• Elvang, Philipp Alexander
• Jacobsen, Ann-Christin
• Brandl, Martin

Abstract

Phospholipid-based oral formulations are generally regarded advantageous for poorly soluble drugs, potentially increasing solubility, permeability and bioavailability, although translation of solubility enhancement into permeability/bioavailability enhancement is not straightforward [1]. Solid phospholipid dispersions (SPDs) are especially promising in oral applications. A recent study indicates that the enhancing effect of SPDs can be ascribed to two mechanisms: 1. Encapsulation of the drug into colloids after hydration and 2. Amorphization of the drug induced by the preparation method and stabilized by the phospholipid (PL) matrix [2].The permeation behavior of celecoxib (CXB) (BCS class II) formulated as either mono- or diacyl based SPDs was studied using a side-by-side diffusion set-up employing Permeapad® as artificial, biomimetic diffusion barrier. To this end CXB SPDs with various ratios of CXB to PL (phosphatidylcholine (PC) or lyso-phosphatidylcholine) were prepared by freeze-drying from a tert-butanol co-solvent system. To investigate the impact of intestinal fluids, permeation studies were carried out both, in presence or absence of fasted state simulated intestinal fluid (FaSSIF). In an attempt to elucidate supramolecular structures, the colloidal phases formed by dispersing CXB SPDs were studied utilizing the combined technique of asymmetrical flow field-flow fractionation (AF4) connected to static light scattering instrumentation i.e. multi-angle laser light scattering (MALLS).CXB permeation was found significantly changed when formulated as SPD with varying CXB to PL ratios compared to the pure (crystalline) drug. Generally, a permeation-enhancing effect was seen with higher CXB/PL-ratios, irrespective of the type of PL used (mono- vs. diacyl). But, no direct correlation between the amount of PL used and permeation enhancement was observed highlighting the complex interplay between the two enhancing mechanisms of SPDs. The presence of FaSSIF had a significant influence on CXB permeation for CXB SPDs with a low PC content. AF4/MALLS analysis of mono- or diacyl based CXB SPDs dispersed in buffer or FaSSIF revealed not more than two distinct particle fractions in all cases. The question, how differences in supramolecular structures influence the permeation of CXB was not fully resolved, but important hints were obtained on how future research activities should be designed to yield a better insight into this highly complex scenario.References: [1] Fong, S. Y. K., Brandl, M. & Bauer-Brandl, A. 2015. Phospholipid-based solid drug formulations for oral bioavailability enhancement: A meta-analysis. European Journal of Pharmaceutical Sciences, 80, 89-110. [2] Fong, S.Y.K., Martins, S.M., Brandl, M., Bauer-Brandl, A. 2016. Solid Phospholipid Dispersions for Oral Delivery of Poorly Soluble Drugs: Investigation into Celecoxib Incorporation and Solubility-In Vitro Permeability Enhancement. Journal of Pharmaceutical Sciences, 105 (3), pp. 1113-1123.DOI: 10.1016/S0022-3549(15)00186-0

Topics

• impedance spectroscopy
• dispersion
• phase
• permeability
• drying
• laser light scattering
• field-flow fractionation
• static light scattering