International Journal of Pharmaceutics 392 (2010) 209–217 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Pharmaceutical Nanotechnology Optimizing partition-controlled drug release from electrospun core–shell fibers Sandeep Kumar Tiwari a , Roey Tzezana b , Eyal Zussman b , Subbu S. Venkatraman a,∗ a School of Materials Science and Engineering, N4.1-1-30, Nanyang Technological University, Nanyang Avenue, Singapore 639798, Singapore b Faculty of Mechanical Engineering, Technion, Israel Institute of Technology, Haifa 32000, Israel article info Article history: Received 17 November 2009 Received in revised form 31 January 2010 Accepted 8 March 2010 Available online 12 March 2010 Keywords: Co-electrospinning Core–shell fibers Controlled drug release Hydrophilic drug Metoclopramide hydrochloride Partitioning abstract Controlled release of hydrophilic entities, such as peptides, proteins and even pDNA, is difficult to accom- plish with conventional approaches. This work suggests one possible approach for controlled release of such actives using electrospun core–shell fiber structures. In particular, we propose strategies for partition control of the release. The fibers consist of two layers, with the outer polymer sleeve serving containing the inner core, in which the drug is encapsulated. By varying the physical and chemical properties of the core and shell solutions, we have shown that the release rate of a hydrophilic drug, metoclopramide hydrochloride, is controllable. Experimental results show a clear difference in the release pattern between monolithic fibers made of hydrophilic and hydrophobic polymers and various core–shell fibers with PCL, PLLA and PLGA 80/20 as shell polymers. The study yields insight into when partition control of release can be achieved in core–shell fibers, and with that, options for controlled release systems for hydrophilic drugs, peptides and pDNA. © 2010 Published by Elsevier B.V. 1. Introduction As drug carriers, biodegradable polymers have found exten- sive use. Commercially, there have been a few systems based on biodegradable carriers, including Lupron-Depot ® , the now- discontinued Nutropin ® depot, as well as Glia-del ® , which is an implanted wafer. As we understand more and more about the prop- erties of biodegradable polymers, their use continues to expand. Various dosage forms have been fabricated using biodegrad- able polymers in order to achieve controlled drug release. These include microspheres (Huang et al., 1999), films, millirods (Qian et al., 2001), nanoparticles (Jeong et al., 2004). These drug delivery vectors have been studied widely for their drug release profiles and all of them have some limitations. Limited drug capacity and the “burst release” effect are two common problems. Attempts to over- come the burst have been made, with varying degrees of success. For example, Huang et al. (1999) coated microspheres of drug- carrying block PLA/PEG with gelatin; however, there were some concerns regarding the interference of gelatin with drug release. Core–shell structures are one of the several approaches made to obtain a controlled release profile, potentially yielding a zero- order profile. He et al. (2006) prepared a reservoir-type drug release device by encapsulating tetracycline hydrochloride (TCH) in the PLLA ultrafine fibers prepared by altering the polymer concentra- tions in the shell solution. Control was achieved over the release of ∗ Corresponding author. Tel.: +65 67904259; fax: +65 67909081. E-mail address: assubbu@ntu.edu.sg (S.S. Venkatraman). the core drug, although the explanation that the drug is released only through PLLA degradation was not substantiated nor does it appear reasonable, given the fairly slow degradation rates for PLLA. Another approach of preparing core–shell structures has been made by loading the shell with the drug. Zilberman (2007) have pre- pared such structures by coating the PLLA fibers and nylon sutures with protein-loaded PDLGA. The idea was to retain the mechanical strength of the fiber while achieving sufficient control over the pro- tein (horse radish peroxidase, HRP) elution. However, the protein (HRP) was loaded in the shell rather than the core; hence most of the protein was released in a burst as expected, due to the relatively hydrophilic character of the eluent. In this work, we evaluate the usefulness of core–shell fibers made by electrospinning (Sun et al., 2003; Dror et al., 2007), with a view to minimize effects such as the burst release. Electrospinning provides a simple and versatile method for generating ultrathin fibers from a variety of materials including polymers (Li and Xia, 2004). Polymeric nanofibers have proved to be attractive materials for a wide range of applications because of their unique proper- ties, especially very high surface area to volume ratio, flexibility in surface functionalities, superior mechanical properties, similar structural morphology to the fibrillar ECM (extracellular matrix), etc. (Boland et al., 2001; Li and Xia, 2004; Li et al., 2005, 2006). How- ever, many of the ultrathin polymeric fibers have failed to control the release of drug because of incompatibility between the polymer and the loaded drug (Kenawy et al., 2002, 2007; Kim et al., 2004; Jing et al., 2005). Control of release of hydrophilic bioactives from biodegradable polymer matrices has always presented a challenge. In general, 0378-5173/$ – see front matter © 2010 Published by Elsevier B.V. doi:10.1016/j.ijpharm.2010.03.021