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By Vibhuti Agrahari and Ashim K. Mitra

Vibhuti Agrahari-finalAshim Mitra-finalBack of the eye diseases such as age-related macular degeneration (AMD), diabetic retinopathy, and diabetic macular edema pathology consequently lead to visual loss in many cases. At present, protein therapeutics such as bevacizumab (Avastin~$60/dose), ranibizumab (Lucentis~$2000/dose), and aflibercept (Eyelea~$2000/dose) are some of the most expensive treatments available for these diseases. These treatments are effective and specific, but frequent injection through the eyeball is very painful for the patients. In addition, poking the eye with a needle frequently may cause other complications such as inflammation, retinal hemorrhaging, and retinal detachment. Therefore, to overcome these challenges, formulation scientists have focused on developing a sustained protein delivery system, such as nanoparticles, or nanoparticles suspended in gel, which are composed of biodegradable and biocompatible polymers.

Considering the above mentioned problem, a novel biodegradable and biocompatible pentablock (PB) copolymers composed of various FDA-approved individual polymeric blocks such as polyethylene glycol, polycaprolactone, and polylactic acid/polyglycolic acid were developed in our lab. The advantages of polymeric approaches include protection from enzymatic degradation, prolonging residence time, sustaining drug release with minimal or no burst effect, and preventing the exposure of biologics from various environmental factors such as pH, temperature, and electrolytes. The formulation and process parameters were optimized on the basis of polymer hydrophobicity, presence of salt, drug-to-polymer ratio, and phase volumes, to achieve the high macromolecule drug loading into PB copolymer-based nanoparticles (NPs). This is a novel concept of composite formulation where protein/peptide-loaded PB-NPs were suspended in PB thermosensitive gel to achieve sustained release. Moreover, the proteins/peptides with different molecular weights ranging from 1-237 kDa can be encapsulated in PB-NPs.

shutterstock_140396860In a graduate student symposium session at the 2015 AAPS National Biotechnology Conference, “2015 AAPS National Biotechnology Conference, “Development, Optimization and Evaluation of Biological Activity of Tailor-Made Pentablock Copolymer Based Composite Formulation for Sustained Delivery of Protein Therapeutics,” we will discuss the improvement in drug loading of nanoformulations. These nanoformulations allow larger doses of therapeutic molecules in a smaller injection volume which may provide extended release over a longer time period (~ up to six months) from one injection, eliminating the need for monthly injections.

The PB composite formulations could be ideal for intravitreal delivery because these formulations:

  • Can carry the sufficient dose in small volume for sustained delivery up to six months or more,
  • Can provide zero-order release throughout the treatment period without any burst effect,
  • Are easy to administer intravitrealy through a 27 G needle,
  • Ensure stability of protein/peptide,
  • Are biodegradable and biocompatible, and
  • Have a biodegradation time that does not exceed 1.5 times of release period.

This research clearly suggests that a PB copolymers-based drug delivery system may serve as a promising platform not only for back of the eye complications but also for the treatment of other diseases that require long term delivery.

Vibhuti Agrahari is an interdisciplinary Ph.D. student in the School of Pharmacy at University of Missouri Kansas City (UMKC). Currently, she is chair-elect of the UMKC AAPS student chapter and president of the UMKC Doctoral Student Council.
Ashim K. Mitra received his Ph.D. in Pharmaceutical Chemistry in 1983 from the University of Kansas. His current research interests are focused on two main areas: delivery and targeting of antiviral agents and development of noninvasive delivery systems for peptide and protein drugs.