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

Abstract

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.

Nature‐Inspired Design and Application of Lipidic Lyotropic Liquid Crystals

“…Inspired by this process, the enzymatic formation of the bicontinuous V 2 cubic phase in the gastrointestinal tract using a rationally designed precursor digestible emulsion formulation has also been shown, as illustrated schematically in Figure . The putative formation of the cubic phase in vivo provided a very slow release behavior allowing absorption to occur over several days (compared to several hours for the drug alone) leading to very high bioavailability . It was shown in this and related studies that the formation of lipid mesophases led to prolonged retention in the stomach for an extended period of time, up to several days, and when a very poorly soluble drug was incorporated into the lipid system, solubility in the gastric fluid was the limiting factor dictating release.…”

“…They can be dispersed as internally mesostructured particles suitable for intravenous, mucosal, or topical skin delivery systems or as an oral medication in a capsule format . Spray‐ dried particles may also be prepared and made into a solid tablet dose form.…”

“…The pharmacokinetics of the easy‐to‐prepare emulsion system reflects that of cubic phase particles prepared from phytantriol alone which are problematic to prepare and stabilize. Reproduced with permission . Copyright 2016, American Chemical Society.…”

Self‐Assembled Nanostructured Lipid Systems: Is There a Link between Structure and Cytotoxicity?

“…To date, there is still lack of documentation on the short‐ and long‐term biosafety of nanostructured LLC systems. A myriad of in vivo investigations have mostly focused on the biopharmaceutical performances of LLC materials in terms of improved oral or topical drug pharmacokinetics; controlled subcutaneous therapeutics via stimuli‐responsive release; as well as enhanced vaccination via systemic potentiation of immunogenic responses . Biosafety profiling of these exotic LLC nanoparticles, which is of paramount importance to their clinical translation, seems to be either underexplored or undisclosed.…”

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

“…Previous studies with these lipids have typically had drug in solution in the lipid which resulted in T max values of 33.0 ± 5.0 and 23.5 ± 5.9 h, respectively [10]. However, one study incorporated gold nanoparticles in PHY that were also retained in the stomach for extended periods (> 8 h) compared with a digestible lipid system when measured by X-ray computer tomographic imaging [25]. Thus it is not unexpected that a suspension of drug in these lipids is also likely to be retained for an extended period of time in the stomach.…”