JP2014070027A - Therapeutic or preventive agent for meibomian gland dysfunction or meibomian gland concretion - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new medicinal use of clarithromycin.SOLUTION: A therapeutic or preventive agent for meibomian gland dysfunction or meibomian gland concretion contains clarithromycin as an active ingredient. The dosage form is preferably an eye drop or an eye ointment.

Description

  The present invention relates to a therapeutic or prophylactic agent for meibomian gland dysfunction or meibomian gland infarction.

  There are about 25 meibomian glands in the upper eyelid of a human eye, and there are about 20 meibomian glands in the lower eyelid, and lipid is secreted from the opening of the meibomian gland. Meibomian gland dysfunction (MGD) is a state in which the function of the meibomian gland has been diffusely abnormal due to various causes, and is accompanied by chronic eye discomfort. Meibomian gland infarction refers to a condition in which the function of the meibomian gland is reduced, a white transparent oily mass is formed in the secretory tract, and the meibomian gland is clogged.

    On the other hand, clarithromycin is one of macrolide antibiotics and is used for the treatment of pharyngitis, tonsillitis, pneumonia, skin infection, acute exacerbation of chronic bronchitis and the like based on its antibacterial action. In recent years, clarithromycin is known to have anti-inflammatory action, immunomodulation action, action against bacterial biofilm, etc. in addition to antibacterial action, and based on these new actions, endometriosis or uterine fibroids, gastrointestinal disorders, In addition to treatment of pruritus, application to acute exacerbation of chronic bronchitis, bronchial asthma, influenza virus infection, atopic dermatitis, rheumatoid arthritis, etc. has been proposed (Patent Documents 1, 2, and 3).

JP 2006-241172 A JP-A-6-92850 JP-A-11-147827

  Therefore, searching for new medical uses of clarithromycin is a very interesting issue.

  The inventors of the present invention conducted intensive studies to search for a new pharmaceutical use of clarithromycin. (1) In a meibomian gland peripheral capillary dilatation test by administration of complete Freund's adjuvant in rats, clarithromycin Markedly improves the telangiectasia score, and (2) in the obstruction test of meibomian gland openings by feeding HR-AD diet using hairless mice, clarithromycin markedly increases the number of obstructions of meibomian gland openings It was found that the occlusion was improved and the present invention was achieved.

  That is, the present invention is a therapeutic or prophylactic agent for meibomian gland dysfunction or meibomian gland infarction containing clarithromycin as an active ingredient.

  A preparation containing clarithromycin as an active ingredient is expected to be effective in treating or preventing meibomian gland dysfunction and meibomian gland infarction.

  Embodiments of the present invention will be described below.

  The clarithromycin in this invention can be easily manufactured by a conventional method, or a commercial item can also be obtained.

  Meibomian gland dysfunction (MGD) is a state in which the function of the meibomian gland has been diffusely abnormal due to various causes, and is accompanied by chronic eye discomfort. Meibomian gland dysfunction is classified into a secreted form and an increased secreted form from the state of meibomian gland fat secretion, and the frequency in the secreted form tends to be higher in the decreased secreted form than in the increased secreted form.

  Decreased meibomian gland dysfunction is a condition in which the secretion of meibomian gland fat is reduced due to accumulation of excess keratin in the meibomian gland ducts or obstruction of the meibomian gland opening caused by various causes. As characteristic findings of decreased secretion type MGD, observation of obstruction of the opening of the meibomian gland and abnormal findings around the opening of the meibomian gland (vasodilation, movement of the mucosal skin transition part, irregular eyelid margin, etc.) are observed.

  Increased secretory meibomian gland dysfunction is a disease characterized by excessive oil secretion from the meibomian gland and large amounts of meibomian gland lipids being squeezed out to the eyelid margin in response to pressure on the pelvis.

  Meibomian gland infarction is a state in which a mixture of keratin and oil is solidified in the meibomian gland duct, and as a characteristic finding, obstruction of the opening of the meibomian gland is observed.

  Symptoms caused by meibomian gland dysfunction or meibomian gland infarction include various symptoms such as eye discomfort, burning sensation and itching.

