Ophthalmic Inserts prepared either by Extrusion or by Freeze-Drying : Technological and Biopharmaceutical Characterization

The main goal of this thesis is the development of an ophthalmic biodegradable insert containing fluocinolone acetonide (FA), to apply in the posterior segment of the eye. The inserts under study were prepared using the hot-melt extrusion technique (HME). In a previous study, an insert based on hydroxypropyl cellulose (HPC-FA) was selected as the best with respect to a wide range of devices tested. New inserts containing amylo-maize starch N-400 (AMYLO), corn starch (CS) or corn starch with magnesium stearate (CS-MS) were prepared. All inserts were added of 3% FA (AMYLO-FA, CS-FA and CS-MS-FA, respectively). Swelling and dissolution properties of the new inserts were analysed in isotonic buffer saline (PBS) by a visual examination. During the examination time (up to 12 days), AMYLO-FA produced no changes in terms of dissolution and gel-like transformation in addition to an initial hydration and light swelling compared to the inserts containing CS; so it has appeared the most suitable for further studies. The physicochemical characteristics of the selected inserts (HPC-FA and AMYLO-FA) were determined by a) in vitro drug release and by b) differential scanning calorimetry (DSC). Drug release performance of AMYLO-FA and HPC-FA inserts was comparatively evaluated using Gummer-type diffusion cells up to 52h, maintaining the sink conditions (continuous receiving phase replacement), to evaluate the device influence on the FA release independently to the surrounding environment. During the time observed, HPC-FA released the drug too quickly (89% of drug released) for our goal unlike AMYLO-FA that showed a remarkable reduction of FA release (36.13%). The test on AMYLO-FA was continued for 8 days and a slow but continuous release was obtained to reach 63.66% of FA at the end of the experiment. A controlled drug delivery with zero order kinetics could be hypothesized when AMYLO-FA release process reached the steady-state. The release rate of FA from AMYLO-FA insert was also determined when the receiving phase (PBS) was totally replaced every 24h and 48h simulating the biological conditions: vitreous humor turnover is considered stagnant. For both performed experiment protocols FA release from AMYLO-FA insert was linear during the 25-day sampling period but the release rate decreased by half for sampling 48 hours. Then it would seem that the release of the drug from the device was mainly influenced and driven by the receiving environment rather than from the insert. The DSC analysis of AMYLO-FA (as physical mixture and extruded) suggested that no polymer-drug interaction occurred using the HME and this means that the release of the drug might depend only on the modified polymer structure. The second part of this thesis aimed at tuning up cylindrical matrices by freeze-drying for administration of vancomycin (VA) in the precorneal area to produce a sustained release of drug and consequently to reduce the number of applications. The matrices prepared contained hydroxypropyl methylcellulose (HPMC) and VA in ratio 0.25 to 1 and were subjected to a) in vitro release study and b) DSC analysis. HPMC-VA matrix released the drug very slowly for our goal, may be due to a drug-polymer interaction during the freeze-drying process. DSC analysis of lyophilized matrix and the single components would suggest this hypothesis

DRUG DELIVERY MICRODEVICE: DESIGN, SIMULATION, AND EXPERIMENTS

Ocular diseases such as glaucoma, age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa require drug management in order to prevent blindness and affecting millions of adults in US and worldwide. There is an increasing need to develop devices for drug delivery to address ocular diseases. This research focused on an implantable ocular drug delivery device design, simulation and experiments with design requirements including constant diffusion rate, extended period of time operation, the smallest possible volume of device and reservoir. The drug delivery device concept uses micro-/nano-channels module embedded between top and bottom covers with a drug reservoir. Several microchannel design configurations were developed and simulated using commercial finite element software (ANSYS and COMSOL), with a goal to investigate how the microchannel dimensions affect the diffusion characteristics. In addition to design simulations, various microchannel configurations were fabricated on silicon wafer using photolithography techniques as well as 3D printing. Also, the top and bottom covers of the device were fabricated from PDMS through replica molding techniques. These fabricated microchannel design configurations along with top and bottom covers were all integrated into the device. Both single straight microchannels (nine different sizes of width and depth) as well as four micro-channel configurations were tested using citric acid (pH changes) and Brimonidine drug (concentration changes using the Ultra-Violet Visible Spectrophotometer) for their diffusion characteristics. Experiments were conducted to obtain the diffusion rates through various single micro-channels as well as micro-channel configurations using the change in pH neutral solution to verify the functionality and normalized diffusion rate of microchannels and configurations. The results of experimental data of diffusion rate were compared with those obtained from simulations, and a good agreement was found. The results showed the diffusion rate and the optimum size of microchannel in conjunction with the required drug release time. The results obtained also indicate that even though specific diffusion rates can be obtained but delivering the drug with constant amount needs a mechanism at the device outlet with some control mechanism. For future studies, this result may be used as a baseline for developing a microfabricated device that allows for accurate drug diffusion in many drug delivery applications