Phospholipid Research Center

Synthetic symmetric single-chain bolalipids (SSCBs) are of interest as new pharmaceutical excipients and might offer new prospects to modulate dermal drug delivery. In contrast to classic anionic surfactants and conventional amphiphilic phospholipids, they have been found to hinder drug penetration of charged permeants into the skin rather than acting as enhancers. However, since only a limited number of permeants have been investigated to date and the underlying mechanism is still unknown, this study aims to investigate the effect of two SSCBs with different alkyl chain length, PC-C24-PC and PC-C32-PC, on ex vivo skin permeation/penetration of an uncharged hydrophilic drug, caffeine, using diffusion cells with dermatomed porcine ear skin as membrane and a quantitative confocal Raman spectroscopy (CRS) approach. In addition, both CRS and attenuated total reflection FTIR spectroscopy (ATR-FTIR) were used to evaluate the effect of the SSCBs on stratum corneum (SC) proteins and the lipid matrix. A novel method was also employed using atomic force microscopy (AFM) to visualize potential SSCB effects on corneocyte surface morphology. Results showed that SSCBs (5 % w/w) reduced skin permeation of caffeine through dermatomed porcine ear skin in comparison to water and 5 % w/w sodium dodecyl sulfate (SDS) solutions as comparator vehicles. Quantitative CRS confirmed these observations. ATR-FTIR studies demonstrated the presence of SSCBs within the SC surface and indicated effects on SC lipid order and protein conformation. AFM revealed trends towards altered corneocyte surface topography after surfactant treatment when compared to the effect of water as solvent. In conclusion, while SSCB formulations interacted with the SC, they did not promote the penetration of caffeine into deeper layers of the epidermis.

By direct deposition of the drug at the local site of action, injectable depot formulations – intended for treatment of a local disease or for local intervention – are designed to limit the immediate exposure of the active principle at a systemic level and to reduce the frequency of administration. To overcome known drawbacks in the production of some marketed phospholipid-based depots, here we propose to manufacture drug-loaded negatively charged liposomes through conventional technologies and to control their aggregation mixing a solution of divalent cations prior to administration. We identified phosphatidylglycerol (PG) as the most suitable phospholipid for controlled aggregation of the liposomes and to modulate the release of the anesthetic bupivacaine (BUP) from liposomal depots. In vivo imaging of the fluorescently-labelled liposomes showed a significantly higher retention of the PG liposomes at the injection site with respect to zwitterionic ones. In situ mixing of PG liposomes with calcium salts significantly extended the area under the curve of BUP in plasma compared to the non-depot system. Overall, controlling the aggregation of negatively charged liposomes with divalent cations not only modulated the particle clearance from the injection site but also the release in vivo of a small amphipathic drug such as BUP.

Abstract The properties and use of liquid non‐aqueous phospholipid concentrates (NAPC) are reviewed. They are mainly used to solubilize poorly water‐soluble drug substances to enhance their oral bioavailability, but they also find applicability in dietetics and cosmetics. Due to the large‐scale availability of these concentrates at good manufacturing practice quality including Drug Master File (DMF) documentation, they can be used for pre‐clinical screening and clinical testing and as market form, as demonstrated by the product of Wyeth/Pfizer, Rapamune, enabling a cost effective and fast dosage form development. When needed, NAPC can be converted to solid dosage forms by means of a capsule fill or addition of adsorbing excipients. It is concluded that NAPC deserve more attention and a broader use in the life science industry.Practical Applications: NAPCs are suitable as pre‐clinical formulation vehicle for screening of the oral bioavailability of poorly water‐soluble compounds. The same formulation can be used for clinical testing and market introduction, allowing a fast track dosage form development. When needed NAPC can be converted to solid dosage forms. NAPC have also applicability in dietetics and cosmetics to solubilize poorly water‐soluble compounds.