapeutic / ameliorating agent and a treatment method for sleep disorders and mood disorders of dry eye patients described below.

(1) A therapeutic / ameliorating agent for sleep disorders and / or mood disorders in dry eye patients, characterized in that the dosage form is eye drops or eye ointments.
(2) The therapeutic / ameliorating drug according to (1), wherein the dry eye patient is a new patient.
(3) The treatment / improving agent according to (1) or (2), wherein the eye drop or eye ointment is an eye drop for dry eye treatment or an eye ointment for dry eye treatment.
(4) The eye drop or eye ointment is an artificial tear composition or cyclosporine, hyaluronic acid, diquafosol, rebamipide, fluorometholone, betamethasone, chondroitin sulfate, levofloxacin, flavin adenine dinucleotide, dexamethasone, methylbredonizolone, fradiomycin Or an ophthalmic solution or ophthalmic ointment containing at least one of ofloxacin or a salt thereof or a solvate thereof as an active ingredient, wherein sleep disorders and / or mood disorders in dry eye patients according to (3) Treatment / improvement drug.
(5) Artificial tear composition or cyclosporine, hyaluronic acid, diquafosol, rebamipide, fluorometholone, betamethasone, chondroitin sulfate, levofloxacin, flavin adenine dinucleotide, dexamethasone, methylbrednisolone, fradiomycin, or ofloxacin or a salt thereof Use of a solvate for treatment / amelioration of sleep disorder and / or mood disorder in at least one dry eye patient.
(6) The use according to (5), wherein the therapeutic / ameliorating agent is an eye drop or an eye ointment.
(7) The use according to (5) or (6), wherein the dry eye patient is a new patient.

  Sleeping disorders and mood disorders in dry eye patients can be treated with locally administered therapeutic agents such as eye drops and eye ointments that are locally administered without systemic side effects.

The figure which shows the change of PSQI of a patient by a dry eye treatment, HADS (Hospital Anxiety And Depression Scale) which is a measure of anxiety and depression. Scatter plot of changes in sleep and mood disorders in dry eye patients. The figure which shows the change of the PSQI average value of the sleep disorder patient in a new patient.

  The possibility that eye diseases are associated with sleep disorders has been pointed out. For example, there are reports that many patients with macular degeneration, glaucoma, cataracts, and dry eye suffer from depression (Non-Patent Documents 2 to 7). Macular degeneration and dry eye are difficult to treat, are progressive and recurrent, and thus are prone to depressive symptoms.

  It was known in cataracts that once the underlying eye disease was cured, the patient could be released from sleep disorders. However, despite the fact that dry eye is a common disease that affects a large number of people, it has only recently been found that dry eye deteriorates quality of life and causes depressive symptoms. (Non-patent Document 1).

  The inventors have further developed this study and completed this study. We compared the quality of sleep in patients with dry eye before and after treatment, and found that treatment of eye diseases improved the psychiatric condition. In addition, the present inventors have found for the first time that sleep disorders and mood disorders of dry eye patients are improved by eye drops and eye ointments.

  In the present invention, dry eye refers to a disease diagnosed in accordance with the guidelines of the Japan Dry Eye Society. According to the diagnostic criteria of this guideline, dry eye is based on subjective symptoms, abnormal tears, keratoconjunctival epithelial disorder, definite dry eye disease (DDED), dry eye suspicion (probable DED, PDED), non-dry Classified as eye syndrome.

In the present invention, the eye drop or eye ointment refers to all eye drops or eye ointment used for the treatment of dry eye. Effective dry eye drops currently used are artificial tear composition (Mightia (registered trademark)), hyaluronic acid preparation (hyalein (registered trademark)), diquafosol sodium that promotes secretion of mucin and water Eye drops (diquas (registered trademark)), eye drops (mucosta (registered trademark)) containing rebamipide producing mucin as an active ingredient, eye drops (flumetholone (flumetholone) containing steroids such as fluorometholone and betamethasone) Registered trademark), Linderon (registered trademark), those containing chondroitin (mucofadin (registered trademark)), antibacterial agents such as levofloxacin, and antiallergic agents such as cyclosporine. In addition, as eye ointments, eye ointments containing flavin adenine dinucleotide which is coenzyme type vitamin B ₂ as an active ingredient (Flavitan (registered trademark)), steroids such as dexamethasone, methylbrednisolone and the like are used. (Santezone (registered trademark), neomedolol (registered trademark)), antibacterial drugs (Talvid (registered trademark), neomedolol (registered trademark)) containing ofloxacin, fradiomycin and the like as active ingredients. Furthermore, the eye drops or eye ointments of the present invention include eye drops and eye ointments effective for dry eye symptoms to be developed in the future. The type of eye drop or eye ointment should be selected and prescribed by the doctor according to the patient's symptoms, but here, hyaluronic acid preparations, mucin secretion promoters, and steroids are mainly used. ing.

