Blepharitis: A Review on Human Clinical Trials with Synthetic and Natural Remedies

Blepharitis is an eyelid disorder characterized by inflammation and pain. It affects all the ages and ethnic groups. Primary cause of blepharitis is poor hygienic condition. Topical antibiotics are the preferred first line therapeutic agents along with eyelid cleansing and warm compresses are recommended. Topical steroids, oral antibiotics and calcineurin inhibitors are also recommended in severe conditions. However, recurrence of disease, dose related side effects and safety regimen are still uncertain with these agents. Blepharitis needs a long term treatment, thus novel formulations and products with natural components may be considered more reliable to overcome such issues. In this review article we have discussed human clinical trials (HCTs) conducted with conventional synthetic drugs, novel drug delivery systems developed with synthetic drugs and drugs of natural origin and other supportive measures. As compared to synthetic drugs, formulations with natural origin were found to be safe with minimum side effects.

Blepharitis is an inflammatory disorder of eyelids affecting all the age and ethnic groups probably because of poor hygienic condition. To find the prevalence of blepharitis, a lot of surveys have been conducted among school going children in India (Table 1) 1, 2-7 . Blepharitis is common among different ocular morbidity and prevailing unhygienic conditions. Apart from poor hygienic conditions microbial infection, clogged meibomian gland, dandruff, eyelash mite and allergy are some of the major causes of this disease 8 . Blepharitis mainly starts with poor hygiene, allergy or meibomian gland dysfunctioning followed by blockage of meibomian gland and decreased production of meibom [8][9][10] . Different causes of blepharitis have been summarized as schematic representation in the figure 1.

Classification and diagnosis
Based upon anatomic location, blepharitis classified as anterior, posterior and mixed type blepharitis. In anterior blepharitis, Inflammation occurs on the base of eyelashes and follicles and it is characterized by redness in lid margin, superficial discomfort, eyelid ulceration, crusting around lashes, blurred vision, light sensitivity, stickiness of eyelidsin morningetc 1,8 . In posterior blepharitis meibomian gland dysfunctioning happens and it is characterized by decreased meibom secretions with foamy tears, chalazia, eyelid scarring, corneal scarring, corneal neovascularization, corneal ulceration, marginal infiltration and pannus. Red swollen eyelids, burning sensations, ocular irritation, loss of eyelashes and misdirected eyelashes are common symptoms of Blepharitis 1,8 .
Techniques used to diagnose blepharitis are slit lamp examination and tear film stability test by using manual keratometry, placidokeratometry precorneal tear film interferometry 1 . Confocal microscopy is the modern technique to diagnose presence of inflammatory cells 10,11 .

Treatment and management
Blepharitis is a common recalcitrant condition; complete recovery from this condition is not possible. The synthetic methods for treatment are not adequate 12 . Topical antibiotics and warm compress is as a first line therapy. Among different antibiotics, macrolides are preferred in the treatment of blepharitis, because along with antibacterial effect it reduces inflammation as well 13 . Long term therapy creates resistance 14 .
Topical steroids are using in chronic conditions of blepharitis to reduce inflammation, but it can use for less duration due to its complications like increased intraocular pressure 15 . Oral antibiotics are preferred in chronic conditions 16 . Calcineurin inhibitors are immunomodulatory agents given as topical, which also reduces the inflammation 1, 8, 9 . They creates side effects like mild and transient ocular irritation and burning sensation 17, 18 . Omega 3 fatty acids are the supportive therapy in blepharitis to improve functioning of meibomian glands 19,20 . Eyelid cleansing, warm compress and eyelid scrub are preferred to reduce some complications by removing the meibom clogging and removes microbes 12,21 . A detailed account on HCTs with synthetic drugs has been presented in the Table 2 [22][23][24][25][26][27][28][29][30] .
In past few decades some review articles published on treatment and management of   blepharitis. Christopher (2016) and Katherine et al. (2015) discussed about synthetic drugs used for blepharitis, but didn't include any treatment using natural products 1, 8 . Stephen et al. (2014) discussed about human clinical trials (HCTs) conducted with synthetic formulations for treatment of blepharitis, they also didn't include any HCTs for drugs from natural origin 10 . In this review we have summarized the HCTs with synthetic drugs in conventional dosage forms, synthetic drugs in novel drug delivery systems and formulations from natural origin for the management of blepharitis (Table 3).

