Publications
Pham, A. C., Hong, L., Montagnat, O., Nowell, C. J., Nguyen, T. H., & Boyd, B. J. (2016). In Vivo Formation of Cubic Phase in Situ after Oral Administration of Cubic Phase Precursor Formulation Provides Long Duration Gastric Retention and Absorption for Poorly Water-Soluble Drugs. Molecular pharmaceutics, 13(1), 280–286. https://doi.org/10.1021/acs.molpharmaceut.5b00784
Anna C. Pham — ACS Publications — 2015-12-15
Summary: Pham et al. (2016) demonstrated that an oral lipid precursor formulation comprising phytantriol and tributyrin (85:15, w/w) formed liquid-crystalline structures in vivo, resulting in prolonged gastric retention and sustained absorption of cinnarizine in rats. Cinnarizine was administered orally at 2.1 mg/kg in 300 mg of lipid formulation. The study provided proof-of-concept that self-assembling lipid systems can enhance the duration of drug exposure and may support the development of extended-release oral formulations for poorly water-soluble drugs.
Lipid-based liquid crystalline systems based on the combination of digestible and nondigestible lipids have been proposed as potential sustained release delivery systems for oral delivery of poorly water-soluble drugs. The potential for cubic phase liquid crystal formation to induce dramatically extended gastric retention in vivo has been shown previously to strongly influence the resulting pharmacokinetics of incorporated drug. In vitro studies showing the in situ formation of cubic phase from a disordered precursor comprising a mixture of digestible and nondigestible lipids under enzymatic digestion have also recently been reported. Combining both concepts, here we show the potential for such systems to form in vivo, increasing gastric retention, and providing a sustained release effect for a model poorly water-soluble drug cinnarizine. A mixture of phytantriol and tributyrin at an 85:15 mass ratio, shown previously to form cubic phase under the influence of digestion, induced a similar pharmacokinetic profile to that in the absence of tributyrin, but completely different from tributyrin alone. The gastric retention of the formulation, assessed using micro-X-ray CT imaging, was also consistent with the pharmacokinetic behavior, where phytantriol alone and with 15% tributyrin was greater than that of tributyrin in the absence of phytantriol. Thus, the concept of precursor lipid systems that form cubic phase in situ during digestion in vivo has been demonstrated and opens new opportunities for sustained release of poorly water-soluble drugs.
Ramirez G, Pham AC, Clulow AJ, Salim M, Hawley A, Boyd BJ. Sustained absorption of delamanid from lipid-based formulations as a path to reduced frequency of administration. Drug Deliv Transl Res. 2021;11(3):1236-1244. doi:10.1007/s13346-020-00851-z
Gisela Ramirez — Drug Delivery and Translational Research
Summary: The study demonstrated that incorporating delamanid into the non-digestible lipids phytantriol and selachyl alcohol markedly prolonged drug absorption in rats compared with an aqueous suspension. The formulations produced substantially higher systemic exposure, with relative bioavailability reaching 556% and 645%, respectively. However, the work was primarily a pharmacokinetic proof-of-concept, and the authors noted that formal preclinical and clinical safety studies of these formulations remained to be conducted.
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.
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