# Polycaprolactone Blended Cosmetic Microneedle for Transdermal Hispidin Delivery System
###### Abstract  
Microneedles (MNs) are a new system of effective drug delivery that create micron-sized pathways to the epidermis or upper dermis regions of the skin. In this study, we developed coated-type microneedles for direct hispidin delivery to the skin. Hispidin is a well-known plant-derived antioxidant component showing antitumor, anti-inflammatory, antiallergic, antiangiogenic, antioxidant, hypoglycemic, hypolipidemic, and immunomodulatory activities. Polymeric blends of polylactic acid (PLA) and polycaprolactone (PCL) were casted as MNs to enhance skin permeability. PLA/PCL MNs exhibited the highest strength of 51.26 MPa with a width of \(\sim\)200 um. Hispidin was directly coated onto the MNs with PLA/PCL blends to form delivery layers. Compared to the hispidin-only delivery layer, skin permeability of hispidin increased by over 50% when using agarose gel in in vitro tests. In a dose-dependent manner, hispidin coated on PLA/PCL MNs also showed a brightening effect, as well as anti-inflammatory activity at the gene and protein level in skin cell culture experiments. It also demonstrated antimicrobial activity, and showed no cytotoxicity to skin cells. These results suggest that the PLA/PCL MN system with hispidin may have great potential as a prototype platform for various drug delivery systems, allowing the development of more effective subcutaneous delivery of vaccines, oligonucleotides, insulin, and many other cosmetic applications. microneedles; hispidin; drug delivery +
Footnote †: journal: Medical  
activity is about 3-5 times that of water-soluble vitamin E, equivalent to the reported value for beta hydroxy acid (BHA). Recently, it was also demonstrated that hispidin can inhibit the macrophage-mediated inflammatory response by downregulating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\(\kappa\)B) activations [13]. Hispidin also inhibits palmitate-induced apoptotic nuclear condensation in mouse myoblast cell line (C2C12) [14]. Hispidin is effective due to its anti-p21 activated kinase 1 (PAK1) activity. As expected, PAK1 silencing clearly reduced the melanogenic activity of this cell line by around 50%, proving that PAK1 is essential for alpha-melanocyte stimulating hormone (MSH)-induced melanogenesis [15]. In a prior study, aimed at identifying active oxygen degradation and whitening effects, 1, 2, and 5 \(\upmu\)M concentrations of hispidin were confirmed to decrease melanin production. Hispidin, a polyphenic substance, identified as 6-(3,4-dihydroxyyryl)-4-hydroxy-2-pyranone by [PERSON] in 1961, was first isolated from the fruiting body of _l. hispidus_ by [PERSON] (1889) [16]. It has also been reported that hispidin has anticancer, antibacterial, and hypoglycemic regulatory functions [16; 17; 18; 19]. Recently, [PERSON] et al. demonstrated that hispidin can inhibit the macrophage-mediated inflammatory response by downregulating NF-\(\kappa\)B activation [20]. Therefore, hispidin itself is also a raw material that can be used in cosmetics. It has a superior effect compared to the existing method of absorbing raw materials through the skin by increasing the skin permeability using a micro epidermal delivery system. Antibacterial patches, whitening patches, wrinkle improvement patches, etc. can be applied using this. However, the effects of hispidin on lipopolysaccharide-induced macrophage reactive oxygen species (ROS) levels, phagocytosis, and cytokine production, as well as its molecular signaling mechanisms, remain unclear [13]. Herein, we developed a polylactic acid (PLA) and polycaprolactone (PCL) MN drug delivery system for hispidin. PLA and PCL were blended for high strength and effective skin permeability. On the casted PLA/PCL layer, a delivery layer was coated with PLA/PCL and hispidin. Blended PLA and PCL were optimized and compared with single-layer-coated hispidin; the skin permeability of the composite delivery PLA/PCL layer was measured. It was confirmed that no single or mixed substance was cytotoxic.