title: In-vitro and in-vivo evaluation of carrageenan/methylcellulose polymeric systems for transscleral delivery of macromolecules.
abstract: In this study, polymeric dispersions composed of methylcellulose (MC) and either kappa carrageenan (KC) or iota carrageenan (IC) were proposed as a platform for transscleral delivery of macromolecules. The additive effects of the two polymers were investigated using oscillatory rheometer and FT-IR spectroscopy. Mechanical spectra demonstrated a conformation dependent association of the two polymers at 37 °C in the presence of selected counter ions. The polymer association was also confirmed by the shifts in MC peaks at 1049.5, 1114 and 1132.9 cm(-1) in the presence of carrageenans, which corresponds to the stretching vibrations of C-O-C bonds of the polysaccharides. The MC-IC polymeric system displayed the highest bio-adhesion, owing to the relatively high negative charge. However, the MC-IC system did not affect the in-vitro scleral permeability of sodium fluorescein and 10 kDa FITC-dextran. Nonetheless, the formulation properties had a substantial impact on the results of the in-vivo studies. The efficacy of transscleral drug delivery was determined using rats with altered connexin 43 (Cx43) levels, a gap junction protein, in the choroid. Periocular injection of Cx43 antisense oligonucleotides (AsODN) incorporated in the MC-IC system lead to a significant reduction in the Cx43 levels in the choroid of rats at 24 h of treatment. AsODN incorporated in phosphate buffered saline (PBS) also demonstrated a trend towards reduced Cx43 levels; however this was not statistically significant owing to great variability between treated animals. Consequently the in-vivo data suggests the transscleral route to be of value in delivering therapeutics to the choroid. Moreover this study identified a new polymeric system based on MC and IC which provides aqueous loading of therapeutics and prolonged retention at the site of administration.
authors: School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. thilinit@gmail.com
authors: T R
authors: TR
authors: Thrimawithana
authors: S A
authors: SA
authors: Young
authors: C R
authors: CR
authors: Bunt
authors: C R
authors: CR
authors: Green
authors: R G
authors: RG
authors: Alany
mesh_terms: D000268:Adhesiveness; D000818:Animals; D002351:Carrageenan / Q000737:chemistry* / Q000493:pharmacokinetics; D002417:Cattle; D002829:Choroid / Q000187:drug effects / Q000378:metabolism; D018031:Connexin 43 / Q000096:biosynthesis; D015536:Down-Regulation; D004337:Drug Carriers / Q000737:chemistry* / Q000493:pharmacokinetics; D004339:Drug Compounding; D066298:In Vitro Techniques; D046911:Macromolecular Substances / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008747:Methylcellulose / Q000737:chemistry* / Q000493:pharmacokinetics; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D012590:Sclera / Q000187:drug effects / Q000378:metabolism*; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D018031:Connexin 43; D004337:Drug Carriers; D046911:Macromolecular Substances; D016376:Oligonucleotides, Antisense; D002351:Carrageenan; D008747:Methylcellulose