Quantification methods comparing in vitro and in vivo percutaneous permeation by microneedles and passive diffusion.

Microneedles (MNs) are needles with a tip diameter ranging from 10 to 100 um and a length ranging up to 1 mm. The first patent for drug delivery device for percutaneous administration filed by Alza corporation dates back to 1976 (Gerstel and Place, 1976), and in between 1989 and 2021 the filed patents for MNs are >4500 [1]. These devices can potential overcome some drawbacks of traditional needles, such as the pain generated during insertion, requirement for trained personnel to manipulate syringes, and difficulty of performing injections in elderly and obese patients. MNs and MN arrays are emerging as a convenient method to deliver compounds and extract blood without causing any pain. A promising application is the use of MNs as alternative solution to topical creams (TC) and transdermal patches (TP) for transdermal drug delivery. The external layer of human skin, the epidermis, offers a major barrier to transdermal drug delivery, thanks to the stratum corneum (SC). Exposed to the external environment, SC ultimately protects the human body from UV light radiation, heat, water loss, bacteria, fungi and viruses, and it is the barrier that controls diffusion rate for almost all compounds. TC and TP applications are limited by the skin permeability to lipophilic compounds and small molecules, and by the slow delivery rate of some compounds. MNs have been around for >35 year now, and it is a general opinion that MNs increase delivery compared to passive diffusion, thanks to the feature of penetrating the SC and reaching the dermis. This review recollects the existing studies that compare MN delivery of drugs with passive diffusion of the same drugs in alive organisms, giving an overview of what are the type of MNs, the chemical delivered and the methods employed to quantify drug delivery into skin and/or in the bloodstream. The final aim is to quantify the enhancement factor of MNs with respect to passive diffusion, and establish a possible standard on how tests can be performed in order to compare different data.