Day 2 :
Keynote: Delivery of peptides by non-invasive routes: Focus on successful oral technologies progressing in the clinic and future challenges
Time : 10:00-10:30
Joël Richard is currently Senior Vice President of Peptides in IPSEN, France. He is globally leading all the pharmaceutical development activities of peptide-based products, including APIs and drug products, with major franchises in oncology, endocrinology and neurology. He has more than 25 years of experience in chemistry and biopharmaceutical R&D, including several global senior positions in various biotech and pharma companies. Since 1996, he has focused his research activity on new formulation technologies and drug delivery systems; such as microspheres, nanoparticles, nanocapsules, chemically-modified proteins, supercritical fluid technology, especially for injectable peptide and protein formulations. He graduated from Ecole Normale Supérieure, Cachan in 1985 and got a PhD in Materials Science from University of Paris VI in 1987. He has published 67 peer-reviewed scientific papers, 8 book chapters and 2 review editorials in fields like polymers, colloids and interfaces, drug delivery, supercritical fluids, protein formulations, nanoparticles, and sustained-release formulations. He is the Author of more than 120 international communications and 53 patent families.
Due to their physicochemical characteristics, peptides are usually administered through the parenteral route, often several times daily. Injectable sustained-release peptide formulations based on biodegradable microparticles or implants have been very successful to enhance patient adherence and convenience, and increase safety and efficacy. They are likely to remain a significant and important part of the new peptide products coming to the market. However, the tremendous developments in alternative non-invasive routes of delivery are likely to result in more and more peptides being delivered by the transdermal, nasal, inhalation and oral routes. The main purpose of this talk will be to analyze and compare the various alternative non-invasive peptide delivery technologies progressing in the clinic, discussing the pros and cons of these technologies in regards to stability, bioavailability, safety/efficacy balance, impact on costs of goods and manufacturability. A special emphasis will be put on oral peptide technologies progressing successfully in the clinic, the key learning from ongoing clinical studies and the future challenges anticipated for filing and launching oral peptide products in the next years.
SungKyunKwan University, South Korea
Time : 10:30-11:00
Kang Choon Lee is Haengdan distinguished Professor at School of Pharmacy, SungKyunKwan University, Korea. For over 30 years, his drug targeting laboratory has been focused on bioconjugation of peptide and protein drugs. He is internationally recognized as one of the leading experts in site-specific peptide/protein PEGylation and firstly demonstrated the therapeutic potential of novel site-specific PEGylated drugs such as GLP-1 and TRAIL. He has published over 170 papers in peer-reviewed journals and served as an invited speaker at many international conferences and EAB Member of many international scientific journals. He is honored as a Fellow of the American Association of Pharmaceutical Scientists (AAPS) in 2003.
Statement of the Problem: The tremendous potential of peptide drugs is hampered by the short half-lives in vivo, resulting in a significantly lowered potency than their activity seen in vitro. These short-acting therapeutic agents require frequent dosing profiles that can reduce applicability to the clinic, particularly for chronic conditions. Therefore, half-life extension technologies are entering the clinic to enable improved or new biologic therapies.
Methodology & Theoretical Orientation: PEGylation is a commonly utilized technique to improve drug blood circulation time, reduce immunogenicity, and decrease dosing frequency of peptide and protein drugs. As with any form of molecular modification, the active site is affected and can drastically decrease the bioactivity of the therapeutic agent due to the steric hindrance, especially when conjugate small molecular weight molecules such as peptides with high molecular weight PEGs. Therefore, it is generally accepted that a balance must be obtained between the molecular weight of the PEG and the activity of the therapeutic molecule to reach a sufficient drug efficacy. To solve this problem, we focused on the balancing between PEG size and shape in addition to the site-specific bioconjugation.
Findings: Unlike the existing PEGylation technology, we developed a novel PEGylation method with a very long half-life combined with the retention of the peptide activity, resulting in a long duration of action with potentially reduced adverse effects in humans. By utilizing this novel PEGylation technique, we designed a new long-acting GLP-1R agonist, PEGylated exendin-4 (Olaedin®). The Olaedin was evaluated extensively in vitro and in vivo with a very long half-life (88 hour in non-human primates vs. 2 hour exendine-4) without the loss of its biological activity. We also tested the therapeutic potential of Olaedin® on the type-2 diabetes and Parkinson’s disease animal models.
Conclusion & Significance: Strategic PEGylation can be a platform technology to extend the half-life while preserving the biological activity of peptide and small protein drugs.
