Gel-forming erodible inserts for ocular controlled delivery of ofloxacin.
A new application of high molecular weight (400 kDa) linear poly(ethylene oxide) (PEO) in gel-forming erodible inserts for ocular controlled delivery of ofloxacin (OFX) has been tested in vitro and in vivo. Inserts of 6 mm diameter, 20 mg weight, medicated with 0.3 mg OFX, were prepared by powder compression. The in vitro drug release from inserts was mainly controlled by insert erosion. The erosion time scale was varied by compounding PEO with Eudragit L100 (EUD) 17% neutralized (EUDNa17) or 71% neutralized (EUDNa71). The insert erosion rate depended on the strength of interpolymer interactions in the compounds, and on the hydrophilic-hydrophobic balance of compounds. Immediately after application in the lower conjunctival sac of the rabbit eyes, the inserts based on plain PEO, PEO-EUDNa17 or PEO-EUDNa71 formed mucoadhesive gels, well tolerated by the animals; then the gels spread over the corneal surface and eroded. The gel residence time in the precorneal area was in the order PEO-EUDNa71 < PEO < PEO-EUDNa17. Compared to commercial OFX eyedrops, drug absorption into the aqueous humor was retarded by the PEO-EUDNa71 inserts, and both retarded and prolonged by the PEO-EUDNa17 inserts, while C(max) (maximal concentration in the aqueous) and AUC(eff) (AUC in the aqueous for concentrations > MIC) were barely altered by either insert type. On the other hand, C(max), AUC(eff) and t(eff) (permanence time in the aqueous at concentrations > MIC) were strikingly increased by plain PEO inserts with respect to commercial eyedrops (5.25 +/- 0.56 vs. 1.39 +/- 0.05 microg ml(-1); 693.6 vs. 62.7 microg ml(-1) min; and 290 vs. 148 min, respectively). Bioavailability increase has been ascribed to PEO mucoadhesion and/or increased tear fluid viscosity.
Di Colo
G
G
Department of Bio-organic Chemistry and Biopharmaceutics, University of Pisa, Via Bonanno 33, 56126, Pisa, Italy. giadic@farm.unipi.it
Burgalassi
S
S
Chetoni
P
P
Fiaschi
M P
MP
Zambito
Y
Y
Saettone
M F
MF
D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D001082:Aqueous Humor / Q000378:metabolism; D001682:Biological Availability; D003692:Delayed-Action Preparations; D005079:Excipients; D005123:Eye / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008422:Materials Testing; D015242:Ofloxacin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011092:Polyethylene Glycols; D011817:Rabbits; D012995:Solubility
D000890:Anti-Infective Agents; D003692:Delayed-Action Preparations; D005079:Excipients; D011092:Polyethylene Glycols; D015242:Ofloxacin