Lipid-polyethylene glycol based nano-ocular formulation of ketoconazole.
Ophthalmic mycoses including corneal keratitis or endophthalmitis affects 6-million persons/year and can cause blindness. Its management requires antifungals to penetrate the ocular tissue. Oral use of Ketoconazole (KTZ), the first broad-spectrum antifungal to be marketed, is now restricted to life-threatening infections due to severe adverse effects and drug-interactions. Local use of KTZ loaded nanocarrier system can address its toxicity, poor solubility, photodegradation, permeation and bioavailability issues. Solid lipid nanoparticles (SLNs) comprising Compritol(®) 888 ATO and PEG 600 matrix, were presently prepared using hot high-pressure homogenization. Employing extensive characterization: TEM, NMR, DSC, XRD and FTIR, it is proposed that SLNs comprise of a polyethylene glycol (PEG) core into which KTZ is dissolved. PEG endows the lipid matrix with amorphousness and imperfections; rigidity; and, stability to aggregation, on storage and autoclaving. PEG is a simple, cost-effective and safe polymer with superior solubilizing and surfactant-supporting properties. Without its inclusion KTZ could not be loaded into SLNs. It ensured high incorporation efficiency (70%) of KTZ; small size (126 nm); and, better permeation into the eye. Pharmacokinetic studies indicated 2.5 and 1.6 fold higher bioavailability (AUC) in aqueous and vitreous humor, respectively. Biocompatibility and in vitro (both in corneal and retinal cell lines) and in vivo (in rabbits) ocular safety is the other highlight of developed formulation.
University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Panjab University, Chandigarh 160014, India.
Shilpa
S
Kakkar
School of Life Sciences, SRTM University, Nanded, 431606 Maharashtra, India.
Sankunny Mohan
SM
Karuppayil
University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Panjab University, Chandigarh 160014, India.
Jayant S
JS
Raut
Department of Translational Medicine and Surgery, Eye Clinic, University of Florence, Viale Morgagni 85, 50134 Florence, Italy.
Fabrizio
F
Giansanti
Department of Experimental and Clinical Biomedical Sciences, Section of Experimental Pathology and Oncology, University of Florence, Viale Morgagni, 50, 50134 Florence, Italy.
Laura
L
Papucci
Department of Experimental and Clinical Biomedical Sciences, Section of Experimental Pathology and Oncology, University of Florence, Viale Morgagni, 50, 50134 Florence, Italy.
Nicola
N
Schiavone
University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Panjab University, Chandigarh 160014, India. Electronic address: indupalkaur@yahoo.com.
Indu Pal
IP
Kaur
D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D005123:Eye / Q000378:metabolism; D005227:Fatty Acids / Q000737:chemistry; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008055:Lipids; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D010713:Phosphatidylcholines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*; D011136:Polysorbates / Q000737:chemistry; D011817:Rabbits; D012995:Solubility
D000935:Antifungal Agents; D005227:Fatty Acids; D008055:Lipids; D010713:Phosphatidylcholines; D011136:Polysorbates; C585968:phospholipon 90G; C086409:glyceryl behenate; D011092:Polyethylene Glycols; D007654:Ketoconazole
Drug delivery; Fungal eye infection; Ocular safety; Permeation; Posterior eye; Solid lipid nanoparticles