  In addition to eye drops and eye ointments, it has become clear that reviewing patient lifestyles as described below, and advice such as lighting, bedtime, drinking, and glasses to block blue light improve sleep quality. It was.

The present invention will be described below.
1. Eligible patients Eight ophthalmology clinics, with the approval of the Ethics Review Board, participated in a study of sleep disorders and dry eyes. In addition, all patients have informed consent to participate in the study.

  Only patients who were consistently diagnosed with DDED or PDED were included. Other diseases thought to be correlated with sleep or mood disorders, such as severe glaucoma (unilateral MD value, <-12 dB, patients with severe visual field loss), bilateral cataract, bilateral visual impairment (binocular Visual acuity, <20/30) was excluded from the subject.

  Here, the MD value is one of criteria for visual field inspection, and is a value representing how much the sensitivity is reduced from normal after age-correcting the result of the entire visual field inspection. The unit is decibel (dB), 0 dB when normal, and -30 dB when there is no visual field. Further, visual acuity <20/30 is 0.66 when expressed in the Japanese standard.

  Further, in the present invention, new patients refer to untreated case patients diagnosed as dry eye for the first time at the time of the present investigation based on the above-mentioned diagnostic criteria, and already treated patients (established patients) This refers to patients who have been diagnosed as dry eye patients before this study and have already been treated.

2. Treatment For the treatment of dry eye, hyaluronic acid (0.1% / 0.3% hyaline ophthalmic solution, Santen Pharmaceutical), mucin secretion promoter (Diquas ophthalmic solution 3%, Santen Pharmaceutical, Mucosta ophthalmic solution UD 2%, Otsuka Pharmaceutical) and steroid eye drops (Flumetholone ophthalmic solution 0.02% / 0.1%, Santen Pharmaceutical) were prescribed.

3. Patient Evaluation At the time of study registration, patients were evaluated using the Japanese version of the Pittsburgh Sleep Questionnaire (PSQI) (Non-patent Document 8) and HADS (Non-patent Document 9), which is a measure of anxiety and depression. Dawn and chronotype (Chronotype, Morning / Night) are two established questionnaires (Questionnaire for Visual Function, National Eye Institute Visual Function Questionnaire-25 (VFQ-25), Morning / Night Question) It was evaluated by a vote (Morningness / Eveningness questionaire) (Non-Patent Documents 10 and 11), which is one of the main symptoms of dry eye and may be associated with sleep disorders and mood disorders Since it was thought, it evaluated.

4). Findings Patients interviewed using the same questionnaire from January to December 2014 for the first evaluation and from November 2014 to February 2015, 3-10 months after the first evaluation. Or mailed a questionnaire. Both the first and last evaluations were performed in winter to eliminate seasonal differences. Patients were rated as improved when PSQI or HADS score decreased by 2 points or more. All statistical analysis was performed using StatFlex (manufactured by Atech) and SPSS version 21 (manufactured by SPSS).

5. Analysis Results Out of 1000 patients with various eye diseases who visited the ophthalmologist, 222 were diagnosed with dry eye. In addition, 71 patients were finally enrolled in the survey based on the above criteria. Of these, 25 were newly diagnosed patients with dry eye (new patients) and 46 were patients who had already been confirmed to have dry eyes (treated patients). Table 1 summarizes the statistics of age, sex, sleep disorder, mood disorder, and type of eye drops used for treatment for the patients studied.

  The age was analyzed by unpaired t-test (ubpaired t test), and other values were analyzed by chi-square test. The P value described was P <0.05 and recognized as having a significant difference (indicated by * in the table). NS means no significant difference.

  The PSQI values are classified as normal for 0-5, sleep disorder for 6-7, and severe sleep disorder for 8-21. HADS values are categorized as ≧ 10 with mood disorders and ≧ 20 with severe mood disorders.

  Analysis by the Mann-Whitney U test revealed that the mean values at the start of the PSQI and HADS studies were 6.9 ± 3.8 and 9.6 ± 6. 6. The number of patients already treated was 5.8 ± 3.2 and 9.5 ± 5.5, and there was no significant difference between them.

  The proportion of patients with confirmed dry eye, suspected sleep disorder (PSQI ≧ 6), and suspected mood disorder (HADS ≧ 10) was higher in new patients than in previously treated patients. The morning / night score and the dawn score were 4.4 ± 2.6 and 81.5 ± 15.9 for new patients, 4.7 ± 2.2 and 85.9 ± 19.1 for previously treated patients, respectively. Met. New patients tend to be prescribed steroid eye drops rather than pre-treated patients, and pre-treated patients tend to be treated with hyaluronic acid eye drops alone.

