In situ forming, resorbable graft copolymer hydrogels providing controlled drug release

Abstract

In situ forming hydrogels are promising drug delivery vehicles due to their ease of delivery as liquids and their ability to be used in sites with irregular geometries. In this work, we report on in situ forming, resorbable hydrogels based on N-isopropylacrylamide (NIPAAm) as a fluid-like controlled release gel. These gels are the first resorbable NIPAAm-based gels providing controlled release without relying on affinity between the drug and device. Therefore, these gels provide a more flexible delivery system which can be used to deliver any drug at a controlled rate. The polymers contain repeat units of NIPAAm with (R)-α-Acryloyloxy-β,β-dimethyl-γ-butyrolactone (DBLA) and varying amounts of hydrophilic Jeffamine® M-1000 acrylamide (JAAm) grafts. The graft copolymer architecture allows the water content of the hydrogels to be tuned over a wide range while keeping the initial gelation temperature below body temperature. Incorporation of JAAm in the polymers led to greater water content, faster gel degradation, and reduced burst release. Sustained release of the antimicrobial drugs cefazolin and vancomycin (over about 5 and 7 days, respectively) was observed from gels containing an intermediate amount of grafts which combined reduced phase separation with a degradation time of 40 days. The degradation byproducts of one hydrogel formulation were cytocompatible to NIH 3T3 fibroblasts at concentrations up to 2.5 wt %. This class of terpolymer hydrogels is a promising local delivery system for a wide variety of drugs, particularly for applications involving irregular geometries such as implant interfaces.

Local Gentamicin Delivery From Resorbable Viscous Hydrogels Is Therapeutically Effective

“…The higher-dose formulation released more gentamicin over a longer duration. Release from the higher-dose G-PNDJ formulation is very similar to the release characteristics of high-dose antimicrobial-loaded bone cement over the first week [41] but G-PNDJ does not have the long-duration subtherapeutic release that occurs with antimicrobial-loaded bone cement because it is fully degraded by 4 weeks [50]. It is generally accepted that high-dose antimicrobial-loaded bone cement is indicated for treatment of established infection.…”

“…The lower critical solution temperature (LCST) was determined by a cloud-point method after dissolving PNDJ polymer in 150 mM phosphate-buffered saline (PBS) using a spectrophotometer at 450 nm [50]. PNDJ polymer solution forms a hydrogel at temperatures above the LCST.…”

“…With the goal of identifying a resorbable delivery vehicle that controls release of the loaded antimicrobial over many days and fully degrades over a few weeks, we have previously developed viscous, resorbable hydrogels based on the temperature-responsive polymer poly(N-isopropylacrylamide-co-dimethyl-c-butyrolactone acrylateco-Jeffamine 1 M-1000 acrylamide (PNDJ) [50].…”

Distribution of Locally Delivered Antimicrobials Is Limited by Cortical Bone: A Pilot Study

“…Vancomycin from an intramedullary depot was measurable in extraosseous fluid (6.7% of the deliverable load in the hydrogel by Day 5) and increased over time. The delivery rate was much slower than would be expected from the same NIPAAm-based hydrogel when it is not surrounded by cortical bone, which was 316 mg at Day 5 (80% of the load) in a previous study [8]. Cortical bone is an important barrier limiting antimicrobial transport.…”

“…For transcortical elution, vancomycin was delivered to the intramedullary canal in N-isopropylacrylamide (NIPAAm)-based hydrogel [7,8], which has been shown to release loaded antimicrobials [8]. The hydrogel consisted of NIPAAm and polyetheramine (Jeffamine 1 ; Huntsman International LLC, Salt Lake City, UT, USA) copolymerized by free radical polymerization, which gelled on warming to temperatures near 37°C.…”