Joseph C. Salamone

Biodegradable fumarate-based drug-delivery systems for ophthalmic applications.

The function of a photocrosslinked poly(propylene fumarate) (PPF)/poly(N-vinyl pyrrolidone) (PVP) matrix for the sustained release of three ophthalmic model drugs, acetazolamide (AZ), dichlorphenamide (DP), and timolol maleate (TM), was investigated. The drugs differ in molecular weight and degree of dissociation in aqueous environments; both are parameters that significantly influence drug diffusivity. AZ, DP, and TM-loaded cylindrical rods (10 mm length, 0.6 mm diameter) were fabricated by photoinduced cross-copolymerization of PPF and N-vinyl pyrrolidone (NVP) in molds. The released amounts of AZ, DP, TM, and NVP were determined by high-performance liquid chromatography (HPLC). The effects of drug properties and loading on the release kinetics were investigated. The in vitro release of AZ, DP, and TM was well sustained from the polymer matrices over a period of approximately 210, 270, and 250 days, respectively. The release kinetics correlated with the HPLC retention profiles of the different drugs. Following a small initial burst release (<10%), a dual modality release controlled by diffusion and bulk erosion was found for all drugs. Drug release rates of up to 4 microg/day were reached. Matrix drug loading generally affected the extent of the burst release, release kinetics, as well as the matrix water content and matrix degradation that were determined gravimetrically. Microcomputed tomography was used to image structural and dimensional changes of the devices. A preliminary rabbit implantation study revealed promising ocular biocompatibility of drug-free PPF/PVP matrices. All results indicate the potential of photocrosslinked PPF-based matrices as polymeric carriers for long-term ophthalmic drug delivery.

Matrix Modifications Modulate Ophthalmic Drug Delivery From Photo-Cross-Linked Poly(propylene Fumarate)-Based Networks

In this work, different modifications of photo-cross-linked poly(propylene fumarate)/poly(N-vinyl pyrrolidone) (PPF/PNVP) matrices were studied for their effect on the release kinetics of two ophthalmic drugs. The hydrophilicity of solid PPF/PNVP matrices loaded with acetazolamide (AZ) or timolol maleate (TM) was increased by adding various amounts of poly(ethylene glycol) (PEG) or by increasing the amount of N-vinyl pyrrolidone (NVP) in the polymer mixture prior to cross-linking. The in vitro release studies that utilized high-performance liquid chromatography for quantification revealed highly accelerated drug release from the matrices with increasing contents of the hydrophilic modifier. AZ was released from matrices containing 5% PEG in 56 days, which equals approximately 25% of the release period found for the unmodified matrices. A comparable acceleration in drug release was found for TM-loaded samples modified with 5% PEG. These studies further revealed that 1% PEG is sufficient to shorten the TM release duration by one-third. A significant acceleration in drug release was also found for the samples that were fabricated from a PPF–NVP mixture with increased NVP content. Matrix water content and erosion were assessed gravimetrically. Micro-computed tomography was used to image structural changes of the release systems and shed light on the drug-release mechanism. This study showed that hydrophilic matrix modifications of PPF/PNVP matrices accelerate the drug release of two ophthalmic drugs and represent a suitable tool to adjust drug-release rates from PPF-based matrices for different therapeutic needs.