Pierre Sado

Ophthalmic drug delivery systems—Recent advances

Eye-drops are the conventional dosage forms that account for 90% of currently accessible ophthalmic formulations. Despite the excellent acceptance by patients, one of the major problems encountered is rapid precorneal drug loss. To improve ocular drug bioavailability, there is a significant effort directed towards new drug delivery systems for ophthalmic administration. This chapter will focus on three representative areas of ophthalmic drug delivery systems: polymeric gels, colloidal systems, cyclodextrins and collagen shields. Hydrogels generally offer a moderate improvement of ocular drug bioavailability with the disadvantage of blurring of vision. In situ activated gel-forming systems are preferred as they can be delivered in drop form with sustained release properties. Colloidal systems including liposomes and nanoparticles have the convenience of a drop, which is able to maintain drug activity at its site of action and is suitable for poorly water-soluble drugs. Among the new therapeutic approaches in ophthalmology, cyclodextrins represent an alternative approach to increase the solubility of the drug in solution and to increase corneal permeability. Finally, collagen shields have been developed as a new continuous-delivery system for drugs that provide high and sustained levels of drugs to the cornea, despite a problem of tolerance. It seems that new tendency of research in ophthalmic drug delivery systems is directed towards a combination of several drug delivery technologies. There is a tendency to develop systems which not only prolong the contact time of the vehicle at the ocular surface, but which at the same time slow down the elimination of the drug. Combination of drug delivery systems could open a new directive for improving results and the therapeutic response of non-efficacious systems.

New Ophthalmic Drug Delivery Systems

AbstractOne of the ways to optimize ocular drug delivery is to prolonge precorneal drug residence time. This review focusses on recent findings on the formulation effects in ocular drug bioavailability, employing polymers for the preparation of hydrogels, bioadhesive dosage forms, in situ gelling systems and colloidal systems including liposomes and nanoparticles. The results observed suggested that mucoadhesion or bioadhesion played a role in the sustained action of drugs more significantly compared to non-mucoadhesive polymers. Encapsulation of drugs in liposomes and nanoparticles was correlated to an increase of the drug concentration in the ocular tissues. However, all the results described suggest that the physico-chemical properties of the encapsulated drug have a significant influence on the effect with the carrier. The results suggest also that the superficial charge, the binding type of the drug onto the nanoparticles and the nature of the polymer were the most important factors regarding the imp...

Effect of cyclosporine A formulations on bovine corneal absorption: ex-vivo study

The purpose of this study was to evaluate, in an ex-vivo study, the absorption of cyclosporine A on bovine cornea after 24 h contact with various drug delivery systems containing 1% cyclosporine A and in comparison with an olive oil formulation as the reference vehicle for cyclosporine A. The different formulations studied were poly(acrylic acid) polymeric gels in aqueous/non-aqueous solvents, polyisobutylcyanoacrylate nanocapsules, and a combination of both formulations. The histological effects of these formulation on corneal cells after 24 h of contact were also studied. The lowest absorption rate of cyclosporine A was found using olive oil with a percent absorption of 2.52 +/- 1.52% (259 +/- 171 micrograms/g cornea). The three formulations developed for this study, nanocapsules, poly(acrylic acid) polymeric gel and nanocapsules gel showed significantly better absorption of CsA than olive oil, with a mean percent absorption of 5.81 +/- 2.04% (621 +/- 218 micrograms/g cornea), 6.09 +/- 2.93% (651 +/- 313 micrograms cornea) and 7.92 +/- 2.55% (847 +/- 273 micrograms/g cornea) respectively. As we studied the penetration of cyclosporine A into the different layers of the cornea, we observed that for all formulations, CsA remained at the corneal surface and did not penetrate the whole cornea. The histological study showed that olive oil, nanocapsules and poly(acrylic acid) gel in aqueous/non-aqueous solvents show some modifications on the cornea, contrary to the nonocapsules gel which did not indicate any toxic effect. The nanocapsule gel, with the highest percent absorption along with its margin of safety on the cornea, seems to present a new promising drug delivery system for ocular administration.

