Complexation hydrogels are three-dimensional hydrophilic structures capable of imbibing water and swelling in response to changes in environmental pH. This pH-responsive behavior has been harnessed to develop microparticle carriers for the oral delivery of protein therapeutics. The pH-responsive hydrogel remains collapsed at gastric pH, protecting the protein payload, and only swells to release the protein at intestinal pH, where it can be absorbed. P((MAA-co-NVP)-g-EG), a random copolymer of methacrylic acid (MAA) and N-vinyl pyrrolidone (NVP) with grafted poly(ethylene glycol) tethers, has shown success in the oral delivery of insulin. However, insulin, while still a large biomacromolecule (5.8 kDa), is small relative to other therapeutic proteins such as growth hormone (22 kDa) and ovalbumin (46 kDa). We investigated whether modifying hydrogel properties, such as crosslinking length and density, or optimizing loading conditions, including ionic strength, can improve loading levels of higher molecular weight protein therapeutics.<br/><br/>P((MAA-co-NVP)-g-EG) hydrogel microparticles were synthesized with varying crosslinking lengths (PEGDMA 200 and 400) and densities (1 – 1.25%) and crushed to 30-45 um microparticles. Protein loading was conducted by swelling the microparticles in a 0.5 mg/mL protein solution for 24 hours at 37<sup>o</sup>C. Insulin, the smallest protein, loaded at 6% (mg protein/mg particle), whereas pGH, 4 times the size, achieved loading up to 8%. Conversely, ovalbumin, the largest molecule, exhibited loading levels of only 1-2%. Decreasing the ionic strength of the loading buffer maintains the molecular weight trend, but increases overall loading levels by 2-5%. While varying crosslinking length and density can modulate swelling behavior, there was no significant impact on protein loading levels. In addition, these gels show no cytotoxicity and exhibit pH-triggered release of loaded proteins.

Optimization of methacrylic acid based pH-responsive hydrogels for the oral delivery of therapeutic proteins

251st National Meeting (2016)

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