Continuous Release of Protein from Biodegradable In Situ Forming Depot

초록

In recent years, a large number of literatures have disclosed in situ forming biodegradable systems that solidify or gel in the body from injectable fluids and are progressively degraded and eliminated after a certain period of application times. They are easy to form desired shape or depot by injecting flowing fluids and safe and less invasive. In situ gels may solve the problems associated with microsphere formulations, such as the initial burst, drug loss, the use of harsh organic solvent and manufacturing costs increases. Thermally reversible gelling materials, such as ReGel� (MacroMed, USA), are a unique class of compounds being developed for parenteral delivery. An ABA triblock copolymer of poly(D,L-lactide-co-glycolide)-block-poly(ethyleneglycol)-block-poly(D,L-lactide-co-glycolide), PLGA-PEG-PLGA, was prepared using a facile ring-opening polymerization. By varying the PEG/PLGA ratio or Mw of PEG, or blending polymers containing different Mw PEGs, the mechanical strength and gelling temperature, Tg, can be modifiable. In the present study, various pharmaceutically safe additives were compared in terms of Tg decreasing potency, gel stability and sustained release pattern of bovine serum albumin (BSA) as a model protein. These additives have been formulated in many parenteral products. Depending on the structure and physico-chemical characteristics, additives were considered to either increase or decrease Tg of negative thermosensitive polymers. Tg was measured by the tube inverting method and quantified. Among the additives investigated, PEG, disaccharide, polysaccharide and salting-out salt were effective in decreasing Tg of ReGel�. When the in vitro BSA release pattern was compared, while pure polymer gels without additives were disintegrated within 14 days, gels containing effective additives were intact even after 2 months. In addition, the initial burst was significantly reduced and sustained release patterns were observed over 2 months period. It was confirmed that the released protein was intact by SDS PAGE. These results represent that pharmaceutical additives stabilize biodegradable thermosensitive polymer as well as protein and are able to modify the initial burst and sustain the release pattern of proteins.