Progress in Lipid Based Drug Delivery

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Percival Skinner
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1 Drug Research Academy (DRA) Symposium University of Copenhagen Progress in Lipid Based Drug Delivery Date: June 20, 2013 Time: 14:00 17:00 Location: Auditorium A3, Universitetsparken 2 14:00-14:15 Welcome A short overview of current lipid based drug delivery research in Copenhagen Anette Müllertz, University of Copenhagen 14:15-14:50 The Use of Lipids to Develop a Novel Oral Formulation of Amphotericin B Kishor Wasan, University of British Columbia, Canada 14:50-15:25 Selected novel aspects in dispersion and lipolysis of oral selfnanoemulsifying drug formulations Martin Kuentz, University of Applied Sciences Northwest. Switzerland 15:25-15:40 Coffee break 15:40 16:05 Supersaturated self-nanoemulsifying drug delivery systems (super-snedds) - improving the delivery of poorly water-soluble drugs Nicky Thomas, University of Copenhagen 16:05 16:30 In situ formation of drug delivery systems based on lipidic lyotropic liquid crystalline phases Anan Yaghmur, University of Copenhagen 16:30 17:00 Podium Discussion: Future trends, challenges and opportunities in lipid based drug delivery Chaired by Thomas Rades, University of Copenhagen; all speakers

2 The Use of Lipids to Develop a Novel Oral Formulation of Amphotericin B Prof. Kishor Wasan, Ph. D. Faculty of Pharmaceutical Sciences Nanomedicines and Drug Delivery Research Group The University of British Columbia Our laboratory has made significant strides toward the development of a lipidbased amphotericin B formulation for oral administration. Initial data from both cell lines and in vivo research indicate that it is highly efficacious and exhibits low toxicity within the dosage range required in treating diseases such as systemic fungal infections and leishmaniasis. Each year in the Indian subcontinent alone, over 500,000 individuals play host to Leishmania donovani, an insidious parasite that invades macrophages, rapidly infiltrates the vital organs and ultimately leads to severe infection of the visceral reticuloendothelial system. Visceral leishmaniasis, also known as Kala-azar, is most prevalent in the weak and the young within a population. Left untreated, almost all infected individuals will die. The therapeutic arsenal against Leishmania is limited to a small number of parenterally administered agents, with daily injections of pentavalent antimony compound for 28 days being the usual course of action. Due to increasing resistance, antimonial drugs can no longer be used in many areas, including northeastern India where the incidence of Kala-azar is highest. Amphotericin B is the current secondary treatment of choice against leishmaniasis and has a 97% cure rate with no reported resistance. However, therapy with the first-generation formulation (FungizoneR) involves IV administration over a period of 30 to 40 days and is associated with infusion and drug-related side-effects (infection of the indwelling catheter, patient chills and shaking due to RBC haemolysis, dose-dependent renal toxicity, fever, bone pain, thrombophlebitis). Although lipid-based second-generation formulations exist (AbelcetR and AmBisomeR), which require a shorter course of therapy (3-5 days), are highly effective and exhibit lower toxicity when compared to FungizoneR, the cost of these formulations is a barrier to widespread use. Due to the difficult route of drug administration, toxicity issues and cost, amphotericin B is failing to reach the infected population and mortality rates continue to rise. The development of an inexpensive, safe and effective oral treatment is paramount in order to address both early and late stages of this deadly disease and drug-resistant forms of VL. This talk will highlight our current findings and future goals. Professor, Associate Dean of Research and Distinguished University Scholar, University of British Columbia CIHR/iCo Therapeutics Research Chair In Drug Delivery For Neglected Global Diseases Director and Co-Founder, Neglected Global Diseases Initiative (NGDI-UBC).

