Viswambaran V. K, Anavadhy K. A, Chandrababu G, Babu A, Rajeev G, Gupta S. Blepharitis: A Review on Human Clinical Trials with Synthetic and Natural Remedies.Biomed Pharmacol J 2020;13(4).

---

Manuscript received on :10-Sep-2020
Manuscript accepted on :7-Dec-2020
Published online on: --

---

Plagiarism Check: Yes
Reviewed by: Tejaswi Chavan  
Second Review by: Hozefa Ujjainwala
Final Approval by: Fai Poon

---

How to Citeclose    |   Publication History close

 Views: (Visited 3,050 times, 1 visits today)    PDF Downloads: 769

Vyshma Kizhuppully Viswambaran, Anavadhya K. A, Gopika Chandrababu, Amritha Babu, Gayathri Rajeev and Swati Gupta*

Amrita School of Pharmacy, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, AIMS-Ponekkara PO, Kochi, Kerala -682041, India.

Corresponding Author E-mail: swatigupta@aims.amrita.edu

DOI : https://dx.doi.org//10.13005/bpj/2072

Abstract

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.

Keywords

Blepharitis; Clinical Trials; Natural Drugs; Novel Drug Delivery Systems; Synthetic Drugs

Introduction

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 ^8-10. Different causes of blepharitis have been summarized as schematic representation in the figure 1.

Figure 1: Causes of blepharitis Click here to View figure

Table 1: Blepharitis survey reports of different places in India

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, becausealong 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 ^22-30.

Table 2: Synthetic drugs used for the management of blepharitis

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 origin¹⁰. 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).

Table 3: Human clinical trials with novel drug delivery systems and formulations of natural origin in treatment of blepharitis.

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 ^35-38.

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 ^39-41. 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 blepharitis⁴⁴.

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-1,3,2-benzodioxabismol-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 intra-ductal 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.

Acknowledgements

I offer my deepest gratitude towards Amrita School of Pharmacy for their constant guidance and facilities.

Conflicts of interest

authors have no conflict of interest.

Funding Source

There are no funding sourse.

