Novel drug delivery methods for the treatment of keratitis: moving away from surgical intervention

ABSTRACT Introduction: Corneal ulceration is one of the leading causes of blindness especially in low- and mid-income countries (LMICs). Surgical treatment of microbial keratitis is associated with multiple challenges that include non-availability of donor corneal tissues, lack of trained corneal surgeons, and poor compliance to follow up care. As a result, the surgery fails in 70–90% cases. Therefore, improving outcome of medical treatment and thereby avoiding the need for the surgery is an unmet need in the care of corneal ulcer cases. Areas covered: In this review article, the authors have tried to compile information on the novel drug-delivery systems that have potential to enhance success of medical management. We have discussed the following systems: cyclodextrins, gel formulations, colloidal system, nanoformulations, drug-eluting contact lens, microneedle patch, and ocular inserts. Expert opinion: The goals of corneal ulcer treatment are as follows: rapid eradication of causative microorganisms, control of damage from induced inflammation and microbial toxins, and facilitation of repair. The ocular surface anatomy poses several challenges for drug delivery using standard topical therapy. The novel drug-delivery systems mentioned above aim to enhanced tear solubility; superior stability; improved bio-availability; reduced toxicity; besides facilitating targeted drug delivery and convenience of administration.

[1]  Isra H Ali,et al.  Noninvasive biodegradable nanoparticles-in-nanofibers single-dose ocular insert: in vitro, ex vivo and in vivo evaluation. , 2019, Nanomedicine.

[2]  S. Cheng,et al.  Phomopsidione nanoparticles coated contact lenses reduce microbial keratitis causing pathogens , 2019, Experimental eye research.

[3]  A. Mitra,et al.  Ocular Pharmacokinetics of a Topical Ophthalmic Nanomicellar Solution of Cyclosporine (Cequa®) for Dry Eye Disease , 2019, Pharmaceutical Research.

[4]  A. P. Serro,et al.  Antibacterial layer‐by‐layer coatings to control drug release from soft contact lenses material , 2018, International journal of pharmaceutics.

[5]  WonHyoung Ryu,et al.  Intracorneal injection of a detachable hybrid microneedle for sustained drug delivery. , 2018, Acta biomaterialia.

[6]  Shubhmita Bhatnagar,et al.  Effect of Mucoadhesive Polymeric Formulation on Corneal Permeation of Fluoroquinolones. , 2018, Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics.

[7]  Juan Li,et al.  Hyaluronic-acid-modified lipid-polymer hybrid nanoparticles as an efficient ocular delivery platform for moxifloxacin hydrochloride. , 2018, International journal of biological macromolecules.

[8]  M. Ramezani,et al.  New cyclodextrin-based nanocarriers for drug delivery and phototherapy using an irinotecan metabolite. , 2018, Carbohydrate polymers.

[9]  W. Pan,et al.  A novel ion-activated in situ gelling ophthalmic delivery system based on κ-carrageenan for acyclovir , 2018, Drug development and industrial pharmacy.

[10]  E. Vasheghani-Farahani,et al.  Self-assembled amphiphilic-dextran nanomicelles for delivery of rapamycin , 2018 .

[11]  N. Huang,et al.  A Mussel-Inspired Facile Method to Prepare Multilayer-AgNP-Loaded Contact Lens for Early Treatment of Bacterial and Fungal Keratitis. , 2018, ACS biomaterials science & engineering.

[12]  S. Mirzaeei,et al.  Preparation of the Potential Ocular Inserts by Electrospinning Method to Achieve the Prolong Release Profile of Triamcinolone Acetonide , 2018, Advanced pharmaceutical bulletin.

[13]  T. Loftsson,et al.  Cyclodextrins: structure, physicochemical properties and pharmaceutical applications. , 2018, International journal of pharmaceutics.

[14]  T. Loftsson,et al.  Cyclodextrin-Based Formulations: A Non-Invasive Platform for Targeted Drug Delivery. , 2018, Basic & clinical pharmacology & toxicology.

[15]  Shubhmita Bhatnagar,et al.  Corneal delivery of besifloxacin using rapidly dissolving polymeric microneedles , 2018, Drug Delivery and Translational Research.

[16]  V. Rodilla,et al.  Ex vivo rabbit cornea diffusion studies with a soluble insert of moxifloxacin , 2018, Drug Delivery and Translational Research.

