Abstract

Variable and low oral bioavailability (4-11%) of lumefantrine (LUF), an anti-malarial agent, is characterized by very low solubility in aqueous vehicle. Thus, the present study was intended to formulate lyophilized nanosuspensions of LUF to resolve its solubility issues for the improvement of oral bioavailability. A three level 3² factorial design was applied to analyze the influence of independent variables, concentration of polysorbate 80 (X₁) and sonication time (X₂) on the responses for dependent variables, particle size (Y₁) and time to 90% release of LUF (t₉₀) (Y₂). Optimized formulation (F3) has shown to possess lowest particle size (95.34 nm) with minimum t₉₀ value (⁓3 mins), which was lyophilized to obtain the dry powder form of the nanosuspension. The characterization parameters confirmed the amorphous form of LUF with good stability and no chemical interactions of the drug with the incorporated components. Further, saturation solubility study revealed increased solubility of the LUF nanosuspension (1670 µg/mL) when compared to the pure drug (212.33 µg/mL). Further, rate of dissolution of LUF from the nanosuspension formulations were found to be significantly (p < 0.05) higher when compared to the pure drug. Fabricated lyophilized nanosuspension was found to be stable at 25 ± 2 °C/60 ± 5% RH and 40 ± 2 °C/75 ± 5% RH for the duration of three months. In conclusion, lyophilized nanosuspension showed ∼8-folds increase in drug release, which indicated a better way to offer higher release of LUF in controlling malaria.

摘要

苯芴醇 (LUF) 是一种抗疟药，具有可变且低的口服生物利用度 (4-11%)，其特征在于在水性载体中的溶解度非常低。因此，本研究旨在配制 LUF 的冻干纳米混悬液，以解决其溶解度问题，以提高口服生物利用度。应用三水平 3 ²因子设计来分析自变量、聚山梨醇酯 80 的浓度 (X ₁ ) 和超声处理时间 (X ₂ ) 对因变量、粒度 (Y ₁ ) 和达到 90% 的时间的响应的影响LUF (t ₉₀ ) (Y ₂ ) 的释放。优化的配方 (F3) 已显示出具有最低粒径 (95.34 nm) 和最小 t ₉₀值（⁓3 分钟），将其冻干以获得纳米悬浮液的干粉形式。表征参数证实了 LUF 的无定形形式，具有良好的稳定性，并且药物与掺入的成分没有化学相互作用。此外，饱和溶解度研究表明，与纯药物 (212.33 µg/mL) 相比，LUF 纳米混悬液 (1670 µg/mL) 的溶解度增加。此外，发现 LUF 从纳米混悬剂制剂中的溶解速率显着（p < 0.05) 与纯药物相比更高。发现制造的冻干纳米混悬液在 25 ± 2 °C/60 ± 5% RH 和 40 ± 2 °C/75 ± 5% RH 下稳定三个月。总之，冻干纳米混悬剂的药物释放增加了约 8 倍，这表明在控制疟疾方面提供更高的 LUF 释放的更好方法。