Reference

1. Christopher MP. Diagnosis and management of blepharitis: an optometrist’s perspective. Dove press journal: clinical optometry 2016; 71-78.
   CrossRef
2. G Nageswar R, SilpaS, Sweta P, HumaR, Bhaskar T, Arttatrana P. Prevalence of ocular morbidity among children aged 17 years or younger in eastern india. Clinical Ophthalmology 2018; 12:1645-1652.
   CrossRef
3. Ajith KD, Ajoy BN. Prevalence of ocular morbidities among school children in a rural block of cachar, Assam. Journal of Evolution of Medical and Dental Sciences 2017; 6:4124-4127.
   CrossRef
4. Vasantha M, Siva SR. Morbidity pattern of geriatric population attending rural community health centre, south India. Akshantala Journal of Research in Preventive and Social Medicine 2017; 1:12-16.
5. Ann MT, Alexander J, Leelamoni K, Natasha R, Swati P, Harsha. Prevalence and Predictors of Ocular morbidity among Primary School Children of Urban Kerala. National Journal of Research in Community Medicine 2015; 4:268-277.
6. Bansal A, KanthamaniK et al. Ocular Morbidity in School going Children of Kolar District, South India. J Clin Biomed Sci. 2012; 2:175-184.
7. Gupta Y, Sukul RR, Gupta M, Phougat A, Jain R, Varshney A. School eye survey in rural population in UP, India. Nepal J Ophthalmol 2011; 3: 78-79.
   CrossRef
8. Katherine D, Bennie HJ. Medical management of Blepharitis. curr.opin.ophthalmol 2015; 26: 289-294.
   CrossRef
9. Ronald ES, Charles WF. Chronic Blepharitis: A review. CLAO journal 1995; 21:200-206.
10. Stephen P et al. Treatment of Blepharitis: Recent Clinical Trials. Ocular Surface 2014. doi: 10.1016/j.jtos.2014.05.005
    CrossRef
11. Mihaela AI, ConstantinC, MihaiL, Daniela L, Mircea T, Simona RG, Alexandra B, Carolina C, Monica N, Sabina AZ, Daniel B. Current and future applications of confocal laser scanning microscopy imaging in skin oncology (Review). ONCOLOGY LETTERS 2019; 17: 4102-4111.
12. Justin S et al. Randomised double masked trial of eyelid cleansing treatment for blepharitis. The Ocular Surface 2018; 16:77-88.
    CrossRef
13. Jodi L. Azithromycin in DuraSite® for the treatment of blepharitis. Clinical Ophthalmology Dove press journal 2010:4: 681–688.
    CrossRef
14. Roland L. Mechanisms of Resistance to Macrolides and Lincosamides: Nature of the Resistance Elements and Their Clinical Implications. Antimicrobial Resistance2002; 34:482-492.
    CrossRef
15. Sonia P, SushmitaK, Savleen K, PandavS S. Steroid-induced Glaucoma: An Avoidable Irreversible Blindness. Journal of Current Glaucoma Practice 2017; 11(2):67-72.
    CrossRef
16. Giacomo DB, Agostino SV. Oral azithromycin and oral doxycycline for the treatment of Meibomian gland dysfunction: A 9‑month comparative case series. Indian Journal of Ophthalmology 2019:67:464-470.
    CrossRef
17. Atsuki F, Yuichi O, Nobuyuki E, Eiichi U, Shigeki O, Naoki K et al. Therapeutic effects of 0.1% tacrolimus eye drops for refractory allergic ocular diseases with proliferative lesion or corneal involvement. Br J Ophthalmol 2014; 98:1023–1027.
    CrossRef
18. Samir SS. Topical Tacrolimus in anterior segment inflammatory disorders. Eye and Vision 2017; 4:1-7.
    CrossRef
19. Stephen P, Paul Karpecki MD, Victor LP. Treatment of Blepharitis: Recent Clinical Trials. Ocular Surface 2014; doi: 10.1016/j.jtos.2014.05.005
    CrossRef
20. Harikrishnan KV, Rajashree R., Mukesh M, Remya R. Role of omega -3 fatty acids in the treatment of cardiovascular disorders. JPR 2012; 5140-5143.
21. Annie S, Daniel NJ, Henry DP, Scheffer CGT. Managing Blepharitis: Tried-and-True and New Approaches. Clinical Update: cornea 2012; 29-31.
22. Jose L, Fernando A, Jaime Q, Renzo R. Comparative clinical study of norfloxacin 0.3% and chloramphenicol 0.5% opthalmic solutions in the treatment of acute bacterial conjunctivitis, blepharitis, and blepharoconjunctivitis. Current Therapeutic Research 1992; 52:64-69.
    CrossRef
23. Foulks GN, Borchman D, Yappert M, Kakar S. Topical azithromycin and oral doxycycline therapy of meibomian gland dysfunction: a comparative clinical and spectroscopic pilot study. Cornea 2013; 32:44-53.
    CrossRef
24. Basak SC, KaladharK, Subburaj T. Doxycycline hyclate delayed release capsules with sodium starch glycolate as a pH-dependent pore forming agent. Indian J Pharm Sci2004; 66:704–707.
25. Mehdi Z, Neda R, Sanaz S. Comparison of therapeutic effect of topical azithromycin solution and systemic doxycycline on posterior blepharitis. Int J. Opthalmol 2016; 9:1016-1019.
26. Hun L, Kyung M, Eung KK, Tae I. Minocycline controls clinical outcomes and inflammatory cytokines in moderate and severe meibomian gland dysfunction. Am J Ophthalmol 2012; 154:949-957.