[17]  K. Kesavan,et al.  Phase-transition W/O Microemulsions for Ocular Delivery: Evaluation of Antibacterial Activity in the Treatment of Bacterial Keratitis , 2017, Ocular immunology and inflammation.

[18]  F. Otero-Espinar,et al.  Improved release of triamcinolone acetonide from medicated soft contact lenses loaded with drug nanosuspensions. , 2017, International journal of pharmaceutics.

[19]  M. A. Kamaleddin Nano-ophthalmology: Applications and considerations. , 2017, Nanomedicine : nanotechnology, biology, and medicine.

[20]  Xiaoyi Sun,et al.  Voriconazole Composited Polyvinyl Alcohol/Hydroxypropyl-β-Cyclodextrin Nanofibers for Ophthalmic Delivery , 2016, PloS one.

[21]  D. Monti,et al.  Solid lipid nanoparticles as promising tool for intraocular tobramycin delivery: Pharmacokinetic studies on rabbits. , 2016, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[22]  H. McCarthy,et al.  Rapidly dissolving polymeric microneedles for minimally invasive intraocular drug delivery , 2016, Drug Delivery and Translational Research.

[23]  Shurong Wang,et al.  Advance of the application of nano-controlled release system in ophthalmic drug delivery , 2016, Drug delivery.

[24]  Tianfu Wu,et al.  A Hydrogel-Based Hybrid Theranostic Contact Lens for Fungal Keratitis. , 2016, ACS nano.

[25]  R. Müller,et al.  Mucoadhesive dexamethasone acetate-polymyxin B sulfate cationic ocular nanoemulsion--novel combinatorial formulation concept. , 2016, Die Pharmazie.

[26]  Bhupinder Singh,et al.  Liposomal fusidic acid as a potential delivery system: a new paradigm in the treatment of chronic plaque psoriasis , 2016, Drug delivery.

[27]  T. Essam,et al.  Nanoparticles as tool for enhanced ophthalmic delivery of vancomycin: a multidistrict-based microbiological study, solid lipid nanoparticles formulation and evaluation , 2016, Drug development and industrial pharmacy.

[28]  Mirza Salman Baig,et al.  Application of Box-Behnken design for preparation of levofloxacin-loaded stearic acid solid lipid nanoparticles for ocular delivery: Optimization, in vitro release, ocular tolerance, and antibacterial activity. , 2016, International journal of biological macromolecules.

[29]  A. Alshamsan,et al.  Delivery of gatifloxacin using microemulsion as vehicle: formulation, evaluation, transcorneal permeation and aqueous humor drug determination , 2016, Drug delivery.

[30]  S. Swift,et al.  Development of gatifloxacin-loaded cationic polymeric nanoparticles for ocular drug delivery , 2016, Pharmaceutical development and technology.

[31]  Malik Y. Kahook,et al.  Fenestrated microneedles for ocular drug delivery , 2016 .

[32]  M. Nireekshan Kumar,et al.  Norfloxacin Loaded pH Triggered Nanoparticulate in-situ Gel for Extraocular Bacterial Infections: Optimization, Ocular Irritancy and Corneal Toxicity , 2016, Iranian journal of pharmaceutical research : IJPR.

[33]  V. Patel,et al.  Development and characterization of in-situ gel for ophthalmic formulation containing ciprofloxacin hydrochloride , 2015, Results in pharma sciences.

[34]  S. Anand,et al.  Cyclodextrins in Ocular Drug Delivery , 2016 .

[35]  C. Alexander,et al.  Imprinted Contact Lenses for Sustained Release of Polymyxin B and Related Antimicrobial Peptides. , 2015, Journal of pharmaceutical sciences.

[36]  Ting Liu,et al.  Nanomicelle formulation for topical delivery of cyclosporine A into the cornea: in vitro mechanism and in vivo permeation evaluation , 2015, Scientific Reports.

[37]  Özgen Özer,et al.  Novel nanostructured lipid carrier-based inserts for controlled ocular drug delivery: evaluation of corneal bioavailability and treatment efficacy in bacterial keratitis , 2015, Expert opinion on drug delivery.

[38]  A. Mitra,et al.  Topical, Aqueous, Clear Cyclosporine Formulation Design for Anterior and Posterior Ocular Delivery. , 2015, Translational vision science & technology.

[39]  D. Jo,et al.  OPHTHALMIC IN-SITU GEL: AN OVERVIEW , 2015 .

