In Situ Gelling Hydrogels Incorporating Microparticles as Drug Delivery Carriers for Regenerative Medicine QINGPU HOU, 1 DAVID Y.S. CHAU, 1 CHAYANIN PRATOOMSOOT, 1 PATRICK J. TIGHE, 3 HARMINDER S. DUA, 2 KEVIN M. SHAKESHEFF, 1 FELICITY R.A.J. ROSE 1 1 Division of Advanced Drug Delivery and Tissue Engineering, School of Pharmacy, Centre for Biomolecular Sciences, The University of Nottingham, University Park, Nottingham NG7 2RD, UK 2 Division of Ophthalmology and Vision Sciences, School of Medical and Surgical Sciences, Queen’s Medical Centre, Nottingham NG7 2UH, UK 3 Division of Immunology, School of Molecular Medical Sciences, Queen’s Medical Centre, The University of Nottingham, NG7 2UH, UK Received 30 July 2007; revised 4 October 2007; accepted 8 November 2007 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21310 ABSTRACT: Aqueous solutions of blends of biodegradable triblock copolymers, com- posed of poly(DL-lactide-co-glycolide) (PLGA) and poly(ethylene glycol) (PEG) with varied D,L-lactide to glycolide ratios, displayed thermosensitivity and formed a gel at body temperature. The gel window of the blend solutions could be tuned by varying the blending ratio between the two components. Furthermore, the storage modulus of the resultant hydrogel from the copolymer blends at body temperature was higher than that of each individual component. Incorporation of poly(D,L-lactide) (PDLLA) microparticles (0.5–40% w/v) within the in situ gelling hydrogel did not change the sol–gel transition temperatures of the polymer solutions, while the mechanical strength of the resultant hydrogels was enhanced when the content of the microparticles was increased up to 30% and 40%. Incorporation of proteins into both the gel and microparticle components resulted in composites that controlled the kinetics of protein release. Protein within the gel phase was released over a 10-day period whilst protein in the microparticles was released over a period of months. This system can be used to deliver two drugs with differing release kinetics and could be used to orchestrate tissue regeneration responses over differing timescales. ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:3972–3980, 2008 Keywords: thermosensitive hydrogels; biodegradable polymers; drug delivery carriers; polymer microparticles INTRODUCTION In situ gelling polymer-based stimuli-responsive systems are attractive drug delivery carriers for sustained and localised release of bioactive molec- ules as they can be administered as low viscosity liquids and converted into positionally stable gels within the body. The sol–gel transition, can be triggered by several environmental changes including pH, 1,2 temperature, 3–6 light, 7,8 and ionic strength. 9 Among the stimuli-responsive polymers, thermosensitive hydrogels utilise the reliable increase in temperature that occurs on adminis- tration to the body. In addition, their sol–gel transition can be tolerated by delicate protein drugs incorporated within the polymer solution. Several natural polymers, such as hyaluronic acid 10 and chitosan, 4,6 and synthetic polymers Correspondence to: Felicity R.A.J. Rose (Telephone: þ44- 115-846-7856; Fax: þ44-115-951-5122; E-mail: felicity.rose@nottingham.ac.uk) Journal of Pharmaceutical Sciences, Vol. 97, 3972–3980 (2008) ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association 3972 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008