Laser-engineered dissolving microneedles for active transdermal delivery of nadroparin calcium

Abstract

There is an urgent need to replace the injection currently used for low molecular weight heparin (LMWH) multidose therapy with a non- or minimally invasive delivery approach. In this study, laser-engineered dissolving microneedle (DMN) arrays fabricated from aqueous blends of 15% w/w poly(methylvinylether-co-maleic anhydride) were used for the first time in active transdermal delivery of the LMWH nadroparin calcium (NC). Importantly, an array loading of 630IU of NC was achieved without compromising the array mechanical strength or drug bioactivity. Application of NC-DMNs to dermatomed human skin (DHS) using the single-step 'poke and release' approach allowed permeation of approximately 10.6% of the total NC load over a 48-h study period. The cumulative amount of NC that permeated DHS at 24h and 48h attained 12.28±4.23IU/cm(2) and 164.84±8.47IU/cm(2), respectively. Skin permeation of NC could be modulated by controlling the DMN array variables, such as MN length and array density as well as application force to meet various clinical requirements including adjustment for body mass and renal function. NC-loaded DMN offers great potential as a relatively low-cost functional delivery system for enhanced transdermal delivery of LMWH and other macromolecules.

Figure 1. SEM images of laser engineered NC DMN arrays, (a) length 400 μm, density 121 MN/array, (b) length 600 μm, density 361 MN/array, (c) length 600 μm, density 196 MN/array, (d) length 600 μm, density 121 MN/array, (e) length 1000 μm, density 121 MN/array. (f) Photoimage of NC DMN array (630 IU of NC/array, length 600 μm, density 121 MN/array).

Figure 2. Influence of NC MN loading on NC in vitro release in PBS, pH 7.4 at 37°C at fixed needle length of 600 μm and density of 121 MN/array.

Error bars represent SD values; with n ≥ 3.

Figure 3. Influence of MN length on NC in vitro release in PBS, pH 7.4 at 37°C at fixed NC loading of 630 IU/array and density of 121 MN/array.

Error bars represent SD values; with n ≥ 3.

Figure 4. Influence of MN density on NC in vitro release in PBS, pH 7.4 at 37°C at fixed NC loading of 630 IU/array and length of 600 μm.

Error bars represent SD values; with n ≥ 3.

Figure 5. Influence of skin model on the in vitro permeation of NC loaded in DMN arrays (630 IU NC/array, 600 μm long and 121 MN/array dense) at 37°C.

Error bars represent SD values; with n≥3. *: P < 0.005.

Figure 6. Influence of NC loading in DMN arrays (600 μm long and 121 MN/array dense) on its in vitro permeation through DHS at 37°C.

Error bars represent SD values; with n≥3.

Figure 7. Influence of MN length on the in vitro permeation of NC loaded in DMN arrays (630 IU NC/array and 121 MN/array dense) through DHS at 37°C.

Error bars represent SD values; with n = 3.

Figure 8. Influence of MN density on the in vitro permeation of NC loaded in DMN arrays (630 IU NC/array and 600 μm long) through DHS at 37°C.

Error bars represent SD values; with n ≥3.

Figure 9. Influence of MN application force on the in vitro permeation of NC loaded in DMN arrays (630 IU NC/array, 600 μm long and 121 MN/array dense) through DHS at 37°C.

Error bars represent SD values; with n≥3.

Figure 10. Microscopic images of NC DMN-treated DHS showing the effect of application mode as visualized by trypan blue staining, (a) manual application, (b) applicator at 4 N/MN array, (c) 7 N/MN array, (d) 11 N/MN array.

Bar scales represent 500 μm.