    CrossRef
27. Junya N, Atsuhiro N, Ryota H, IwaoT. A Case of Seborrheic Blepharitis; Treatment with Itraconazole. Jpn. J. Med. Mycol 2002; 43:189-191.
    CrossRef
28. Michael R, Sanjay NR. Efficacy of Topical Cyclosporin 0.05% in the Treatment of Posterior Blepharitis. Journal of ocular pharmacology and therapeutics 2006;22: https://doi.org/10.1089/jop.2006.22.47
    CrossRef
29. Fernando ESN, Helena MMR, Bernardo KM, Daniela AM, Brenda BC, Ricardo H, Ruth MS, Richard YH. Tacrolimus Ointment for Refractory Posterior Blepharitis. Current Eye Research 2017: DOI: 10.1080/02713683.2017.1339805 1-6.
    CrossRef
30. Rahul B, Prachi K. Comparison of the safety and efficacy of topical Tacrolimus (0.03%) versus dexamethasone (0.05%) for subepithelial infiltrates after adenoviral conjunctivitis. Indian Journal of Ophthalmology 2019; 67:594-598.
    CrossRef
31. Tinu TS, Litha T, Anil KB. Polymers used in ophthalmic in Situ gelling system, International Journal of Pharmaceutical Sciences Review and Research 2013; 20:176-183.
    CrossRef
32. Jackson WB. Blepharitis: current strategies for diagnosis and management. Can J Ophthalmol 2008:43:170-179.
    CrossRef
33. Krenzer KL, Zhang JZ, Coffey MJ, Richardson ME. Safety of repeated topical ocular administration of a polycarbophil-based formulation in several models of ocular surgery in rabbits. J Cataract Refract Surg2012; 38:696-704.
    CrossRef
34. Esen KA, Jason V, Rozemarijn SV, Kurt B, Thierry A, Kendall DP et al. Ocular Surface Distribution and Pharmacokinetics of a Novel Ophthalmic 1% Azithromycin Formulation. Journal of Ocular pharmacology and therapeutics 2009; 25:433-439.
    CrossRef
35. Jesse SP, Kara C, Kevin SS, Joseph AC. Demodex Blepharitis Treated with a Novel Dilute Povidone-Iodine and DMSO System: A Case Report. Ophthalmol Ther 2017; 6:361–366.
    CrossRef
36. Pelletier JS, Capriotti KD, Stewart KS, Barone SB, Capriotii JA. A Novel Transdermal Ophthalmic Preparation for Blepharitis in a Dilute Povidone-Iodine and Dimethyl Sulfoxide (DMSO) System: A Case Series. EC Ophthalmology 2018; 9: 129-134.
37. Jesse SP, Kevin PS, Kara C, Joseph AC. Rosacea Blepharoconjunctivitis Treated with a Novel Preparation of Dilute Povidone Iodine and Dimethylsulfoxide: a Case Report and Review of the Literature. Ophthalmol Ther 2015; 4:143–150.
    CrossRef
38. Diana GH, Alejandro JV, Gustavo AM, Lorena LO. Demodex and rosacea: Is there a relationship. Indian Journal of Ophthalmology 2018; 66:36-38.
    CrossRef
39. Chen WS, Sean T, HosamS, Anny MS Cheng, Scheffer CG Tseng. Safety and efficacy of 4-terpineol against microorganisms associated with blepharitis and common ocular diseases. BMJ Open Ophth 2018; 1-6.
40. Gao YY, Di Pascuale MA, Li W, A Baradaran Rafii, Elizondo A, C-L Kuo, Raju VK, S C G Tseng. In vitro and in vivo killing of ocular Demodex by tea tree oil. Br J Ophthalmol 2005; 89:1468–1473.
    CrossRef
41. Yucel K, Erhan Z. Evaluation of the efficacy of tea tree oil on the density of demodex mites (acari: demodicidae) and ocular symptoms in patients with demodectic blepharitis. J. Parasitol 2018; 104: 473–478.
    CrossRef
42. Orla M, Veronica O, Aoife L-McK. The efficacy of tea tree face wash, 1, 2-Octanediol and microblepharoexfoliation in treating Demodex folliculorum blepharitis. Contact Lens and Anterior Eye.2018; 41:77–82.
    CrossRef
43. Divya G, RajithaP, Swati G, Jayakumar R, Sabitha M. Acitretin and aloe-emodin loaded chitin nanogel for the treatment of psoriasis. European Journal of Pharmaceutics and Biopharmaceutics 2016; 107:97–109.
    CrossRef
44. Valentina DL, Adriano C, Giovanna CS, Gabriele P, Donatella B, Vincenzo S. Efficacy and Safety of Wet Wipes Containing Hy-Ter^®Solution Compared with Standard Care for Bilateral Posterior Blepharitis: A Preliminary Randomized Controlled Study.Ophthalmol Ther 2019; 8:313–321.
    CrossRef
45. Serge D. Tolerability and acceptability of Blephagel: a novel eyelid hygiene aqueous gel. Clinical Ophthalmology 2012; 6: 71–77.
    CrossRef
46. Jennifer PC, Michael TM Wang, KalaivarnyG, Ilva DR, Simon S, Chee SL et al. Randomised masked trial of the clinical safety and tolerability of MGO Manuka Honey eye cream for the management of blepharitis. BMJ Open Ophth 2017; 1-10.
    CrossRef
47. Pavel AB, Nikolai S, YuriyD, Andrei K, NikN, Matthias M et al. Successful treatment of blepharitis with bibrocathol (Posiformin® 2 %). Graefes Arch ClinExpOphthalmol 2012; 250:1869–1875.
    CrossRef
48. Fermon S, Hindi Zaga I, Alvarez MD. Intraductal meibomian gland probing for treatment of blepharitis. Arch SocEspOftalmol 2015; 90:76–80.
    CrossRef