title: Principles of inner ear sustained release following intratympanic administration.
abstract: OBJECTIVE
  Previous studies revealed that intratympanic administration of the steroid dexamethasone in poloxamer 407 hydrogel, a class of thermoreversible polymers, resulted in significant and durable exposure in the inner ear. Interestingly, varying the concentrations of the poloxamer vehicle and of the steroid impacted the pharmacokinetic profile of dexamethasone in the perilymphatic compartment. Here, the respective contributions of different vehicles (aqueous solution, poloxamer hydrogel) and steroid drugs (dexamethasone, methylprednisolone) were investigated. In particular, various forms of the steroids, discriminated by their aqueous solubility, were compared.
  
  
  METHODS
  In vitro studies characterized the gelation profile and drug release kinetics of the various formulations. The inner ear pharmacokinetic profile of the different formulations was investigated in guinea pigs.
  
  
  RESULTS
  Drugs formulated in poloxamer 407 shared significantly more prolonged exposure than those formulated in aqueous solutions both in vitro and in vivo in the inner ear. Furthermore, drugs with low aqueous solubility yielded increased degree and duration of exposure in the inner ear relative to water-soluble drugs.
  
  
  CONCLUSIONS
  The inner ear pharmacokinetic profile of drugs administered intratympanically is not only highly dependent upon the nature of the vehicle but also upon the physicochemical properties of the drug delivered.
authors.affiliation: Otonomy Inc., San Diego, California 92121, USA.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Wang
authors.forename: Luis
authors.initials: L
authors.lastname: Dellamary
authors.forename: Rayne
authors.initials: R
authors.lastname: Fernandez
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ye
authors.forename: Carl
authors.initials: C
authors.lastname: LeBel
authors.forename: Fabrice
authors.initials: F
authors.lastname: Piu
mesh_terms: D000818:Animals; D003692:Delayed-Action Preparations / Q000008:administration & dosage*; D003907:Dexamethasone / Q000008:administration & dosage / Q000493:pharmacokinetics; D007758:Ear, Inner / Q000187:drug effects*; D006168:Guinea Pigs; D008775:Methylprednisolone / Q000008:administration & dosage / Q000493:pharmacokinetics; D020442:Poloxamer / Q000008:administration & dosage; D013256:Steroids / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014432:Tympanic Membrane
chemical_list: D003692:Delayed-Action Preparations; D013256:Steroids; D020442:Poloxamer; D003907:Dexamethasone; D008775:Methylprednisolone