3 Dr. Kishor M. Wasan has been a faculty member at the University of British Columbia for 18 years, during which time he has published over 210 peerreviewed articles and 260 abstracts in the area of lipid-based drug delivery and lipoprotein-drug interactions. His work was recently highlighted in the January 2008 Issue of Nature Reviews, Drug Discovery. Dr. Wasan did his undergraduate degree in Pharmacy at the University of Texas at Austin and his Ph.D. at the University of Texas Medical Center in Houston Texas at MD Anderson Cancer Center in Cellular and Molecular Pharmacology. After completing a postdoctoral fellowship in Cell Biology at the Cleveland Clinic, Dr. Wasan joined the Faculty of Pharmaceutical Sciences at UBC. Dr. Wasan was one of the recipients of the 1993 American Association of Pharmaceutical Scientists (AAPS) Graduate Student Awards for Excellence in Graduate Research in Drug Delivery, the 2001 AAPS New Investigator Award/Grant in Pharmaceutics and Pharmaceutics Technologies, the 2002 Association of Faculties of Pharmacy of Canada New Investigator Research Award and recently was named an AAPS fellow in In addition, Dr. Wasan was awarded a Canadian Institutes of Health Research University-Industry Research Chair in Pharmaceutical Development ( ), was named a University Distinguished Scholar in April 2004, received the 2007 AAPS Award for Outstanding Research in Lipid-Based Drug Delivery, and received the 2008 AFPC-Pfizer Research Career Award. In April 2009 Dr. Wasan was named CIHR/iCo Therapeutics Research Chair in Drug Delivery for Neglected Global Diseases and on September 30, 2010 Dr. Wasan was named a Fellow of the Canadian Academy of Health Sciences. In May 2011, Dr. Wasan received the Canadian Society of Pharmaceutical Sciences (CSPS) Leadership award for outstanding contributions to Pharmaceutical Sciences in Canada and in June 2013 received the CSPS Fellow Award for significant contributions to science in Canada. Currently Dr. Wasan's research is supported by grants from The Canadian Institutes of Health Research (CIHR), The Natural Sciences and Engineering Research Council of Canada (NSERC) and several Pharmaceutical companies.

Selected novel aspects in dispersion and lipolysis of oral self-nanoemulsifying drug formulations Prof. Martin Kuentz, PhD University of Applied Sciences Northwest.

4 Selected novel aspects in dispersion and lipolysis of oral self-nanoemulsifying drug formulations Prof. Martin Kuentz, PhD University of Applied Sciences Northwest. Switzerland Institute of Pharma Technology Self-nanoemulsifying drug delivery systems are among the most promising formulation technologies to cope with drugs that are biopharmaceutically challenging. Important for the fate of such lipid-based formulations is their dispersion and digestion behavior in the gastro-intestinal tract. In vitro tests mimic these processes and the talk is first emphasizing the physical nature of the evolving nano-dispersions. Focused beam reflectance results are then presented to analyze drug precipitation from surfactant/co-solvent systems. Finally, in vitro lipolysis is considered using inline Raman spectroscopy as monitoring tool. A mathematical model is presented to describe the kinetics of drug precipitation in the course of lipolysis. Relevant insights were obtained into formulation dispersion and digestion and the findings can be integrated into physiologically-based drug absorption models. Martin Kuentz is since 2007 a professor of pharmaceutical technology at the University of Applied Sciences and Arts Northwestern Switzerland. He is leading a research group in the area of Quality by Design of oral dosage forms with a particular focus on oral lipid-based formulations. Prior to his academic assignment, Dr. Kuentz spent almost seven years in pharmaceutical research at F. Hoffmann-La Roche in Basel, where he was a Senior Scientist and had among other functions the role of a global contact person in the area of lipid-based drug delivery systems. Martin Kuentz earned his PhD in 1999 in the group of Prof. Leuenberger at the University of Basel, where he also earlier graduated as a pharmacist in Prof. Kuentz has published more than 50 articles in peer reviewed journals and is a member of the American Association of Pharmaceutical Scientists (AAPS) and of the Arbeitsgemeinschaft der Pharmazeutischen Verfahrenstechnik (APV). Moreover, Professor Dr. Kuentz is member of CISDEM (Catedra Iberoamericana-Suiza de Desarrollo de Medicamentos).

In situ formation of drug delivery systems based on lipidic lyotropic liquid crystalline phases Anan Yaghmur, PhD Faculty of Health and Medical Sciences Department of Pharmacy, University of

