Droplette‐ A Fluid Dynamics Driven Platform for Transdermal and Intra‐Cellular Delivery of Large Molecules
Authors: Mahmood Abuzar , Raja Ahmad , Pulakat Lakshmi 
Published: November 2023

In the United States, chronic wounds affect 5.7 million patients and cost an estimated 20 billion dollars annually. Effective delivery of therapeutics for dermal conditions are often limited by transdermal absorption (upper limit 500DA) while systemic delivery causes side effects including vital organ damage or even death. Therefore, the development of painless, low‐pressure transdermal delivery systems that can cover large surface areas and effectively deliver drugs within a critical size range (500–800DA) is an important need for patients suffering from chronic wounds.Novopyxis INC developed Droplette, a novel transdermal delivery system that generates an enhanced aerosol in a turbulent‐transitional flow regime (Weber number ~2.4) containing sub‐micron droplets that can effectively and painlessly penetrate a surface area of skin. Their qualitative comparison of the force generated as well as the spray pattern of fluids passed through Droplette compared to a commercial aerosol and topical application showed that Droplette created a tight circular spray pattern that had both increased intensity and a cross‐sectional diameter approximately half that of a standard aerosol.We investigated the utility and efficacy of Droplette in delivering a wound healing peptide, NP‐6A4 or saline into open wounds of Zucker lean (ZL) rats. NP‐6A4 is a 784DA peptide that activates Angiotensin II type 2 receptor AT2R and promotes wound healing. Droplette delivery of NP‐6A4 improved wound healing by about 3 fold compared to saline (n=3 rats, 6 wounds per group; p<0.05) indicating that a) NP‐6A4 could promote wound healing and b) Droplette delivery did not inactivate this peptide. MALDI‐TOF mass spectrometry of NP‐6A4 samples showed that the most abundant peptide peak in NP‐6A4 before and after passing through Droplette was 768.3 Da indicating that Droplette did not induce any significant degradation of the agonist. Additionally, Droplette could deliver a pMIR‐GFP expression vector (7.741 Kb or 5.15 MDa) into mammalian cells and epi‐ocular tissue (MatTek). DNA size was not altered after passing through Droplette and pMIR‐GFP retained its ability to express GFP after being passed through Droplette. Importantly, GFP expression was detected in the inner layers of the 8‐layer thick epi‐ocular tissue. These data suggest that macromolecules (protein or DNA) ranging in size from 780 Da up to 5.15 MDa can be passed through Droplette and delivered to inner layers of tissue while retaining their biological function.We conclude that Droplette, which is capable of generating an enhanced aerosol in a turbulent‐transitional flow regime (Weber number ~2.4) containing sub‐micron droplets, is efficient in delivering very high molecular weight compounds. This ability of Droplette makes it a unique and novel tool for efficient and painless transdermal delivery of high molecular weight therapeutic molecules.Support or Funding InformationThis work was supported by NIH grant 1R01HL118376‐01 (LP), a small grant from Novopyxis Inc (LP), and Research Services facilities of HSTMVH.