[40]  A. Mitra,et al.  Nanomicellar Topical Aqueous Drop Formulation of Rapamycin for Back-of-the-Eye Delivery , 2014, AAPS PharmSciTech.

[41]  S. Eğrilmez,et al.  Preparation and in vitro-in vivo evaluation of ofloxacin loaded ophthalmic nano structured lipid carriers modified with chitosan oligosaccharide lactate for the treatment of bacterial keratitis. , 2014, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[42]  Dinesh M Pardhi,et al.  Formulation and evaluation of in situ ophthalmic gel of moxifloxacin hydrochloride , 2014 .

[43]  I. Singh,et al.  Design and Evaluation of Voriconazole Eye Drops for the Treatment of Fungal Keratitis , 2014, Journal of pharmaceutics.

[44]  J. Pluta,et al.  Ophthalmic Drug Dosage Forms: Characterisation and Research Methods , 2014, TheScientificWorldJournal.

[45]  R. Patil IN SITU GELLING SYSTEM: NOVEL APPROACH FOR OPHTHALMIC DRUG DELIVERY , 2014 .

[46]  Asgar Ali,et al.  Nanoparticles laden in situ gel of levofloxacin for enhanced ocular retention , 2013, Drug delivery.

[47]  S. Honary,et al.  Effect of Zeta Potential on the Properties of Nano-Drug Delivery Systems - A Review (Part 2) , 2013 .

[48]  B. Malaekeh-Nikouei,et al.  Controlled release of prednisolone acetate from molecularly imprinted hydrogel contact lenses , 2012 .

[49]  Thorsteinn Loftsson,et al.  Cyclodextrins as functional excipients: methods to enhance complexation efficiency. , 2012, Journal of pharmaceutical sciences.

[50]  S. Arora,et al.  Ocular drug delivery system: a reference to natural polymers , 2012, Expert opinion on drug delivery.

[51]  Hiba M. Salmo,et al.  Development and Clinical Evaluation of Clotrimazole–β-Cyclodextrin Eyedrops for the Treatment of Fungal Keratitis , 2012, AAPS PharmSciTech.

[52]  N. Shafiq,et al.  Optimization, in vitro-in vivo evaluation, and short-term tolerability of novel levofloxacin-loaded PLGA nanoparticle formulation. , 2012, Journal of pharmaceutical sciences.

[53]  M. Geetha,et al.  Formulation and evaluation of an in situ gel-forming ophthalmic formulation of moxifloxacin hydrochloride , 2012, International journal of pharmaceutical investigation.

[54]  Manisha Pandey,et al.  Formulation and characterization of a novel pH-triggered in-situ gelling ocular system containing Gatifloxacin , 2012 .

[55]  A. Nokhodchi,et al.  Physicochemical and anti-bacterial performance characterization of clarithromycin nanoparticles as colloidal drug delivery system. , 2011, Colloids and surfaces. B, Biointerfaces.

[56]  G. Fink,et al.  A prototype antifungal contact lens. , 2011, Investigative ophthalmology & visual science.

[57]  Asgar Ali,et al.  Biodegradable levofloxacin nanoparticles for sustained ocular drug delivery , 2011, Journal of drug targeting.

[58]  S. MacNeil,et al.  Hyperbranched poly(NIPAM) polymers modified with antibiotics for the reduction of bacterial burden in infected human tissue engineered skin. , 2011, Biomaterials.

[59]  J. Lovrić,et al.  A nonionic surfactant/chitosan micelle system in an innovative eye drop formulation. , 2010, Journal of pharmaceutical sciences.

[60]  R. He,et al.  Treatment of experimental autoimmune uveoretinitis with intravitreal injection of tacrolimus (FK506) encapsulated in liposomes. , 2010, Investigative ophthalmology & visual science.

[61]  Uday B Kompella,et al.  Nanomicellar formulations for sustained drug delivery: strategies and underlying principles. , 2010, Nanomedicine.

[62]  Asgar Ali,et al.  Sparfloxacin-loaded PLGA nanoparticles for sustained ocular drug delivery. , 2010, Nanomedicine : nanotechnology, biology, and medicine.

[63]  R. Tiwari,et al.  Cyclodextrins in delivery systems: Applications , 2010, Journal of pharmacy & bioallied sciences.

