Optimisation of HPMC ophthalmic inserts with sustained release properties as a carrier for thermolabile therapeutics.

A methodology was developed and optimised for the preparation of a new drug delivery system (DDS) with sustained release properties to allow ocular protein delivery and to limit destructive production steps during manufacturing. Elevated temperatures, shear forces and an oxidative environment should be avoided in order to prevent denaturation or oxidation of proteins. An aqueous HPMC solution was prepared using heat and casted into small semi-rod-shaped PVC blisters. The polymer solution was allowed to cool down and was partially dehydrated at room temperature. A drug solution containing glycerol, drug and water was subsequently added to rehydrate the partially dehydrated polymer matrix at a temperature of 2°C. Several parameters of the production process were varied to determine their influence on the release kinetics from HPMC inserts from three different molecules of different molecular weight. This production method was further optimised in order to shorten the rehydration time from weeks to days, while eliminating heat and shear forces on the selected drug molecules sodium fluorescein, lysozyme and albumin. Slow release kinetics were achieved for sodium fluorescein and lysozyme as model drug molecules. The higher molecular weight of albumin prevented a good penetration into the insert during the rehydration process resulting in predominantly burst release. The biocompatibility of a viscous HPMC solution was evaluated on SV40-human corneal epithelial cells with PrestoBlue® and no cytotoxic effects were observed.

Evaluation of a newly developed HPMC ophthalmic insert with sustained release properties as a carrier for thermolabile therapeutics.

A novel drug delivery system (DDS) with sustained release properties was developed to allow ocular protein delivery. The DDS developed is aimed at overcoming stability issues during preparation such as denaturation of proteins caused by shear forces applied or due to elevated temperatures and air entrapment potentially causing oxidation of the molecule. The rod-shaped HPMC inserts were loaded with lysozyme and several HPMC types were studied and compared. An aqueous colloidal HPMC solution (hydrogel) was prepared and subsequently dried at 150°C to dehydrate the polymer solution. This partially dehydrated polymer cylinder was loaded with an aqueous glycerol/lysozyme solution at 2°C. A 2(4) full factorial design was set up to evaluate the effect of the different preparation parameters on water uptake and release properties. As a result, four out of sixteen formulations revealed homogenous distribution for lysozyme in both duplicates. The change in water uptake over time was dependent on the type of HPMC polymer used but not between the chosen HPMC percentages. After 240min, 50% of lysozyme loaded was released depending on the chosen formulation. Lysozyme molecules exhibit slower release from a K100M matrix compared to E10M inserts, albeit the overall effect is relatively limited.

Full factorial design, physicochemical characterisation and biological assessment of cyclosporine A loaded cationic nanoparticles.

Cyclosporine A loaded poly(lactide-co-glycolide) nanoparticles coated with chitosan were prepared using the o/w emulsification solvent evaporation method. A 2(3) full factorial design was used to investigate the effect of 3 preparation parameters on the particle size, polydispersity index, zeta potential and drug release. In vitro experiments were performed in order to evaluate the cytotoxicity and anti-inflammatory activity of the developed nanoparticles. Particle sizes varied from 156 nm to 314 nm, and polydispersity index values of 0.07-0.56 were obtained depending on the different preparation parameters. All nanoparticles showed positive zeta potential values. Nanoparticles prepared with the highest concentration chitosan retained a positive zeta potential after dispersion in simulated lachrymal fluid, which supports the possibility of an electrostatic interaction between these particles and the negatively charged mucus layer at the eye. The in vitro release profile of cyclosporine A from the chitosan-coated nanoparticles was strongly dependent on the release medium used. None of the cationic nanoparticle formulations showed significant cytotoxicity compared to the negative control using human epithelial cells (HaCaT). Cyclosporine A encapsulated in the various nanoparticle formulations remained anti-inflammatory active as significant suppression of interleukine-2 secretion in concanavalin A stimulated Jurkat T cells was observed.