National Institute for Materials Science, Japan
Keynote: What is happening in GI tract? – Recent progress in formulation technologies for oral delivery of poorly soluble drugs
Time : 11:15-11:45
Kohsaku Kawakami is currently working for National Institute for Materials Science in Japan, where he is leading Medical Soft Matter Group. His interest is in basic science and development of amorphous dosage forms, and also on development of a novel drug carrier using phospholipids. He has published more than 130 papers and book chapters, and has given more than 120 invited lectures. He was working for pharmaceutical companies including Merck and Co. and Shionogi and Co. for 13 years as a Senior Scientist prior to joining the current organization, where he was taking care of physicochemical characterization, formulation studies, and DDS studies for new chemical entities. He was in University of Connecticut, School of Pharmacy from 2001 to 2002 as a Visiting Scholar. He holds a PhD in chemical engineering from Kyoto University.
In addition to biological performances including efficacy and safety, drug candidates must have adequate physicochemical properties such as sufficient aqueous solubility. Physicochemical problems may be overcome by modifying chemical structure of the candidate, by employing salt or cocrystal, or by applying formulation technologies. It must be recognized that increase in solubility with aid of formulation technologies does not necessarily lead to improvement in oral absorption. Great attention has been paid to super saturatable dosage forms such as amorphous solid dispersions (ASDs) and nanocrystals, because such solids in energetically higher state frequently has an advantage in enhancing oral absorption unlike simple solubilisation technologies. When ASDs are subjected to dissolution studies, supersaturation relative to the crystalline solubility is frequently created. The true supersaturation is a state where compound is molecularly dissolved at higher concentration than its solubility. Recent observations indicate that the state created after dissolution of ASDs is not in molecularly dissolved supersaturation but includes concentrated dispersed phase, which may be transformed to solid micro/nanoparticles. This phenomenon is what we can observe in the in vitro dissolution study, and the situation in in vivo is not necessarily the same. Self-emulsifying formulations form (micro) emulsions which accommodate poorly soluble drugs in GI tract. The carrier needs to be metabolized in a well-controlled manner for delivering drug molecules across the membrane efficiently. Too stable or too unstable carrier does not improve the absorption. Novel knowledges for understanding absorption behaviors from super-saturatable formulation technologies will be presented with emphasis on prediction of the absorption from in vitro studies.
Université d’Angers, France
Time : 11:45-12:15
Emilie Roger has a fundamental background in nanomedicine formulation and a strong expertise in oral drug delivery (especially, in vitro and in vivo evaluation). After, a PhD thesis on oral administration of lipid nanoparticles in Jean-Pierre Benoit team (Angers, France), she has formulated polymeric for intravenous or oral administration). She has specialized in oral administration having a strong expertise in FRET and uptake studies. She has published 17 articles in international peer-reviewed journals, one patent and three book chapters.
The oral route is the most common route for drug delivery. However, oral bioavailability is influenced by drug solubility and permeability. For drugs belonging to the biopharmaceutical classification system class II, class III, and class IV, drug encapsulation in nanocarriers provides an alternative solution to enhance bioavailability. Lipid nanocapsules (LNCs) developed by our group, have proven to be very interesting for the oral administration. These nanoparticles have a size that ranges from 20 to 100 nm and are prepared by a well-known low energy emulsification process: The phase-inversion temperature method. They have already shown promising properties for the oral delivery of paclitaxel, Sn38, fondaparinux and miltefosine. LNCs have demonstrated in vitro stability in simulated gastrointestinal media. They have also shown their stability and diffusion in intestinal mucus. Furthermore, LNCs were taken up by Caco-2 cells (intestinal cell model) mainly via active endocytosis. This active transport was not size-dependent in the range investigated. Moreover, tight junctions were not disrupted by LNCs and consequently the paracellular transport was not possible. Additionally, these nanocarriers have demonstrated a direct effect of P-gp on their endocytosis. Finally, LNCs have the ability to enhance the bioavailability of BCS class IV drugs. Besides, another challenge of drug delivery via the oral route is to target pharmacological receptors after absorption, like nanocarriers injected via the intravenous route. For this purpose, it is important to design nanocarriers that are able to be absorbed while keeping their integrity, and thus able to behave as circulating nanocarriers. This lecture will show how LNCs allow enhancing oral bioavailibity of drugs. Special attention will be paid to the ability of those LNCs to maintain their full integrity after crossing a human epithelium model. For this purpose, two complementary techniques were employed: Förster resonance energy transfer (FRET) and nanoparticle tracking analysis (NTA).