Roger Leverge

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.

Spray-dried redispersible oil-in-water emulsion to improve oral bioavailability of poorly soluble drugs.

A physically stabilized dry emulsion dosage form reforming the original emulsion after rehydration was developed by spray-drying a liquid oil-in-water emulsion containing maltodextrin as carrier and sodium caseinate as emulsifying agent. Several oil:water as well as maltodextrin:water ratios were tested, the homogenization and spray-drying processes and the reconstitution properties were investigated and an optimum formulation was selected for poorly soluble drug incorporation, having an identical oil:water and carrier:water ratio of 10% (w/w) and a load of solid material of 20% (w/w). Lipophilic 5-phenyl-1,2-dithiole-3-thione (5-PDTT) was selected as a model drug. 5-PDTT release from the solid state emulsion was studied using an in vitro two-phase stirred model and the relative bioavailability of 5-PDTT in the dry emulsion was obtained in the rabbit after oral administration of the reconstituted emulsion, compared to a 5-PDTT-sulfobutyl ether 7 beta-cyclodextrin complex in solution. Incorporation of 5-PDTT in the oil phase neither affects the surface morphology of the powder nor the reconstitution, the droplet size or the drug releasing properties and, furthermore, allows a 3-fold improvement of 5-PDTT relative bioavailability in rabbit after oral administration. These results indicate that dry emulsions may be considered as relevant dosage forms to improve bioavailability of poorly absorbable lipophilic drugs.

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...

A dose-response study of epidural liposomal bupivacaine in rabbits.

Liposomes are drug delivery systems used to prolong local effects of bupivacaine. We studied the relationships between motor and hemodynamic changes and epidural doses of plain bupivacaine (P) and liposomal bupivacaine (L) in rabbits equipped with chronical lumbar epidural and femoral arterial catheters. Liposomal (phosphatidylcholine-cholesterol) suspensions contained 20 mg ml-1 of lipid, and different doses of bupivacaine (Lipo 7.5=7.5-; Lipo 3.7=3. 75-; Lipo 2.5=2.5-; Lipo 1.2=1.25-; and Lipo 0.7=0.65-mg of bupivacaine per ml). Forty rabbits were randomly assigned to five groups to receive epidural anesthesia (1 ml) as follows: Groups I to V received 0.65 to 7.5 mg of bupivacaine as P then as L. Release rate of bupivacaine from liposome was significantly slower using Lipo 3.7 than after Lipo 2.5 (Td was 3.9 h and 1.7 h respectively). Increasing the doses of L and P resulted in faster onset time for complete motor blockade and in a prolonged duration of motor effects. Liposomal formulation appears to be a powerful delivery system to prolong the motor effects of bupivacaine since E50 was lower and Emax higher than after the use of plain solution (E50 4.49+/-1.81 mg and Emax 152+/-40 min for P; and E50 2.61+/-0.23 mg and Emax 202+/-9 min for L). Hemodynamic changes were linearly related to doses of bupivacaine injected. The best bupivacaine-to-lipid ratio to prolong motor effects using our model was 3.75 mg and 20.0 mg respectively (Lipo 3.7).

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.

Prolongation of spinal anesthesia with bupivacaine-loaded (DL-lactide) microspheres.

There is considerable interest in developing a sustained-release local anesthetic formulation to provide long-lasting anesthesia and to decrease systemic toxicity. Bupivacaine (B), 10 mg, loaded in two different types of polylactide microspheres (PLA1 and PLA2) was evaluated after spinal injection and compared with plain bupivacaine (pB), 2 mg. Experiments were performed in six New Zealand rabbits. Duration of motor block was significantly prolonged for PLA1 compared to pB (177.5 +/- 79.5 min vs 44.6 +/- 18.0 min; P < 0.05), as well as for the recovery time (545.0 +/- 299.6 min vs 44.2 +/- 21.5 min; P < 0.05). The duration and recovery were not prolonged for PLA2. Systemic release of B after intrathecal injection was measured from blood samples by using high-performance liquid chromatography. There was no significant difference in maximum B plasma concentration between pB and PLA1 (326 +/- 81 mg/mL vs 321 +/- 57 ng/mL). The time taken to reach the maximum plasma concentration (6.6 +/- 2.6 min vs 41.7 +/- 20.4 min; P < 0.05) was significantly different. This study demonstrated that the use of bupivacaine-loaded (DL-lactide) microspheres can prolong spinal motor block. (Anesth Analg 1995;81:99-103)