Deferasirox Nanosuspension Loaded Dissolving Microneedles for Intradermal Delivery

Abstract

Microneedles are minimally invasive systems that can deliver drugs intradermally without pain and bleeding and can advantageously replace the hypodermal needles and oral routes of delivery. Deferasirox (DFS) is an iron chelator employed in several ailments where iron overload plays an important role in disease manifestation. In this study, DFS was formulated into a nanosuspension (NSs) through wet media milling employing PVA as a stabilizer and successfully loaded in polymeric dissolving microneedles (DMNs). The release studies for DFS-NS clearly showed a threefold increased dissolution rate compared to pure DFS. The mechanical characterization of DFS-NS-DMNs revealed that the system was sufficiently strong for efficacious skin penetration. Optical coherence tomography images confirmed an insertion of up to 378 µm into full-thickness porcine skin layers. The skin deposition studies showed 60% drug deposition from NS-DMN, which was much higher than from the DFS-NS transdermal patch (DFS-NS-TP) (without needles) or pure DFS-DMNs. Moreover, DFS-NS without DMNs did not deposit well inside the skin, indicating that DMNs played an important role in effectively delivering drugs inside the skin. Therefore, it is evident from the findings that loading DFS-NS into novel DMN devices can effectively deliver DFS transdermally.

Keywords: deferasirox; dissolving microneedles; intradermal delivery; nanocrystals; nanosuspension.

Figure 1

Schematic representation of the fabrication of the DFS-NS.

Figure 2

Schematic representation of the fabrication of DFS-NS DMNs and their application.

Figure 3

Particle size and PDI at 6, 12, 24, 48 h of milling and RD after freeze-drying at (A) 1000 rpm and 1500 rpm milling speed expressed as means + SDs, n = 3. (B) Differential scanning calorimetry thermogram of PVA, physical mixture of DFS and PVA, DFS-NS and DFS, (C) Powder X-ray diffraction of plain DFS, PVA, physical mixture of DFS and PVA and DF-NS, (D) Fourier transform infrared analysis of DFS, PVA, and DFS-NS. (E) In vitro release profile of DFS-NS and pure DFS by employing dialysis membrane and PBS as release media, expressed as the means ± SDs, n = 3.

Figure 4

(A–C) Digital images of DFS-NS-DMNs at different magnifications. (D–F) SEM images of DFS-NS-DMNs. (G) The percentage of holes created in Parafilm M^® layers and the corresponding approximate insertion depth. Mechanical strength determination of DMNs by a texture analyzer by applying a force of 32 N for 30 s (mean ± SD, n = 6). (H) Mean height reduction of DFS-NS-DMNs, (I) Mean height reduction of DFS-DMNs.

Figure 5

Mechanical strength determination of DMNs by a texture analyzer by applying a force of 32 N for 30 s (mean ± SD, n = 6). (A) Heights of DFS-NS-DMNs before compression; (B) Heights of DFS-NS-DMNs after compression; (C) Heights of DFS-DMNs before compression; (D) Heights of DFS-DMNs after compression.

Figure 6

Scanning electron micrographs of (A) DFS crystals, (B) freeze-dried DFS-NS before DMN loading, and (C) magnified image of DFS-NS embedded into the DMN tips.

Figure 7

Dissolution study of DFS-NS-DMNs after insertion into excised porcine skin. Images taken after (A) 10 min of insertion, (B) 15 min of insertion, (C) 30 min of insertion, and (D) 60 min of insertion. Digital and OCT images of DFS-NS-DMNs; (E,F) DFS-NS-DMNS inserted in parafilm layers, (G,H) DFS-NS-DMNs inserted into excised porcine skin. (I) DFS deposited in excised porcine skin following the insertion of DFS-NS, DFS-DMNs, DFS-NS-DMNs, and DFS-NS-TP (without needles). Data are expressed as the mean ± SD, n = 3.