PEGylated PLGA nanospheres optimized by design of experiments for ocular administration of dexibuprofen—in vitro, ex vivo and in vivo characterization

Abstract

Dexibuprofen-loaded PEGylated PLGA nanospheres have been developed to improve the biopharmaceutical profile of the anti-inflammatory drug for ocular administration. Dexibuprofen is the active enantiomer of ibuprofen and therefore lower doses may be applied to achieve the same therapeutic level. According to this, two batches of nanospheres of different drug concentrations, 0.5 and 1.0mg/ml respectively, have been developed (the latter corresponding to the therapeutic ibuprofen concentration for inflammatory eye diseases). Both batches were composed of negatively charged nanospheres (--14.1 and --15.9mV), with a mean particle size below 200nm, and a high encapsulation efficiency (99%). X-ray, FTIR, and DSC analyses confirmed that the drug was dispersed inside the matrix of the nanospheres. While the in vitro release profile was sustained up to 12h, the ex vivo corneal and scleral permeation profile demonstrated higher drug retention and permeation in the corneal tissue rather than in the sclera. These results were also confirmed by the quantification of dexibuprofen in ocular tissues after the in vivo administration of drug-loaded nanospheres. Cell viability studies confirmed that PEGylated-PLGA nanospheres were less cytotoxic than free dexibuprofen in the majority of the tested concentrations. Ocular in vitro (HET-CAM test) and in vivo (Draize test) tolerance assays demonstrated the non-irritant character of both nanosphere batches. In vivo anti-inflammatory effects were evaluated in albino rabbits before and after inflammation induction. Both batches confirmed to be effective to treat and prevent ocular inflammation.

Memantine‐Loaded PEGylated Biodegradable Nanoparticles for the Treatment of Glaucoma

“…On both cases, the parameter was highly influenced by P 2 ( K p = P 1 · P 2 ). P 2 corresponds to the partition coefficient inside both tissues although, as demonstrated in previous publications, PLGA‐PEG NP show significant corneal tropism, with a suggestion that memantine could be released slowly from within the cornea . In addition, free drug retention in corneal tissue was 0.01 µg mg −1 whereas in sclera it was tenfold higher (0.11 µg mg −1 ).…”

“…The light source, pulsed near infrared light‐emitting diode LED (λ = 880 nm), was received by a backscattering detector at an angle of 45° from the incident beam. Readings were carried out every hour for 24 h …”

“…Ocular Tolerance Test—HET‐CAM and Draize Irritation Test : In order to evaluate the risk of ocular irritation caused by free memantine and MEM‐NP administered as eye drops, ocular tolerance tests in vivo and in vitro were conducted. Ocular tolerance was assessed in vitro using the HETCAM test (Figure S4, Supporting Information) . Scores of irritation potential were grouped into four categories .…”

“…Ocular tolerance was assessed in vitro using the HETCAM test (Figure S4, Supporting Information) . Scores of irritation potential were grouped into four categories . Subsequent in vivo ocular tolerance assays were performed using primary eye irritation test of Draize et.…”

Functional intercalated nanocomposites with chitosan-glutathione-glycylsarcosine and layered double hydroxides for topical ocular drug delivery

“…Ocular irritation index (OII) was evaluated according to the observed injuries (Table S2). [32][33][34] Following completion of in vivo ocular tolerance assays, all the rabbits were euthanized by air embolism. Then cornea, conjunctiva and iris of the ocular tissues were fixed with 10% formaldehyde.…”