Capsaicin nanocrystals burdened topical polymeric gel: An encouraging tactic for alleviation of paclitaxel-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is triggered by clinically recommended chemotherapeutics. Topical capsaicin (CAP) is a US-FDA-approved therapeutic entity for the mitigation of CIPN. Besides good skin permeation efficiency, CAP concentration in a topical dermal dosage form must be controlled due to its dose-dependent therapeutic and adverse effects. Therefore, in the present investigation, capsaicin nanocrystals (CAP-NCs) were scaled up using the nanoprecipitation technique. CAP-NCs exhibited 145.4 ± 0.90 nm particle size, 0.254 ± 0.005 polydispersity index (PDI), -17.2 ± 0.80 mV surface charge (ζ), and markedly higher cumulative percentage drug release (85.68 ± 0.89 %) compared to pure CAP (12.56 ± 0.57 %) in 12 h. Later, capsaicin nanocrystals burdened polymeric gel (CAP-NCs-Gel) was characterized using analytical and spectral techniques. Furthermore, CAP-NCs-Gel depicted remarkable textural properties, and desirable viscosity along with ∼2.23-fold enhancement in permeability, ∼1.61-fold augmentation of CAP steady-state flux, and permeability coefficient. Additionally, the in vivo therapeutic efficacy assessment of CAP-NCs-Gel in the paclitaxel-induced peripheral neuropathy (PIPN) demonstrated remarkable improvements in mechanical hyperalgesia, heat hyperalgesia, cold allodynia, and locomotor behavior. Capsaicin nanocrystals burdened polymeric gel once-a-day (CAP-NCs-Gel-OD) and twice-a-day (CAP-NCs-Gel-TD) applications outstandingly diminished the levels of TNF-α (P < 0.0001) and IL-6 (P < 0.01) in the sciatic nerve homogenate in contrast to the positive control group and insignificant difference (P > 0.05) was noticed compared to the normal control group. Correspondingly, significant modulation of oxidative stress biomarkers, and noticeable regeneration of nerve fibers, a typical arrangement of the axon, with preserved intact myelin sheath integrity were professed in sciatic nerve; aimed at diminishing neuroinflammation, oxidative stress, and mitigating nerve damage in PIPN. In conclusion, CAP-NCs-Gel is a top-notch nanotherapeutic for translating into a clinically viable dosage form for treating CIPN.