  The mean values at the end of the PSQI and HADS studies were analyzed by Mann-Whitney U test. New patients were 6.5 ± 4.4 and 9.8 ± 8.0, respectively. 6 ± 3.4 and 10.5 ± 4.7, both were not significantly different. However, as shown in FIG. 1, in the new patients, the proportion of patients with improved PSQI score and HADS score was significantly higher than that in the already treated patients (P <0.05, chi-square test).

  FIG. 1a summarizes the changes in PSQI values after treatment with eye drops in already treated patients and new patients. Among new patients, the proportion of patients with improved sleep disorder (Improved) is about 35%, which is significantly higher than 20% of the already treated patients. FIG. 1b summarizes the changes in HADS due to treatment, with about 50% of new patients having improved HADS, whereas about 25% of previously treated patients have seen an improvement effect.

  According to the PSQI and HADS scores, both “impaired” patients in the new patients greatly exceeded “worsened” patients in both sleep disorders and mood disorders. Therefore, it is shown that the treatment of dry eye with eye drops is effective for the treatment of sleep disorders and mood disorders. In addition, it is noteworthy that there are 20% or more patients who have already been treated, and who answered that both sleep disorder and mood disorder have improved.

  The morning / night score and light score were 4.4 ± 2.3 and 86.5 ± 17.6 for new patients, and 4.1 ± 2.0 and 86.8 ± 18.7 for previously treated patients, respectively. Met. In addition, although details of the data are not shown here, Akiraaki showed a significant improvement in new patients (P <0.05, paired t test when paired).

  Next, the results were analyzed by regression analysis. It was revealed that the difference between the PSQI value at the end of the survey and the start PSQI (ΔPSQI) and the difference between the HADS value at the end of the survey and the start HADS (ΔHADS) were significantly correlated (P <0. 05, Pearson's product moment correlation (Pearson product moment correlation). However, there was no correlation with age, severity of dry eye, prescribed eye drops, and initial PSQI values (Table 2).

  In the table, * indicates a Pearson product moment correlation coefficient that was significant (P <0.05). The gender is calculated with male = 1 and female = 0, and the DED severity is calculated with confirmed dry eye = 1 and suspected dry eye = 0. Δ = (final value (score at the end of the survey)) − (initial value (score at the time of examination registration)).

In addition, the initial HADS value and PSQI value at the time of the survey registration showed a very high correlation (P <0.05). However, it did not correlate with the severity of dry eye symptoms. Further, the ΔHADS score showed a correlation with only the ΔPSQI score. In FIG. 2, ● and solid lines indicate data of new patients, and ○ and dotted lines indicate data of already treated patients. In new patients, changes in PSQI values and changes in HADS values are significantly stronger than those in previously treated patients (new patients; y = 0.2972x + 0.3056, R ² = 0.2554, pretreated) Patient; y = 0.1165x−0.5707, R ² = 0.0696, P <0.05, Pearson's product moment correlation coefficient). That is, it is shown that mood disorders improve with improvement of sleep disorders in new patients.

  In addition, a detailed analysis of sleep disorders was performed on 25 new patients (FIG. 3). Of the 25 dry eye patients, 16 complained of sleep disorders with PSQI6 or higher. As for the degree of sleep disorder of 16 persons, 6 persons were sleep disorders having PSQI values of 6 to 7, and 10 persons were severe sleep disorders having PSQI values of 8 to 21.

  Among them, 9 patients (56%) improved sleep disorder by PSQI value by 2 or more by treatment of dry eye with eye drops. The change in the average value of PSQI values of 16 patients with sleep disorders was a change from 9.0 (± 3.1) before treatment to 7.8 (± 4.7) after treatment (FIG. 3a). Moreover, when only 9 patients with improved sleep disorders were analyzed, the PSQI value before treatment was 9.1 (± 2.7), and after treatment was significantly improved to 5.7 (± 5.7). (Fig. 3b).

  Of the 16 dry eye patients with sleep disorders, 6 sleep disorder groups improved to 2 normal groups after treatment. In addition, 10 patients in the severe sleep disorder group improved to 4 normal patients or sleep disorder groups after treatment. In these analyzed patients, there was no correlation between the presence or absence of steroid use, the type of eye drops, and improvement in sleep disorders.

