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The kinetics of in vitro drug release from nanoparticulate systems is extensive, though uncritically, being studied by dialysis. Evaluating the actual relevance of dialysis data to drug release was the purpose of this study. Diclofenac- or ofloxacin-loaded chitosan nanoparticles crosslinked with tripolyphosphate were prepared and characterized. With each drug, dynamic dialysis was applied to nanoparticle dispersion, solution containing dissolved chitosan·HCl, and solution of plain drug. Drug kinetics in receiving phase (KRP), nanoparticle matrix (KNM) and nanoparticle dispersion medium (KDM) were determined. Release of each drug from nanoparticles was also assessed by ultracentrifugation. Although KRP data may be interpreted in terms of sustained release from nanoparticles, KNM and KDM data show that, with both drugs, the process was in fact controlled by permeation across dialysis membrane. Analysis of KRP data reveals a reversible interaction of diclofenac with dispersed nanoparticle surface, similar to the interaction of this drug with dissolved chitosan·HCl. No such interactions are noticed with ofloxacin. The results from the ultracentrifugation method agree with the above interpretation of dialysis data. This case study shows that dialysis data from a nanoparticle dispersion is not necessarily descriptive of sustained-release from nanoparticles, hence, if interpreted uncritically, it may be misleading., (Copyright © 2012 Elsevier B.V. All rights reserved.)

N-trimethyl chitosan (TMC) polymers differing in quaternization degree (QD) and molecular weight (MW) were prepared from two chitosans 90% deacetylated, one of higher MW (1460 kDa) (TMCH), the other of lower MW (580 kDa) (TMCL), by one (TMCH1, QD = 4%; TMCL1, QD = 3%), two (TMCH2, QD = 35%; TMCL2, QD = 46%), or three (TMCH3, QD = 90%; TMCL3, QD = 78%) reductive methylation steps. The derivatives were tested and compared for their ability to enhance the permeability of ofloxacin across rabbit corneal epithelium, reconstituted in vitro. TMC polymers of intermediate QD (TMCH2 and TMCL2), at the concentration of 0.001% w/v, produced significant permeability enhancements, independent of polymer MW. The enhancing effect did not increase when QD was increased (TMCH3 and TMCL3), while it was not significant with low QD values (TMCH1 and TMCL1). Such an effect was specific of chitosan derivatives, because fully quaternized DEAE-dextran (MeDD) was ineffective. The transcorneal permeability-enhancing property of TMCH2 and TMCL2, and the inefficacy of MeDD were confirmed by in vivo tests on rabbit eyes. However, unlike the in vitro experiments, the in vivo ones showed a stronger effect of the TMC having higher MW. TMCH2 produced antibiotic levels in the aqueous humor higher than the MIC(90%) for the more resistant ocular pathogens. These results point to this derivative as a potential ofloxacin absorption enhancer for the topical treatment of endophthalmitis.

The effects of chitosan hydrochloride (Ch-HCl) and of N-carboxymethylchitosan (CMCh), formulated in ophthalmic solutions, on the ocular pharmacokinetics of ofloxacin were studied in rabbits. The carboxymethylation of a chitosan of high molecular mass (1460 kDa) and deacetylation degree (89.9%) introduced 0.84 N-carboxymethyl groups per repeating unit. Aqueous solutions containing 1% (w/v) of either polymer showed a pseudoplastic rheologic behaviour, and, when instilled in rabbit eyes, produced no irritation. The kinetics of drug disappearance from tear fluid and the profiles of drug concentration in the aqueous humour versus time were determined and interpreted in the light of a pharmacokinetic model and of drug-polymer binding. Ch-HCl significantly enhanced intraocular drug penetration with respect to an isoviscous drug solution containing poly(vinyl alcohol) and to commercial ofloxacin eyedrops. This effect, which resulted in about 190% increase of the peak concentration in the aqueous, was ascribed to an increased corneal permeability. The polyanionic CMCh failed to enhance intraocular drug penetration. It nevertheless increased precorneal drug retention in virtue of its viscosity and of ofloxacin binding. Consequently, the residence time at concentrations higher than the MIC90 and the bioavailability of the antibiotic in the aqueous were increased by about 150 and 240%, respectively, with respect to the reference vehicle.