  The therapeutic or prophylactic agent for meibomian gland dysfunction or meibomian gland infarction of the present invention can be administered either orally or parenterally. Examples of the dosage form include parenteral dosage forms such as eye drops, eye ointments and injections, and oral dosage forms such as tablets, capsules, granules and powders, with eye drops being particularly preferred.

  Formulation into these can be performed using a widely used technique. For example, in the case of eye drops, isotonic agents such as sodium chloride and concentrated glycerin, buffering agents such as sodium phosphate and sodium acetate, polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil, etc. A surfactant can be used as necessary, and stabilizers such as sodium citrate and sodium edetate, and preservatives such as benzalkonium chloride and paraben can be used as necessary. The pH may be in a range that is acceptable in ophthalmic preparations, and is preferably in the range of 4-8.

  In the case of an eye ointment, it can be formulated using a widely used base such as white petrolatum or liquid paraffin.

  In the case of oral preparations such as tablets, capsules, granules and powders, bulking agents such as lactose, crystalline cellulose, starch and vegetable oil, lubricants such as magnesium stearate and talc, binders such as hydroxypropylcellulose and polyvinylpyrrolidone , Disintegrating agents such as carboxymethylcellulose / calcium and low-substituted hydroxypropylmethylcellulose, coating agents such as hydroxypropylmethylcellulose, macrogol and silicone resin, and coating agents such as gelatin film, etc. it can.

  The dosage of clarithromycin can be appropriately selected according to symptoms, age, dosage form, etc. In the case of eye drops, 0.0001 to 5% (w / v), preferably 0.01 to 3% (w / V) may be instilled about 1 to 6 times a day. In the case of oral preparations, 0.1 to 5000 mg, preferably 1 to 1000 mg of clarithromycin may be administered once or divided into several times per day.

The present invention includes the following inventions.
(1) Clarithromycin for use in the treatment or prevention of meibomian gland dysfunction or meibomian gland infarction.
(2) The clarithromycin according to (1), formulated into an eye drop or eye ointment dosage form.
(3) Use of clarithromycin in the manufacture of a medicament for the treatment or prevention of meibomian gland dysfunction or meibomian gland infarction.
(4) The use according to (3), wherein the pharmaceutical dosage form is eye drops or eye ointment.

  Formulation examples and results of pharmacological tests are shown below, but these are for better understanding of the present invention and do not limit the scope of the present invention.

Formulation Example 1
1g Clarithromycin in 100ml
Concentrated glycerin 2g
Sodium hydrogen phosphate hydrate 0.1g
Stearate polyoxyl 40 0.1g
Dilute hydrochloric acid / sodium hydroxide appropriate amount Sterile purified water appropriate amount pH 7.0

  By changing the amount of clarithromycin added, dissolved eye drops having a concentration of 0.01% (w / v), 0.1% (w / v), and 1.0% (w / v) can be prepared.

Formulation Example 2
1g Clarithromycin in 100ml
Sodium chloride 0.75g
Disodium hydrogen phosphate 0.06g
Sodium dihydrogen phosphate 0.6g
Polysorbate 80 0.005g
0.001 g of hypromellose
Edetate sodium hydrate 0.01g
Dilute hydrochloric acid / sodium hydroxide appropriate amount Sterile purified water appropriate amount pH 7.0

  By changing the amount of clarithromycin added, suspension type eye drops having a concentration of 0.1% (w / v) and 0.5% (w / v) can be prepared.

Formulation Example 3
2ml of clarithromycin in 100ml
Liquid paraffin 30g
White petrolatum

  By changing the amount of clarithromycin added, an eye ointment having a concentration of 1% (w / w) and 5% (w / w) can be prepared.

[Pharmacological test]
1. Peripheral capillary dilatation test by administration of complete Freund's adjuvant in rats (Method for preparing test solution)
Clarithromycin (LKT laboratories, Inc.), concentrated glycerin, sodium hydrogenphosphate hydrate and polyoxyl 40 stearate were added to purified water and dissolved to give a final concentration of 1% (w / v) clarithromycin, pH 7 A test solution was prepared.

