Studies on the release behavior of drugs in hyaluronic acid-nano/micro carrier composite hydrogels
Date of Issue2015
School of Materials Science and Engineering
Hyaluronic acid (HA) is a natural polymer that has gained significant attention as a potential biomaterial for a wide range of biomedical applications due to its unique physical and chemical properties. The mechanical and degradation properties of HA can be improved by physically or chemically crosslinking the chains into hydrogels. HA hydrogels have been extensively investigated as drug delivery carriers; however, the release of entrapped drugs is rapid and cannot be sustained significantly. Composite hydrogels of HA with drug loaded particulate carriers have been developed recently that combine advantages of physical/chemical properties of HA and sustained release property of entrapped drug carriers. These systems have not been studied in detail in terms of the transport behavior of drugs through the crosslinked networks. This transport is affected by several factors and understanding the mechanisms of drug transport would help to optimize the design of HA based composite hydrogels for specific therapeutic applications. In this work, HA based composite hydrogels were developed with drug loaded egg phosphatidylcholine (EPC) liposomes, poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), and PLGA microparticles (MPs) and investigated for in vitro drug release and physical stability of entrapped carriers. 5-Fluorouracil (5Fu) and latanoprost (Ltp) were selected as model hydrophilic and hydrophobic drug, respectively. HA was modified using methacrylic anhydride (MA) and adipic dihydrazide (ADH) moieties and then crosslinked to obtain hydrogels and characterized for morphology, swelling behavior, rheology, and in vitro drug release. 5Fu was loaded into PLGA MPs and Ltp was loaded into EPC liposomes, PLGA NPs, and PLGA MPs. The delivery carriers were characterized for morphology, size distribution, % encapsulation efficiency (EE), and in vitro drug release. From drug release studies, it was found that 5Fu was rapidly released from HA hydrogels alone but encapsulating it inside PLGA MPs prolonged the release up to several days. Ltp was found to release slowly from HA hydrogels alone but the release was sustained from PLGA MPs and EPC liposomes for several days and weeks, respectively. In case of composite hydrogels, the release of 5Fu and Ltp was significantly retarded as compared to MPs and liposomes alone. Retardation from composite hydrogels was dependent upon hydrogel network structure surrounding the entrapped particulate carriers in case of 5Fu release but not for Ltp release. Degradation studies showed that there was no difference in the degradation rate of drug loaded PLGA MPs with or without hydrogel, thus indicating that the retardation of drugs from composite hydrogels was due to the additional diffusion barrier of gel network surrounding the MPs and liposomes. Future work should involve further evaluation and optimization of various factors that affect drug transport in these HA based composite hydrogels to develop them into potential sustained release carriers for different types of drugs. Drug release from composite hydrogels in the presence of enzyme hyaluronidase would be useful to study for estimating the in vivo release behavior. In addition, quantitative estimation of diffusion coefficients and resistances would be important to understand the drug release kinetics of composite systems in detail and to develop a generalized model.