A Nanoporous, Biodegradable Thin-Film Polymer Device for Sustained-Release Delivery of Biopharmaceuticals to the Eye

SourceURL:file://localhost/Users/nat/Desktop/AIChE_Abstract_NCiaccio_2012.doc

The traditional dosage forms of ocular drug delivery, such as eye drops and ointments, are widely used to treat a variety of ophthalmic disorders, but they have several limitations.  They often require frequent daily administration, commonly three of four times a day, and are difficult to self-administer, especially for elderly patients. Importantly, they also provide little to no penetration into the vitreous and retina and are thus ineffective in treating diseases affecting the posterior segment of the eye.   Retinal diseases are therefore most commonly treated using intraocular injection.  A prime example is the intravitreal administration of ranibizumab (LucentisÓ, Roche, Inc.) used for the treatment of age-related macular degeneration (AMD), a disease affecting more than two million people in the United States alone. 

While intraocular injection can effectively deliver drug to the retinal tissue, this method has limitations as well.  The drug is often cleared rapidly from the eye (i.e. 9 day half-life for ranibizumab), reducing the time that the drug concentration stays within the therapeutic window.  Additionally, there is potential for rare but serious complications associated with the injection, including endophthalmitis and retinal detachment.  Consequently, minimizing the frequency of intraocular injection is an important objective in patient care.  However, a number of therapies require repeated injections, including AMD treatment, which requires monthly injections of ranizibumab often lasting for several years.  The risk and cost associated with such frequent injections has resulted in reduced compliance with the recommended treatment regimen limiting therapeutic response.  Improvements in drug delivery technology to more effectively deliver drugs to the retina while reducing the risk of complication are sorely needed and actively being investigated. 

Progress had been made in the development of sustained-release devices to more effectively deliver drugs to the posterior segment of the eye, but nearly all advances focus on the delivery of small molecule therapeutics.  Recent breakthroughs in ophthalmic pharmaceutical care, particularly in the area of AMD, are attributed to the development of novel protein therapeutics.  Given the success of these new biological products and increased investment in biotechnology, it seems inevitable that future ophthalmic treatment will include a greater number of biological drug products.  A current and growing challenge then will be how to more effectively and safely deliver protein therapeutics to the back of the eye.

Our approach in developing a technology to meet this need is to utilize a syringe-deployable, biodegradable polymer that can facilitate zero-order drug release over a period of several months.  Zero-order release allows drug levels to remain constant throughout delivery, avoiding the peak and trough drug levels that result from standard bolus injection.  This ensures drug levels remain in the therapeutic range, reducing the risk of adverse affects and improving therapeutic outcome.  To achieve this release profile, we have employed the use of nanopore technology through the fabrication of a nanoporous thin-film device.  Thin-film nano-fabrication permits the selection and formation of a product containing the desired pore size and density to facilitate controlled drug release.  By engineering the pore size to be roughly 1-2 times the molecular diameter of the drug target, one can achieve zero-order release throughout the lifetime of the device.  This porous film can then be fitted with an isolated drug reservoir that will provide the necessary therapeutic payload while also isolating and protecting drug product. 

While nanofabrication can be performed using a number of materials, we have carefully selected a flexible polycaprolactone (PCL) polymer for the purposes of this project.  This polymer has been previously demonstrated to be both biocompatible and biodegradable in vivo.  Moreover, our preliminary work shows that PCL demonstrates excellent biocompatibility and integrity within the eye.  We also aim to develop a device that is syringe-deployable allowing for office-based administration that is minimally invasive.  Using a thin-film device made from a soft, flexible PCL polymer will permit furlability.  The device can be injected using a standard bore needle in a rapid office procedure minimizing ocular trauma and procedural costs.  Once injected the thin-film can then unfurl providing access to device nanopores and facilitating drug release. 

A major concern with biologic drug molecules is their propensity for rapid degradation.  Protein-based therapeutics are susceptible to numerous mechanisms of chemical and physical degradation.  This is likely to be a limiting factor in the ability to deliver biological products in a sustained-release manner.   Rather than absorb the protein molecules to the surface of a particle or polymer, which can cause protein unfolding and subsequent aggregation, we have chosen to encapsulate lyophilized drug product inside our device in order to improve protein stability.  We will also carefully evaluate the physical and chemical structure of released drug product. 

Using ranibizumab as our selected biopharmaceutical we have demonstrated zero-order release kinetics over a period of several months from our PCL thin-film nanoporous device. Moreover, we have also successfully demonstrated that ranibizumab maintains its physical and chemical stability throughout this time period of release.