title: Zero-order therapeutic release from imprinted hydrogel contact lenses within in vitro physiological ocular tear flow.
abstract: Zero-order or concentration independent release kinetics are highly desirable from drug delivery devices. In this paper we demonstrate experimentally, for the first time, zero-order release of a small molecular weight therapeutic, ketotifen fumarate (MW=425), from molecularly imprinted hydrogels used as therapeutic contact lenses. We performed dynamic, in vitro drug release studies from imprinted hydrogel contact lenses within a novel microfluidic device that simulates the volumetric flow rates, tear volume and tear composition of the eye. Imprinted gels with multiple functional monomers and complexation points to the drug demonstrated a significantly delayed release of drug compared to less functionalized systems. There were no statistical differences in experimentally determined equilibrium swollen polymer volume fractions, which correlate with molecular weight between crosslinks and mesh size of the gel. Under infinite sink conditions, imprinted contact lenses demonstrated Fickian (concentration dependent) release kinetics with diffusion coefficients ranging from 4.04 x 10(-9) to 5.57 x 10(-10) cm(2)/s. The highest functionalized gel exhibited a diffusion coefficient averaging ten times smaller than less functionalized gels and released drug for over 5 days with 3 distinct rates of release. Under physiological volumetric flow rates, the release rate was constant for a duration of 3.5 days delivering a therapeutically relevant dosage and was fit to a power law model indicating zero-order release characteristics with n=0.981+/-0.006 (r(2)=0.997). This work demonstrates the potential of micro/nanofluidic devices to determine physiological release rates and stresses the importance of matching local conditions to adequately characterize drug delivery devices. It also demonstrates the enormous potential for molecular imprinting to further tailor therapeutic release kinetics via the imprinting process.
authors.affiliation: Biomimetic & Biohybrid Materials, Biomedical Devices, and Drug Delivery Laboratories, Department of Chemical Engineering, Auburn University, Auburn, AL 36849, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Ali
authors.forename: Shin
authors.initials: S
authors.lastname: Horikawa
authors.forename: Siddarth
authors.initials: S
authors.lastname: Venkatesh
authors.forename: Jishnu
authors.initials: J
authors.lastname: Saha
authors.forename: Jong Wook
authors.initials: JW
authors.lastname: Hong
authors.forename: Mark E
authors.initials: ME
authors.lastname: Byrne
mesh_terms: D020106:Acrylamide / Q000737:chemistry; D000179:Acrylates / Q000737:chemistry; D001672:Biocompatible Materials / Q000737:chemistry; D032701:Biomimetics; D003261:Contact Lenses; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D004058:Diffusion; D006634:Histamine H1 Antagonists / Q000737:chemistry / Q000627:therapeutic use; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000138:chemical synthesis / Q000737:chemistry*; D066298:In Vitro Techniques; D007665:Ketotifen / Q000737:chemistry / Q000627:therapeutic use; D007700:Kinetics; D008689:Methacrylates / Q000737:chemistry; D044085:Microfluidics / Q000295:instrumentation / Q000379:methods; D008970:Molecular Weight; D009570:Nitriles / Q000737:chemistry; D000442:Octanols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011760:Pyrrolidinones / Q000737:chemistry; D012995:Solubility; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D013666:Tears / Q000378:metabolism*; D014867:Water / Q000737:chemistry
chemical_list: D000179:Acrylates; D001672:Biocompatible Materials; D003692:Delayed-Action Preparations; D006634:Histamine H1 Antagonists; D008689:Methacrylates; D009570:Nitriles; D000442:Octanols; D011108:Polymers; D011760:Pyrrolidinones; D014867:Water; D020106:Acrylamide; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; C005044:hydroxyethyl methacrylate; C036658:acrylic acid; D007665:Ketotifen