Current treatments for hemophilia B, a hereditary bleeding disorder, require painful IV injections of coagulation factor IX. The goal of this work is to develop an oral delivery system for human FIX (hFIX) as a convenient prophylatic treatment. Complexation hydrogels have been engineered to protect biologics from the harsh environment of the GI tract and deliver them to the small intestine for absorption. We have successfully developed pH-responsive hydrogel networks based on poly(methacrylic acid)-grafted-poly(ethylene glycol) [P(MAA-g-EG)] as delivery vehicles for hFIX. We focused on optimizing the drug loading and release, as well as evaluating in vitro drug absorption and in vivo carrier toxicity. P(MAA-g-EG) hydrogels were synthesized with 1 mol% of pol(ethylene glycol) dimethacrylate (PEGDMA) crosslinking agent (MW of PEG=400, 600, 1000) by UV polymerization and then crushed into 30-45 µm particles. pH-responsive swelling and in vitro cytocompatibility were previously established. Particles were loaded by swelling in a hFIX solution at pH 7.4, and then collapsed with acid. Increasing PEGDMA length increased hFIX loading levels. Loading conditions were further optimized by testing reduced ionic strength solutions and increased times, resulting in significantly higher loading up to 40 ± 2 µg hFIX/mg particle. Release studies showed desired release profiles (Figure 1A) using two-stage dissolution in biorelevant fasted state simulated gastric fluid (FaSSGF, pH 1.6) and fasted state simulated intestinal fluid (FaSSIF, pH 6.5). Increasing PEGDMA length maintained higher hFIX activity (Figure 1B) due to uniform distribution within particles as visually confirmed by confocal images of hFIX-FITC loaded particles. hFIX permeability using in vitro intestinal epithelial models increased up to 3.4-fold due to particle presence. Particles are non-toxic in vivo as indicated by histology and biomarker levels.

Evaluation of pH-responsive hydrogel networks as oral delivery systems for hematologic factor IX

251st National Meeting (2016)

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