Research paper Studies on the lipase-induced degradation of lipid-based drug delivery systems. Part II – Investigations on the mechanisms leading to collapse of the lipid structure Martin Schwab a , Cushla M. McGoverin b , Keith C. Gordon b , Gerhard Winter a , Thomas Rades c , Julia Myschik a,⇑ , Clare J. Strachan c a Ludwig-Maximilians-University Munich, Department of Pharmacy, Munich, Germany b Department of Chemistry and MacDiarmid Institute, University of Otago, Dunedin, New Zealand c School of Pharmacy, University of Otago, Dunedin, New Zealand article info Article history: Received 20 July 2012 Accepted in revised form 21 December 2012 Available online xxxx Keywords: Lipid-based depot systems Biodegradation Erosion Extrudates Implants Lipase abstract It has recently been found that lipid composition appears to have a major influence on the rate of lipase- induced degradation of lipid-based extended release drug delivery systems (microparticles, compressed implants and extrudated implants). Previously, we have found that during lipase incubation, depending on the lipid used, lipidic extrudates can lose their physical strength and collapse generating lipid particles in the lm-range. The aim of this study was to characterise the processes leading to collapse of solid lipid- based drug delivery systems during in vitro lipase incubation. Compressed lipid implants were used as model systems. Free fatty acids (FFA) generated in the incubation experiments were derivatised and sub- sequently analysed via reversed phase-HPLC in order to characterise the degradation behaviour of single lipid components (glyceryltrilaurate (D112), glyceryltrimyristate (D114), glyceryltripalmitate (D116) and glyceryltristearate (D118)) used for the preparation of compressed lipid implants. Further, Raman spec- troscopy/microscopy, differential scanning calorimetry, scanning electron and light microscopy were used to investigate the physical and chemical changes in the implants upon lipase incubation. This study revealed that the lipid component D112 plays a major role in the degradation and erosion processes occurring during lipase incubation of lipid implants. The production of D112/lauric acid mixtures, with a melting point below human body temperature, leads to lipid matrices melting and losing their physical integrity. Ó 2013 Elsevier B.V. All rights reserved. 1. Introduction Recently, there has been an increasing interest in parenterally administered lipid-based drug delivery systems for the formula- tion of proteins due to their outstanding performance in stabilising incorporated protein molecules [1,2]. However, there is currently little known about the fate of lipid-based depot devices in the hu- man body. In most of the publications dealing with triglyceride- based drug delivery systems, biodegradation and bioerosion in vivo have not been reported [3,4]. Nevertheless, biodegradation and bioerosion are key to the use of these drug delivery systems. As lipases play a crucial role in the metabolic system by hydrolysing triglycerides to produce free fatty acids (FFAs), which serve as a major source of energy, human lipase activity in the subcutaneous fat tissue and the serum could affect the structure and the stability of lipid-based drug delivery systems [5–7]. In a recent study, we conducted in vitro lipase incubation stud- ies with different lipidic delivery systems (microparticles, com- pressed implants and extrudated implants) and investigated the chemical degradation rate of these systems. We reported that for some of the investigated systems, mainly extrudates, there was a tendency for the samples to disintegrate during lipase incubation resulting in suspended particles in the lm-range [8]. In particular, extrudates containing glyceryltrilaurate (D112) exhibited a higher degree of disintegration upon incubation than those containing tri- glycerides with longer fatty acid chain lengths. In the present study, the physical and chemical degradation behaviours of im- plants prepared from single lipid components (triglycerides with different chain lengths) during incubation have been analysed, as models for drug depot systems. Raman spectroscopy/microscopy, scanning electron microscopy, differential scanning electron microscopy, as well as HPLC analysis have been used to gain in- sight into the physical and chemical mechanisms behind the pro- cess of lipid matrix breakdown. 0939-6411/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejpb.2012.12.023 ⇑ Corresponding author. Ludwig-Maximilians-University Munich, Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Butenandtstr. 5, D- 81377 Munich, Germany. Tel.: +49 89 2180 77024; fax: +49 89 2180 77020. E-mail address: julia.myschik@cup.uni-muenchen.de (J. Myschik). European Journal of Pharmaceutics and Biopharmaceutics xxx (2013) xxx–xxx Contents lists available at SciVerse ScienceDirect European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb Please cite this article in press as: M. Schwab et al., Studies on the lipase-induced degradation of lipid-based drug delivery systems. Part II – Investigations on the mechanisms leading to collapse of the lipid structure, Eur. J. Pharm. Biopharm. (2013), http://dx.doi.org/10.1016/j.ejpb.2012.12.023