(M1130-02-08) The Development and Characterization of Nanocrystal-Loaded Dissolving Microarray Patches for Transdermal Atorvastatin Delivery

Purpose: Nanoparticles have been widely used in the delivery of many conventional drugs, proteins, vaccines and nucleotides [1]. Nanocrystals (NCs) can be fabricated using scalable techniques, which renders them suitable for industrial manufacture. NCs are crystalline drug particles, possessing sizes within the nanometer range. They are derived from the therapeutic agent itself, meaning that their drug content is higher than that of other nanoparticle systems and could reach 100% [2]. Herein, a lab-scale wet bead-milling technique was used, for the first time, to prepare ATR NCs. This method was selected due to its simplicity and reproducibility, especially that most NCs products in the market were fabricated using wet-milling technique [3].

Methods: NCs were prepared using a wet bead-milling technique as detailed in Figure 1. A bilayer casting method was used to prepare the NC-loaded dissolving MAPs (D-MAPs). The first layer was comprised of ATR NCs in water at 3500 rpm for 3 mins (Figure 1). The second layer was made from hydrogel blends containing PVP 360 kDa, glycerol and water. The amount of ATR in each D-MAP was quantified, and the mechanical properties were evaluated. Ex vivo skin deposition studies were then conducted using Franz cells and full thickness excised neonatal porcine skin to quantify the amount of ATR delivered ex vivo.

Results: NCs were shown to possess sizes between 150-250 nm. When loaded into D-MAPs, each MAP contained approximately 2.4 mg of ATR. Thermal analysis, FTIR and PXRD studies were used to characterize NCs. Ex vivo skin deposition studies using Franz cells showed that a mean of 0.75 ± 0.1 mg ATR was extracted from the skin and 0.2 ± 0.06 mg from the receiver compartment. This translates to approximately 0.89 ± 0.12 mg ATR delivered into both compartment, which resembles 38.42 ± 5.13% of the initial ATR loaded into D-MAPs.

Conclusion: A lab-scale wet bead-milling technique was successfully used to produce ATR NCs within 150-250 nm size. ATR NCs were successfully incorporated into D-MAPs in an easy two step casting method. NCs D-MAPs could successfully deliver 0.75 mg of ATR/75 cm² patch across porcine skin. This proves the system’s ability to successfully facilitate the transdermal delivery and deposition of the hydrophobic drug ATR across the skin, and shows potential for the transdermal delivery of other hydrophobic compounds in the future. Future in vivo studies can investigate their efficacy in the sustained delivery of ATR.

References: 1. Parveen, S., R. Misra, and S.K. Sahoo, Nanoparticles: A boon to drug delivery, therapeutics, diagnostics and imaging. Nanomedicine, 2012. 8(2): p. 147-66.
2. Paredes, A.J., et al., Microarray patches: Poking a hole in the challenges faced when delivering poorly soluble drugs. Advanced Functional Materials, 2021. 31(1): p. 2005792.
3. Kulkarni, S.A. and A.S. Myerson, Methods for nano-crystals preparation, in Engineering Crystallography: From Molecule to Crystal to Functional Form 2017. p. 275-287.

Figure 1. Schematic representation showing the fabrication of ATR NCs, and their incorporation into dissolving MAPs.

Figure 2. Differential scanning calorimetry (DSC) (A), Thermogravimetric analysis (TGA) (B), Powder X-Ray diffraction (PXRD) (C), and Fourier transform infrared spectroscopy (FTIR) spectra (D) of ATR powder, NCs of choice, and all the other excipients.