5 In situ formation of drug delivery systems based on lipidic lyotropic liquid crystalline phases Anan Yaghmur, PhD Faculty of Health and Medical Sciences Department of Pharmacy, University of Copenhagen In this contribution, the main attention is to present our recent investigations on the in situ formation of highly viscous non-lamellar liquid crystalline phases with sustained release properties. The proposed tolerability of these formulations and potential significant reduction in unwanted toxic effects upon injection, and also the possibility of controlling the release of solubilized drugs make these systems highly attractive for sustained drug release applications. We focus on discussing the structural characterization of these in situ formed depots under conditions mimicking the biological environment and also their drug release properties. We mainly describe the latest developments in using advanced setups of the small-angle X-ray scattering (SAXS) method for these dynamic investigations. The non-lamellar liquid crystalline phases are formed in situ via the self assembly of safe and biocompatible surfactantlike lipids with biological relevance upon direct exposure to excess of aqueous media or biological fluid. The adoption of the highly viscous bicontinuous cubic (V2) and hexagonal (H2) phases, which are attractive - as will be discussed in the meeting - for the formation of stimuli-triggered drug delivery systems, is affected by different factors including the lipid molecular structure, the lipid composition, electrostatic interactions, hydration level, the presence of guest additives, and the applied experimental conditions. Besides covering recent studies on the in situ formation of promising lipidic drug delivery systems with sustained release properties, we aim at briefly presenting our recent studies on the use of nanoparticlulate formulations based on lyotropic liquid crystalline particles (cubosomes and hexosomes) as drug nanocarriers. Anan Yaghmur is associate professor at the Department of Pharmacy, Faculty of Health & Medical Sciences, University of Copenhagen. His research interests are the formulation of drug nanocarriers based on self-assembled systems including lyotropic liquid crystalline particles (cubosomes, hexosomes, micellar cubosomes) and microemulsions. He worked as a young scientist between in Peter Laggner s Laboratory at the Institute of Biophysics and Nanosystems Research (IBN) of the Austrian Academy of Sciences, Graz (Austria). He had also a postdoctoral position between in Otto Glatter s research laboratory at the Chemistry Institute, Karl-Franzens University of Graz (Austria). Anan earned his PhD in applied chemistry under the supervision of Prof. Nissim Garti at The Hebrew University of Jerusalem in His M.Sc. degree was earned also in the same research group in He has published 45 published articles in refereed international scientific journal, 8 book chapters & Proceedings, 1 international patent, and 2 articles of science news for general public. He is serving as a referee for at least 10 prominent journals including Soft Matter, PLoS ONE, PCCP, Chemical Communications, Journal of Physical Chemistry B, and Langmuir.

Supersaturated self-nanoemulsifying drug delivery systems (super-snedds) - improving the delivery of poorly water-soluble drugs Nicky Thomas, PhD Faculty of Health and Medical Sciences Department of

6 Supersaturated self-nanoemulsifying drug delivery systems (super-snedds) - improving the delivery of poorly water-soluble drugs Nicky Thomas, PhD Faculty of Health and Medical Sciences Department of Pharmacy, University of Copenhagen Lipid-based formulations such as self-nanoemulsifying drug delivery systems ( SNEDDS ) have received increased attention during the last years to improve the solubility and bioavailability of the increasing number of pharmaceutically problematic drugs emerging from drug discovery programs. However, the limited solubility of many drugs in SNEDDS has been the major obstacle for the broader utilisation of SNEDDS often requiring inconvenient dosing of multiple units. Nicky Thomas and coworkers have developed novel supersaturated SNEDDS ( super- SNEDDS ) that allowed the dosing of single units as the drug load in the super- SNEDDS was substantially increased compared with conventional SNEDDS. The super-snedds were physically stable and bio-pharmaceutically comparable and, in some cases, superior to conventional SNEDDS. Moreover, the project revealed that a previously valid paradigm required revision when interpreting the results obtained from simulated intestinal digestion of SNEDDS and super-snedds, highlighting the need for extensive physico-chemical characterisation of such experiments. Since 2012 Nicky Thomas is a post-doc in the rational oral drug delivery (RODD) group of Anette Muellertz and Thomas Rades at the University of Copenhagen. As a member of this group his research is concerned with the development and characterization of novel lipid-based drug delivery systems, in particular supersaturated self-nanoemulsifying drug delovery systems (super-snedds). His recent research efforts also aim at the integration of an absorption model for in vitro digestion models to improve the predictability of this widely utilized model in lipid research. Furthermore he is involved in the digestion working group of the LFCS Consortium which aims at the standardization of in vitro protocols. Nicky studied pharmacy at the University of Freiburg, Germany, and worked as a pharmacist in both community and hospital pharmacies before he pursued his PhD at the University of Otago, New Zealand, under the supervision of Prof Thomas Rades and A/Prof Anette Muellertz. The Division of Heath Sciences at the University of Otago recognised his PhD thesis being of exceptional quality, resulting in the publication of six peer reviewed articles. Nicky is a member of the Controlled Release Society, American Association of Pharmaceutical Scientists (AAPS), and of the DPhG (German Pharmaceutical Society).

Fourth Symposium on Phospholipids in Pharmaceutical Research. 21 st 22 nd, September 2015 Heidelberg, Germany. 3rd Circular

Fourth Symposium on Phospholipids in Pharmaceutical Research 21 st 22 nd, September 2015 Heidelberg, Germany 3rd Circular page 2 Introduction Phospholipids excipients are worldwide being used in many registered