Sustained absorption of delamanid from lipid-based formulations as a path to reduced frequency of administration

Abstract

Delamanid is a poorly water-soluble drug currently being used for the treatment of tuberculosis. The high frequency of dosing leads to poor adherence for patients who live in lower economic and nomadic populations. Non-digestible self-assembling lipids as a formulation approach for poorly water-soluble drugs have previously been shown to extend the window of absorption through gastric retention. We hypothesise that this approach could lead to the reduction of dosing frequency for delamanid and thereby has potential to improve adherence. Formulations of delamanid were prepared in selachyl alcohol and phytantriol as non-digestible self-assembling lipid vehicles, and their behaviour was compared with reconstituted milk powder, as a digestible lipid-based formulation, and an aqueous suspension. The self-assembly of selachyl alcohol and phytantriol in aqueous media in the presence of delamanid was studied using small angle X-ray scattering and produced the inverse hexagonal (H2) and inverse bicontinuous cubic (V2) liquid crystal structures, respectively. The times at which maximum delamanid levels in plasma were observed (Tmax) after oral administration of the phytantriol, selachyl alcohol and reconstituted milk powder formulations of delamanid to rats were 27 ± 3, 20 ± 4 and 6.5 ± 1.0 h, respectively, compared with the aqueous suspension formulation with a Tmax of 3.4 ± 1 h, which confirms the hypothesis of an extended duration of absorption after administration in non-digestible self-assembling lipids. The digestion products of the triglycerides in the milk formulation increased the solubilisation of delamanid in the gastrointestinal tract, leading to an increase in exposure compared with the aqueous suspension formulation but did not significantly extend Tmax. Overall, the non-digestible nanostructured lipid formulations extended the duration of absorption of delamanid well beyond that from milk or suspension formulations.

Nanosized Drug Delivery Systems to Fight Tuberculosis

“…Here, we show two relevant examples. In 2021, Ramirez et al loaded DLM onto nanostructures made of self-assembling lipids, selachyl alcohol and phytantriol [ 143 ]. These lipids formed liquid crystals endowed with high drug-loading capacities, and the ability to achieve controlled release ( Figure 14 ).…”

“… Concentrations of delamanid in plasma following oral administration to mice in aqueous saline suspension and through lipid-based formulations (phytantriol, selachyl alcohol and milk) over 96 h. n = 4. Adapted from reference [ 143 ], used under Creative Commons BY 4.0 license. …”

Advances of new drugs bedaquiline and delamanid in the treatment of multi-drug resistant tuberculosis in children

“…To improve the effectiveness of delamanid, it may be necessary to increase food intake or employ other measures such as liposomal formulations or co-administration with other drugs to ensure its effective delivery and absorption into the body. In a study aimed at optimizing the route of administration, an indigestible nanostructured lipid formulation was found to absorb duration of delamanid, outperforming milk or suspension formulations ( Ramirez et al., 2021 ). This finding could be beneficial in reducing treatment costs for patients in low-income regions by reducing the number of doses required for successful outcomes.…”