Polymeric nanoparticles based on carboxymethyl chitosan in combination with painless microneedle therapy systems for enhancing transdermal insulin delivery

Biodegradable nanoparticles (NPs) have been frequently used as insulin transdermal delivery vehicles due to their grand bioavailability, better encapsulation, controlled release and less toxic properties. However, the skin's barrier properties prevent insulin-loaded NP permeation at useful levels. Nowadays, microneedles have been spotlighted as novel transdermal delivery systems due to their advantages such as painlessness, efficient penetration and no hazardous residues. Herein, we introduce polymeric nanocarriers based on carboxymethyl chitosan (CMCS) for insulin delivery, combining with microneedle therapy systems, which can rapidly deliver insulin (INS) into the skin. The resulting CMCS-based nanocarriers are spherical nanoparticles with a mean size around 200 nm, which could generate supramolecular micelles to effectively encapsulate insulin (EE% = 83.78 ± 3.73%). A nanocrystalline microneedle array (6 × 6, 75/150 μm) was used to penetrate the stratum corneum (SC) for enhancing transdermal insulin delivery, while minimizing the pain sensation caused by intravenous injection. Compared with the transdermal rate of passive diffusion [2.77 ± 0.64 μg (cm-2 h-1)], the transdermal rate of the insulin-loaded NP combined with microneedle penetration shows a 4.2-fold increase [10.24 ± 1.06 μg (cm-2 h-1)] from permeation experiment in vitro. In vivo hypoglycemic experiments demonstrate the potential of using nanocarrier combination with microneedle arrays for painless insulin delivery through the skin in a clinical setting. Thus, the developed combination scheme of nanoparticles and microneedle arrays offers an effective, user-friendly, and low-toxicity option for diabetes patients requiring long-term and multiple treatments.