Discussion
In synthetic therapy eye drops of antibiotics alone or in combination with steroids are given for the management of blepharitis. Azithromycin, erythromycin, norfloxacin, tobramycin, moxifloxacin, doxycycline and minocycline are the most commonly used antibiotics. These are recommended for the short term applications because of development of antibiotic resistance, steroid induced intra ocular pressure raise and other complications as listed in the Table 2. Novel drug delivery systems and formulations with natural origin are reported to be more effective and safe with minimum side effects 31,32 .
Azithromycin, a broad spectrum antibiotic is prescribed in the form of eye drops. In a study reported by Jodi Luchs (2010) azithromycin combined with durasite drug delivery vehicle in Azasite ® and this combination contains polycarbophil known to improve the bio adhesiveness of formulation followed by drug penetration to cornea, conjunctiva and eyelids and further improves effectiveness in the treatment of blepharitis 13,33,34 . Low dose Povidone iodine is very safe and effective antiseptic in ocular tissues. It interacts with cells via poisoning electron transport system, inhibits cellular respiration and destabilize cell membrane. In two different studies, Povidone iodine has been reported in the form of gel formulation for topical application in the eyelashes and eyelids for demodex blepharitis and blepharo-conjuctivitis without any reported side effects [35][36][37][38] . Terpineol is the essential oil from tea tree oil which is very effective against microorganisms causing skin and ocular infection especially against demodex mite, within 4 weeks [39][40][41] . The efficacy of terpineol has been studied in two different formulations of face wash and wet wipes 42 . The wet wipes also had hyaluronic acid and aloe, which are very effective anti-inflammatory agent 43 . Daily hygiene and use of tea tree face wash or wipes has been found to be very safe and effective in reducing the symptoms of all type of blepharitis 44 . Blephagel ® is a poloxamer based cosmetic gel for cleansing the eyelid in patients with sensitive skin or eyes or contact lens users. It removes mucous, debris, bacteria from eyelid and hydrates eyelid skin. Blephagel´s soothing effect help to use in periocular region routinely without any adverse effects 45 .
Manuka honey has antibacterial and anti-inflammatory effect which helps to treat blepharitis symptoms. From study conducted in blepharitis patients with manuka honey loaded microemulsion eye cream found to be more safe and tolerable in periocular area without any adverse effects 46 . Bibrocathol (4,5,6,7-Tetrabromo-1,3,2benzodioxabismol-2-ol) is a topical antiseptic available as 2 or 5 % eye ointment with liquid paraffin, white soft paraffin, and lanolin. According to Pavel et al (2012), the ointment found to be safe and well tolerable in patients with blepharitis 47 .
Fermon et al (2015) conducted HCT to treat meibomian gland dysfunctioning by intraductal meibomian gland probing using 2 mm cannula under biomicroscopy. Meibomian gland dysfunction is a major problem in severe posterior blepharitis. Long term relief is possible by single treatment itself 48 .

conclusion
Blepharitis is an inflammatory disorder of eyelids and manly observed in school going children with poor hygienic conditions. If remained unattended, this infection may lead to keratopathy, permanent eyelid morphology change, and corneal neovascularization. Topical antibiotics, steroids and calcineurin inhibitors are the recommended first line therapy but their safety and duration of treatment is largely unknown. When compared with synthetic agents, formulations developed with natural ingredients were found to be equally effective with minimum side effects for treatment of blepharitis.