The effects of chitosan hydrochloride (CH-HCl) on in vitro release of ofloxacin (OFX) from mucoadhesive erodible ocular inserts and on the relevant ocular pharmacokinetics have been studied both to contribute evidence of the ability of CH-HCl to enhance transcorneal penetration of drugs and to increase the therapeutic efficacy of topically applied OFX. Circular inserts of 6 mm in diameter, 0.8-0.9 mm in thickness and 20 mg in weight, medicated with 0.3 mg drug, were prepared by powder compression. The addition of 10, 20 or 30% medicated CH-HCl microparticles, obtained by spray-drying, to formulations based on poly(ethylene oxide) of MW 900 kDa (PEO 900) or 2000 kDa (PEO 2000) produced changes in the insert microstructure which accelerated both insert erosion and OFX release from inserts. The effect was stronger with higher CH-HCl fractions. Of the CH-HCl-containing formulations based on either PEO 900 or PEO 2000, PEO 900-CH-HCl (9:1 w/w) was more suitable for a prolonged OFX release. Following insertion in the lower conjunctival sac of the rabbit's eye, such an insert produced no substantial increase of AUC(eff) (AUC in the aqueous humour for concentrations >MIC(90%)) with respect to inserts based on plain PEO; however, it produced a concentration peak in the aqueous significantly higher than that produced by any of the CH-HCl-free PEO inserts, and well higher than the MIC(90%) for the more resistant ocular pathogens (7 microg/ml vs. 4 microg/ml). It has been argued that the increase was due to the ability of CH-HCl to enhance the transcorneal permeability of the drug.

A previous study of the present authors on gel-forming erodible inserts, based on high molecular weight (MW, 400 kDa) poly(ethylene oxide) (PEO), for ocular controlled delivery of ofloxacin (OFX) has been extended to investigate the effects of PEO MW, in the 200-2000 kDa range, on insert properties relevant to therapeutic efficacy. Mucoadhesion has shown a dependence on MW, with a maximum for PEO 400. The in vitro drug release from inserts based on PEO 200, PEO 400 and PEO 900 was mainly controlled by insert erosion, whereas with PEO 2000 it was mainly diffusion-controlled in a first phase, followed by an erosion-controlled phase. The erosion time scale depended directly on MW. Immediately after application in the lower conjunctival sac of the rabbit eye, the inserts based on PEO of whichever MW formed mucoadhesive gels, well tolerated by the animals; then the gels spread over the corneal surface and eroded. PEO 2000 was unsuitable as an insert material, since the resulting gel spilled from the eye, due to excessive swelling. The gel residence time in the precorneal area, the drug permanence time in the aqueous humor at concentrations > MIC and the time to reach the maximal drug concentration in the aqueous humor (C(max)) depended directly on MW, indicating that transcorneal absorption was governed by gel erosion. All inserts increased Cmax and AUCeff (AUC for concentrations > MIC) with respect to the commercial eyedrops. The increases caused by PEO 400 and PEO 900 were similar (3.78- and 3.16-fold, respectively, for Cmax; 11.06- and 12.37-fold, respectively, for AUCeff), whereas smaller increases were produced by PEO 200. The PEO 400 and PEO 900 inserts have shown a potential for a topical treatment of endophthalmitis.

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.

When topical controlled delivery of ophthalmic drugs is realised via erodible inserts, drug bioavailability is maximised, if release is controlled exclusively by insert erosion, since parallel mechanisms which increase the release rate, also increases the dose fraction cleared from the precorneal area by tear fluid draining. The respective contributions of diffusion and erosion to the release mechanism of different drugs, namely, prednisolone (PDS), oxytetracycline hydrochloride (OTH) and gentamicin sulfate (GTS), from erodible ocular inserts based on poly(ethylene oxide) (PEO) of molecular weight 400 or 900 kDa was determined by an in vitro technique adequate to predict the release mechanism in vivo. PDS and OTH were released with erosion-controlled kinetics. With therapeutic doses of these drugs in the inserts (0.3 mg, 1.5%), the possibility of a purely erosive mechanism was shown to rely upon drug–PEO molecular interactions, which limit drug diffusion in the swollen matrix. This was the case with OTH, for which strong interactions with PEO were measured, whereas some contribution from the parallel diffusive mechanism was evidenced for PDS, which showed weaker interactions with polymer. Such a contribution disappeared when the PDS concentration in the insert was increased to 6%, which suggested that the erosive mechanism is favoured by a drug concentration in the hydrated insert substantially higher than solubility. On the other hand, the release of about 50% GTS dose was controlled by diffusion, due to the high water solubility of this drug, accompanied by weak drug–PEO interactions. In this case the residence time of drug in the precorneal area is expected to be significantly shorter than that of the PEO carrier. [Copyright &y& Elsevier]