[64]  G. Cavallaro,et al.  Polyhydroxyethylaspartamide-based micelles for ocular drug delivery. , 2009, International journal of pharmaceutics.

[65]  E. Frohman,et al.  PEG Minocycline-Liposomes Ameliorate CNS Autoimmune Disease , 2009, PloS one.

[66]  Huiyun Xia,et al.  Ocular pharmacokinetics of topically-applied ketoconazole solution containing hydroxypropyl beta-cyclodextrin to rabbits. , 2008, Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics.

[67]  Yoshihiro Saito,et al.  Emulsion preparation using beta-cyclodextrin and its derivatives acting as an emulsifier. , 2008, Chemical & pharmaceutical bulletin.

[68]  R. Banerjee,et al.  Comparison of ciprofloxacin hydrochloride-loaded protein, lipid, and chitosan nanoparticles for drug delivery. , 2008, Journal of biomedical materials research. Part B, Applied biomaterials.

[69]  D. Mishra,et al.  DESIGN AND CHARACTERIZATION OF BIOADHESIVE IN-SITU GELLING OCULAR INSERTS OF GATIFLOXACIN SESQUIHYDRATE , 2008 .

[70]  D. Golan,et al.  Disruption of CFTR-dependent lipid rafts reduces bacterial levels and corneal disease in a murine model of Pseudomonas aeruginosa keratitis. , 2008, Investigative ophthalmology & visual science.

[71]  M. Prausnitz,et al.  Coated microneedles for drug delivery to the eye. , 2007, Investigative ophthalmology & visual science.

[72]  T. Xu,et al.  Polyamidoamine (PAMAM) dendrimers as biocompatible carriers of quinolone antimicrobials: an in vitro study. , 2007, European journal of medicinal chemistry.

[73]  Dominique Duchêne,et al.  Cyclodextrins and their pharmaceutical applications. , 2007, International journal of pharmaceutics.

[74]  A. Ludwig,et al.  Evaluation of ciprofloxacin-loaded Eudragit RS100 or RL100/PLGA nanoparticles. , 2006, International journal of pharmaceutics.

[75]  M. Gremião,et al.  Colloidal carriers for ophthalmic drug delivery. , 2005, Current drug targets.

[76]  S Tommasini,et al.  Combined effect of pH and polysorbates with cyclodextrins on solubilization of naringenin. , 2004, Journal of pharmaceutical and biomedical analysis.

[77]  J. Remon,et al.  Ocular bioerodible minitablets as strategy for the management of microbial keratitis. , 2004, Investigative ophthalmology & visual science.

[78]  A. Ludwig,et al.  Factorial design, physicochemical characterisation and activity of ciprofloxacin-PLGA nanoparticles. , 2004, International journal of pharmaceutics.

[79]  S. Rossi,et al.  Carrageenan-gelatin mucoadhesive systems for ion-exchange based ophthalmic delivery: in vitro and preliminary in vivo studies. , 2004, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[80]  D. Aggarwal,et al.  Vesicular systems in ocular drug delivery: an overview. , 2004, International journal of pharmaceutics.

[81]  M. Másson,et al.  Preparation of solid drug/cyclodextrin complexes of acidic and basic drugs. , 2004, Die Pharmazie.

[82]  E. Stefánsson,et al.  Cyclodextrins in eye drop formulations: enhanced topical delivery of corticosteroids to the eye. , 2002, Acta ophthalmologica Scandinavica.

[83]  Jeong-Sook Park,et al.  rhEGF/HP-β-CD complex in poloxamer gel for ophthalmic delivery , 2002 .

[84]  E. Y. Kim,et al.  rhEGF/HP-beta-CD complex in poloxamer gel for ophthalmic delivery. , 2002, International journal of pharmaceutics.

[85]  M. Lawrence,et al.  Microemulsion-based media as novel drug delivery systems , 2000 .

[86]  Loftssona,et al.  Cyclodextrins in ophthalmic drug delivery. , 1999, Advanced drug delivery reviews.

[87]  P. Garg,et al.  Corneal ulcer: diagnosis and management. , 1999, Community eye health.

[88]  M. Srinivasan,et al.  Corneal ulceration in the developing world—a silent epidemic , 1997, The British journal of ophthalmology.

[89]  M. Brewster,et al.  Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. , 1996, Journal of pharmaceutical sciences.

[90]  K. A. Connors,et al.  Aqueous solubility behavior of three cyclodextrins , 1985 .