  Next, the treatment results of 9 dry eye patients out of 10 patients who were treated at our sleep disorder outpatient will be shown. All patients undergo an interview and a comprehensive ophthalmic examination before being diagnosed by an ophthalmologist. Each patient takes 1 hour for new patients and 15 minutes for returning patients. Table 3 shows the degree of patient information, sleep disorder, and mood disorder.

  HADS-A indicates a subscale regarding HADS anxiety and HADS-D (depression) indicates a subscale regarding depression. CES-D stands for Center for Epidemic Studies Depression Scale. The Schirmer test is a method of examining tear volume by a typical test of dry eye. A thin filter paper (tears paper) is placed on the punctum, and the amount of tears is inspected with the amount of tears infiltrated by closing the eyelid for 5 minutes. BUT (tear break-up time) is an examination of how long tears covering the surface of the eye begin to dry.

  The visual field and retinal nerve fiber layer thickness obtained by optical coherence tomography (OCT) were normal in all patients. Of the 9 patients, 2 are already treated patients and 7 are newly diagnosed patients with dry eye.

  Four patients were prescribed eye drops containing hyaluronic acid as an active ingredient, three patients were given eye drops containing diquafosol as an active ingredient, and one person was given eye drops containing rebamipide as an active ingredient. Three patients were recommended to wear glasses that cut blue light at night. Two patients were also recommended to wear a wearable blue light treatment lamp (Re-Timer (registered trademark), manufactured by Weatherly) in the morning. Two patients were prescribed rameltheon (Rozelum (registered trademark), Takeda) as a melatonin receptor agonist and one patient was given a sedative herb (Yokukansan, Tsumura). However, none of the patients needed to be treated by a psychiatrist or referred to a psychiatrist for a severe neuropsychiatric disorder.

  Of the 9 dry eye patients, 8 responded to follow-up 3-6 months after the first treatment. The average values of PSQI, HADS, and VFQ-25 are 5.9 ± 4.4, 11.6 ± 4.4, and 88.5 ± 6.7, respectively, which is a significant improvement over the values investigated at the start of treatment. I did not. However, the satisfaction with sleep outpatient and the effect of sleep improvement are 8.8 ± 0.7 (highest value = 10, lowest value = 1), 7.3 ± 1.3 (highest value = 10, lowest value = respectively). 1) and a very good value. This result indicates that prescription of eye drops by an ophthalmologist and lifestyle review by medical staff have improved patient sleep disorders and mood disorders. That is, the treatment of sleep disorders and mood disorders in dry eye patients has shown the possibility of entering the field of liaison psychiatry in collaboration with ophthalmologists and psychiatrists.

  As described above, the results of treating dry eye with hyaluronic acid, a mucin secretion promoter, and a steroid eye drop have been described in detail as eye drops. However, eye drops for dry eye treatment containing active ingredients other than these, Even eye ointments for eye treatment have improved sleep disorders and mood disorders as well as improved dry eyes.

  For patients with dry eye, especially those who are newly diagnosed with dry eye, prescription of eye drops and eye ointment can improve sleep disorder and mood disorder. Is very beneficial for the patient.

  A therapeutic agent that has no systemic side effects such as eye drops or eye ointments and is easy to use for patients can improve not only sleep improvement but also mood disorders.

Claims (7)

  A therapeutic / ameliorating agent for sleep disorders and / or mood disorders in dry eye patients, characterized in that the dosage form is eye drops or eye ointments.   The therapeutic / ameliorating drug according to claim 1, wherein the dry eye patient is a new patient. The eye drop or eye ointment is
The therapeutic / improving drug according to claim 1 or 2, which is an eye drop for dry eye treatment or an eye ointment for dry eye treatment. The eye drop or eye ointment is
Artificial tear composition or cyclosporine, hyaluronic acid, diquafosol, rebamipide, fluorometholone, betamethasone, chondroitin sulfate, levofloxacin, flavin adenine dinucleotide, dexamethasone, methylbrednisolone, fradiomycin, or ofloxacin or a salt thereof or a solvate thereof The therapeutic / ameliorating agent for sleep disorder and / or mood disorder in dry eye patients according to claim 3, which is an eye drop or eye ointment containing at least one of the above as an active ingredient.   Artificial tear composition or cyclosporine, hyaluronic acid, diquafosol, rebamipide, fluorometholone, betamethasone, chondroitin sulfate, levofloxacin, flavin adenine dinucleotide, dexamethasone, methylbrednisolone, fradiomycin, or ofloxacin or a salt thereof or a solvate thereof Use of at least one of the above for the treatment and improvement of a sleep disorder and / or mood disorder in a dry eye patient.   The use according to claim 5, wherein the therapeutic / ameliorating agent is an eye drop or an eye ointment. Use according to claim 5 or 6, characterized in that the dry eye patient is a new patient.