Direct enantiomeric resolution of disopyramide and its metabolite using chiral high-performance liquid chromatography : Application to stereoselective metabolism and pharmacokinetics of racemic disopyramide in man

A method for the simultaneous determination of disopyramide and mono-N-desisopropyldisopyramide enantiomers extracted from human plasma and urine is presented. Separation and quantitation were carried out using two columns coupled in series, and UV detection at 254 nm. First, the racemates of the two compounds were separated using a reversed-phase column, and then the enantiomers were separated using a stereoselective column packed with human alpha 1-acid glycoprotein. The mobile phase was 8 mM phosphate buffer, pH 6.20-2-propanol (92:8, v/v). The coefficients of variation (%) for the plasma daily determination were 6.7% for R(-)- and S(+)-disopyramide at drug levels of 1.5 micrograms/ml, and 8.5% and 7.7% for R(-)- and S(+)-mono-N-desisopropyldisopyramide, respectively, at drug levels of 0.375 micrograms/ml. The method has allowed the study of stereoselective metabolism and pharmacokinetics of disopyramide after oral administration as a racemate.

Clinical pharmacokinetics of levorotatory and racemic disopyramide, at steady state, following oral administration in patients with ventricular arrhythmias

Electrophysiological effects, antiarrhythmic activity and kinetics of levorotatory disopyramide (R(–) DP) and racemic disopyramide (equimolar mixture of R(–) DP and S(+) DP) were compared in patients with ventricular arrhythmias. This double blind crossover randomized trial was achieved, at steady‐state, following oral administration of 200 mg three times a day. In comparison with baseline values, electrophysiological data indicated that R(–) DP and racemic DP prolonged, significantly and similarly, PR interval (+11.7% and +10%, respectively, P < .01), and QTc interval (+9.2% and +7%, respectively, P < .001), while QRS interval was not significantly affected. The antiarrhythmic activity, assessed by percent reduction in ventricular extrasystoles frequency, showed a similar efficiency of levorotatory and racemic DP: 80% and 74%, respectively (P = .24). Ventricular tachycardias disappeared with both treatments in the three patients concerned. During the racemic period, the mean total plasma clearance, expressed as CL/F, of S(+) DP (114.6 ml/min), was significantly lower than that of R(–) DP (157 ml/min), (P < .001). The mean total plasma clearance of R(–) DP, during the levorotatory period (163 ml/min), did not differ from the respective value determined during the racemic period (P = .32). During the racemic period, the stereoselective difference in total plasma clearances, which is not observed when DP enantiomers are administered separately, may result from an increase in unbound fraction of R(–) DP, due to the presence of S(+) DP, which is known to be a potent displacer of R(–) DP.

Dosage simultanéde la vinburnine et dela 6-hydroxyvinburnine par chromatographie liquideàhaute performance

Summary Simultaneous determination of vinburnine and 6-hydroxyvinburnine in human plasma by high-performance liquid chromatography An isocratic high-performance liquid chromatographic method has been developed to allow the simple and rapid determination of both vinburnine (I) and its main metabolite, 6-hydroxyvinburnine (II), in heparinized human plasma (0.5 ml). Compounds I and II and p -chlorodisopyramide (internal standard) were first extracted with alkalinized ethyl acetate and then with sulphuric acid. Separation was achieved on a reversed-phase μBondapak C 18 column with a mobile phase of acetonitrile-water-0.1 M heptanesulphonate in acetic acid and with detection at 254 nm. Each required 20 min. The within-day coefficients of variation for identical samples (20 ng/ml) were 7 and 6% and betweenday coefficients of variation 8 and 26% for I and II, respectively. The detection limit was 5 ng/ml (normal therapeutic concentration, 10–300 ng/ml). The application of the method to drug monitoring was compared to that of a thin-layer chromatographic procedure.