268657 pH-Responsive Hydrogels for Oral Delivery of Therapeutic Proteins
pH-Responsive Hydrogels for Oral Delivery of Therapeutic Proteins
Michael C. Koetting and Nicholas A. Peppas, The University of Texas at Austin, Department of Chemical Engineering, Austin, TX
Introduction: Therapeutic delivery of proteins via intravenous injection is an invasive and often painful method which has been shown to cause low patient compliance with doctor-recommended treatment. Delivery via the transmucosal and especially the oral route is strongly preferred to avoid the pain and embarrassment of injection and therefore increase patient compliance. However, several challenges currently prevent this route from being used. The protein must first be protected from proteases and strongly acidic conditions present in the stomach to arrive in its therapeutic form, must then be released in the 2-3 hour window during which it is in the small intestine, and must finally be absorbed through the epithelial lining of the small intestine to enter the bloodstream. Environmentally-responsive hydrogel systems have shown great promise as drug delivery vehicles to overcome these obstacles. Our group has previously developed copolymer hydrogel delivery vehicles—notably poly(methacrylic acid) grafted with poly(ethylene glycol), or P(MAA-g-EG)—for the oral delivery of insulin. These hydrogels protect the protein through the gastrointestinal tract and release the protein in the small intestine by swelling at the higher pH found in the intestine.
Our current work is focused on creating a pH-responsive copolymeric hydrogel delivery vehicle for other proteins, specifically salmon calcitonin which is used to treat osteoporosis, Paget's disease, and hypercalcaemia. Calcitonin displays very different properties than insulin, primarily a high isoelectric point of 8.86 compared to 5.39 for insulin. As a result, new hydrogel delivery systems have been investigated as carriers appropriate for the delivery of calcitonin.
Methods and Results: We have synthesized copolymers of itaconic acid and N-vinylpyrrolidone, designated as poly(itaconic acid-co-N-vinylpyrrolidone) or P(IA-co-NVP), that possess pH-dependent swelling properties. Hydrogel films were synthesized via UV-initiated free radical polymerization using tetra(ethylene glycol) dimethacrylate (TEGDMA) as a crosslinker. The effect of composition on the swelling profile has been investigated with equilibrium and dynamic pH swelling studies. The carriers displayed favorable swelling characteristics for delivery in the small intestine, remaining collapsed at acidic conditions and swelling to weight ratios of up to 20 at neutral conditions. Compositions with higher itaconic acid content relative to N-vinylpyrrolidone displayed greater swelling ratios and more anionic properties. Furthermore, all carriers displayed faster swelling dynamics than previous formulations of P(MAA-g-EG) or P(MAA-co-NVP), indicating the potential for greater release of the loaded drug during the narrow time frame in the small intestine. Loading and release studies using P(IA-co-NVP) microparticles sieved to sizes between 90 and 150 μm and loaded with bovine serum albumin or salmon calcitonin have also been performed to demonstrate the suitability of the copolymer as a drug delivery vehicle.
Conclusions: The copolymer hydrogels of P(IA-co-NVP) demonstrate favorable pH-dependent swelling for efficient oral delivery of drugs to the small intestine. The polymer network remains collapsed at low pH, protecting the protein from proteases in the stomach, and swells rapidly at neutral conditions, releasing the protein in the small intestine for uptake into the bloodstream. The carriers are therefore considered viable candidates for the oral delivery of various therapeutic proteins such as calcitonin or insulin.
Acknowledgment: This work was supported by grant 1R01-EB000246-19 from the National Institutes of Health.