Synthesis and characterization of sorbitol laced hydrogel-forming microneedles for therapeutic drug monitoring

Abstract

The dermal interstitial fluid (ISF) is rich in biomarkers that are of great heuristic value for disease diagnosis and therapeutic drug monitoring. Nevertheless, the current strategies for sampling dermal ISF are both technical and invasive, limiting the potential utility of ISF for clinical medicine and research purposes. In the current work, we present, for the first time, the development, characterization, and evaluation of a novel sorbitol-laced hydrogel-forming microneedles (Sor-Hyd-MN) for sampling dermal ISF. The hydrogel system is fabricated from sorbitol and PEG 10,000 crosslinked with Gantrez® S-97 via esterification in a solvent-free manner. The sorbitol-laced hydrogel rapidly absorbs fluid when placed in aqueous media, reaching a total rise in the mass of 685% relative to the control hydrogel that only reached 436% within 15 mins. When formulated into MNs, the Sor-Hyd-MN exhibited significantly superior (p < 0.001) mechanical properties as evidenced by the minimal MN height reduction (0.9%) relative to the control-MN (3.9%) and Man-Hyd-MN (28.5%) when subjected to a compressive force of 32 N, an analog of patients' thumb pressure. The skin insertion capability of the Sor-Hyd-MN and the control-MN formulation was demonstrated using the in vitro skin simulant, Parafilm® M, and ex vivo neonatal porcine skin. When inserted into ex vivo neonatal porcine skin, the Sor-Hyd-MN showed rapid imbibement of dermal ISF within 15 mins, evidenced via the formation of swollen microchannels, which was 1.2-folds wider than the control formulation. In addition, we also demonstrated for the first time that incorporating sorbitol into Gantrez® S-97 hydrogel-forming MN improved the utility of this formulation in sampling dermal ISF. This was shown from the capability of the Sor-Hyd-MN in extracting the model compounds, isoniazid and theophylline, present within the ISF of ex vivo porcine skin. The Sor-Hyd-MN exhibited an extraction efficiency of 52.4% for isoniazid and 54.4% for theophylline which was significantly higher (p < 0.05) relative to the control formulation in a simple and straightforward manner. This work illustrates that incorporating a hyperosmolyte, such as sorbitol, can further enhance the potential utility of hydrogel-forming MN as a minimally-invasive tool for ISF sampling while providing a potential strategy to extract analytes with ease for subsequent sample analysis.

Keywords: Hydrogel; Interstitial fluid; Microneedles; Sorbitol; Therapeutic drug monitoring.