(experimental method)
Five-week-old female Lewis rats were administered 25 μL of complete Freund's adjuvant in one place on the right upper eyelid. On day 7 of induction, the periphery of the meibomian gland opening in the upper right eyelid was observed using a slit lamp, and a capillary dilation score was determined. According to the criteria in Table 1, the upper eyelid margin is equally divided into ear, center and nose, and the capillary dilation score around the meibomian gland opening is determined for each fraction. The sum of the image scores was calculated as the score per eye. In addition, the presence or absence of the expansion | swelling of a capillary blood vessel was determined by whether it exists in the state which can confirm the capillary blood vessel which cannot be normally visually recognized as a result of the blood vessel diameter expanding.

  The group was divided into a physiological saline administration group and a 1% (w / v) clarithromycin aqueous solution administration group, and each group was tested with 6 eyes so that the variation of the average value of each score was small. Then, physiological saline (5 μL / eye, 6 times a day) and 1% clarithromycin aqueous solution (5 μL / eye, 3 times or 6 times a day) were instilled into the right eye for 21 days. On the 28th day after induction, the periphery of the meibomian gland opening in the upper right eyelid was observed using a slit lamp, and score determination was performed.

(result)
Table 2 shows the results (average value of capillary dilation score).

(Discussion)
On the 7th day after induction (day 0 of administration start), there was no difference in the average value of the telangiectasia score of each group, but on the 28th day after administration (day 21 of administration start), 1% (w / V) The clarithromycin aqueous solution administration group (3 or 6 infusions per day) significantly reduced the telangiectasia score near the meibomian gland opening compared to the physiological saline administration group.

2. Occlusion test of meibomian gland opening by feeding HR-AD diet using hairless mice (Test solution preparation method)
A 1% (w / v) clarithromycin test solution was prepared in the same manner as in Pharmacological Test 1.

(experimental method)
Five-week-old male Hos: HR-1 hairless mice, 6 normal feed groups (CRF-1 feed, manufactured by Oriental Yeast Co., Ltd.), 12 HR-AD feed groups (manufactured by Nippon Nosan Kogyo Co., Ltd.) ), And each was fed with normal feed or HR-AD feed and allowed to ingest spontaneously. On day 28 after the start of feeding, the meibomian gland openings were observed using a slit lamp, and the number of obstructed openings was counted among the eight meibomian gland openings in the center of the upper eyelid. In addition, the presence or absence of obstruction | occlusion of the meibomian gland opening part was determined by whether the meibomian gland opening part was in the state which became cloudy and raised.

  Divide 12 HR-AD feed feeding groups into a physiological saline administration group and a 1% clarithromycin aqueous solution administration group so that the variation in the average number of obstructions of the meibomian gland opening measured is reduced The test was conducted with 6 animals in each group, and from the 29th day after the start of feeding, physiological saline (2 μL / eye, 3 times a day), 1% (w / v) clarithromycin aqueous solution (2 μL / eye, 3 times a day) Was instilled for 14 days. On day 42 after the start of feeding, the meibomian gland openings were observed using a slit lamp, and the number of obstructed openings was counted among the eight meibomian gland openings in the center of the upper eyelid.

(result)
Table 3 shows the results (average value of the number of closed openings).

(Discussion)
On the 28th day from the start of feeding (day 0 of administration), the meibomian glands of the saline administration group (HR-AD feed feeding) and the 1% (w / v) clarithromycin aqueous solution administration group (HR-AD feeding) There was almost no difference between the number of occlusions of the opening, but on the 42nd day after the start of feeding (on the 14th day of administration), the 1% (w / v) clarithromycin aqueous solution administration group had a meibomian gland opening. It significantly reduced the number of obstructions and improved meibomian gland infarction.

  According to the present invention, by using clarithromycin as an active ingredient, meibomian gland dysfunction and meibomian gland infarction can be treated or prevented.

Claims (4)

  A therapeutic or prophylactic agent for meibomian gland dysfunction or meibomian gland infarction containing clarithromycin as an active ingredient.   The therapeutic or prophylactic agent according to claim 1, which is a therapeutic or prophylactic agent for meibomian gland dysfunction.   The therapeutic or prophylactic agent according to claim 1, which is a therapeutic or prophylactic agent for meibomian gland infarction.   The therapeutic agent or prophylactic agent according to any one of claims 1 to 3, wherein the dosage form is an eye drop or an eye ointment.