Formulation and optimization of ivermectin nanocrystals for enhanced topical delivery

Abstract

The increasing resistance to antiparasitic drugs and limited availability of new agents highlight the need to improve the efficacy of existing treatments. Ivermectin (IVM) is commonly used for parasite treatment in humans and animals, however its efficacy is not optimal and the emergence of IVM-resistant parasites presents a challenge. In this context, the physico-chemical characteristics of IVM were modified by nanocrystallization to improve its equilibrium water-solubility and skin penetration, potentially improving its therapeutic effectiveness when applied topically. IVM-nanocrystals (IVM-NC) were prepared using microfluidization technique. The impact of several process/formulation variables on IVM-NC characteristics were studied using D-optimal statistical design. The optimized formulation was further lyophilized and evaluated using several in vitro and ex vivo tests. The optimal IVM-NC produced monodisperse particles with average diameter of 186 nm and polydispersity index of 0.4. In vitro results showed an impressive 730-fold increase in the equilibrium solubility and substantial 24-fold increase in dissolution rate. Ex vivo permeation study using pig's ear skin demonstrated 3-fold increase in dermal deposition of IVM-NC. Additionally, lyophilized IVM-NC was integrated into topical cream, and the resulting drug release profile was superior compared to that of the marketed product. Overall, IVM-NC presents a promising approach to improving the effectiveness of topically applied IVM in treating local parasitic infections.

Keywords: Antiparasitic; Dermal drug delivery; Ivermectin; Nanocrystal; Quality by design (QBD); Skin.

Graphical abstract

Fig. 1

Response surface plots for the effects of IVM concentration (IVM Conc.) and stabilizer to drug ratio (S:IVM Ratio) on PS with processing for different number of microfluidization cycles using PVA, SDS and Tween® 80 as stabilizers.

Fig. 2

Response surface plots for the effects of IVM concentration (IVM Conc.) and stabilizer to drug ratio (S:IVM Ratio) on PDI with processing for different number of microfluidization cycles using PVA, SDS and Tween® 80 as stabilizers.

Fig. 3

Response surface plots for the effects of IVM concentration (IVM Conc.) and stabilizer to drug ratio (S:IVM Ratio) on ZP with processing for different number of microfluidization cycles using PVA, SDS and Tween® 80 as stabilizers.

Fig. 4

Response surface plots of the desirability values and the optimum levels of the studied factors used in the optimization of IVM-NC using SDS as stabilizer.

Fig. 5

Equilibrium solubility of IVM-NC-L, IVM-SDS-PM (1:4), IVM-PVA-PM (1:4), and IVM-RM in acetate buffer (pH = 5.5) at 25 °C (n = 3). * P < 0.0001.

Fig. 6

In vitro dissolution profiles of IVM-NC-L, IVM-SDS-PM and IVM-RM in acetate buffer (pH = 5.5) at 32 °C (n = 3).

Fig. 7

XRD spectra of IVM-RM, SDS, IVM-SDS-PM (1:4) and IVM-NC-L.

Fig. 8

TEM micrographs and DLS spectra of IVM-NC-S (A and B) and IVM-NC-L (C and D), and SEM micrograph of IVM-RM (E).

Fig. 9

Stability results for (A) PS, (B) PDI and (C) ZP for IVM-NC-S and IVM-NC-L under 25 °C/ 60 %RH and 5 ± 3 °C.

Fig. 10

Ex vivo permeation profiles of IVM-NC-S (untreated and treated skin) and IVM solution (acetonitrile in water, 3.5:6.5) through pig ear skin at 32 °C (n = 2).

Fig. 11

The percentage of IVM permeated, residing in the donor chamber, and retained in the skin (estimated) of IVM-NC-S (untreated and treated skin) and IVM solution (acetonitrile in water, 3.5:6.5) through pig ear skin at 32 °C (n = 2).

Fig. 12

In vitro release profiles of IVM from IVM-NC cream and Soolantra Cream in PBS (pH = 7.4) at 32 °C (n = 3).