Kinetics of reciprocating drug delivery to the inner ear.

Reciprocating drug delivery is a means of delivering soluble drugs directly to closed fluid spaces in the body via a single cannula without an accompanying fluid volume change. It is ideally suited for drug delivery into small, sensitive and unique fluid spaces such as the cochlea. We characterized the pharmacokinetics of reciprocating drug delivery to the scala tympani within the cochlea by measuring the effects of changes in flow parameters on the distribution of drug throughout the length of the cochlea. Distribution was assessed by monitoring the effects of DNQX, a reversible glutamate receptor blocker, delivered directly to the inner ear of guinea pigs using reciprocating flow profiles. We then modeled the effects of those parameters on distribution using both an iterative curve-fitting approach and a computational fluid dynamic model. Our findings are consistent with the hypothesis that reciprocating delivery distributes the drug into a volume in the base of the cochlea, and suggest that the primary determinant of distribution throughout more distal regions of the cochlea is diffusion. Increases in flow rate distributed the drug into a larger volume that extended more apically. Over short time courses (less than 2h), the apical extension, though small, significantly enhanced apically directed delivery of drug. Over longer time courses (>5h) or greater distances (>3mm), maintenance of drug concentration in the basal scala tympani may prove more advantageous for extending apical delivery than increases in flow rate. These observations demonstrate that this reciprocating technology is capable of providing controlled delivery kinetics to the closed fluid space in the cochlea, and may be suitable for other applications such as localized brain and retinal delivery.

[1]  O W Henson,et al.  Cochlear Fluid Space Dimensions for Six Species Derived From Reconstructions of Three‐Dimensional Magnetic Resonance Images , 1999, The Laryngoscope.

[2]  Juichi Ito,et al.  Novel Strategy for Treatment of Inner Ears using a Biodegradable Gel , 2005, The Laryngoscope.

[3]  M. Hoffer,et al.  Distribution of PLGA nanoparticles in chinchilla cochleae , 2007, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[4]  A. Salt,et al.  Drug delivery to the cochlea after implantation: consideration of the risk factors. , 2005 .

[5]  Gordon G Wallace,et al.  Polypyrrole-coated electrodes for the delivery of charge and neurotrophins to cochlear neurons. , 2009, Biomaterials.

[6]  W. Arnold,et al.  Novel Slow- and Fast-Type Drug Release Round-Window Microimplants for Local Drug Application to the Cochlea: An Experimental Study in Guinea Pigs , 2004, Audiology and Neurotology.

[7]  M. McKenna,et al.  A method for intracochlear drug delivery in the mouse , 2006, Journal of Neuroscience Methods.

[8]  C. Klingmann,et al.  Transsynaptic delivery of nanoparticles to the central auditory nervous system , 2007, Acta oto-laryngologica.

[9]  Brian P. Grady,et al.  Magnetic Assisted Transport of PLGA Nanoparticles Through a Human Round Window Membrane Model , 2010 .

[10]  Y. Raphael,et al.  Cochlear gene transfer: round window versus cochleostomy inoculation , 1999, Hearing Research.

[11]  M. Berggren,et al.  Organic electronics for precise delivery of neurotransmitters to modulate mammalian sensory function. , 2009, Nature materials.

[12]  Josef M. Miller,et al.  Technical report: chronic and acute intracochlear infusion in rodents , 2000, Hearing Research.

[13]  Michael J Banker,et al.  Development and validation of a 96-well equilibrium dialysis apparatus for measuring plasma protein binding. , 2003, Journal of pharmaceutical sciences.

[14]  Earl E. Bakken,et al.  Temporal Control of Drugs , 1991 .

[15]  H. Silverstein,et al.  Use of a New Device, the MicroWick™, to Deliver Medication to the Inner Ear , 1999, Ear, nose, & throat journal.

[16]  J. Ito,et al.  Drug Delivery to the Cochlea Using PLGA Nanoparticles , 2005, The Laryngoscope.

[17]  K. Ehrenberger,et al.  New approaches for inner ear therapy with glutamate antagonists. , 1999, Acta oto-laryngologica.

[18]  J. Fiering,et al.  Local drug delivery with a self-contained, programmable, microfluidic system , 2009, Biomedical microdevices.

[19]  Jeffrey T Borenstein,et al.  Inner ear drug delivery via a reciprocating perfusion system in the guinea pig. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[20]  James E. Evans,et al.  Proteomics analysis of perilymph and cerebrospinal fluid in mouse , 2009, The Laryngoscope.

[21]  Bruce C. Wheeler.  The Tradition Continues to Improve , 2007 .

[22]  Andrew K. Wise,et al.  Neurotrophic Factors and Neural Prostheses: Potential Clinical Applications Based Upon Findings in the Auditory System , 2007, IEEE Transactions on Biomedical Engineering.

[23]  M. Liberman,et al.  Intracellular labeling of auditory nerve fibers in guinea pig: central and peripheral projections , 1997 .

[24]  J. Puel,et al.  The quinoxalinediones DNQX, CNQX and two related congeners suppress hair cell-to-auditory nerve transmission , 1989, Hearing Research.

[25]  D. D. Greenwood.  Comparing octaves, frequency ranges, and cochlear-map curvature across species , 1996, Hearing Research.

[26]  D. Borkholder.  State-of-the-art mechanisms of intracochlear drug delivery , 2008, Current opinion in otolaryngology & head and neck surgery.

[27]  C. Jolly,et al.  Cochlear implantation: an opportunity for drug development. , 2010, Drug discovery today.

[28]  Jeffrey T Borenstein,et al.  Inner ear drug delivery for auditory applications. , 2008, Advanced drug delivery reviews.

[29]  Sharon G. Kujawa,et al.  Development of a Microfluidics-Based Intracochlear Drug Delivery Device , 2009, Audiology and Neurotology.