Day 2 :
Keynote Forum
Joël Richard
IPSEN, France
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
Biography:
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.
Abstract:
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.
Keynote Forum
Kang Choon Lee
SungKyunKwan University, South Korea
Keynote: Peptide PEGylation strategies for drug development
Time : 10:30-11:00
Biography:
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.
Abstract:
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.
Keynote Forum
Kohsaku Kawakami
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
Biography:
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.
Abstract:
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.
Keynote Forum
Emilie Roger
Université d’Angers, France
Keynote: Lipid nanocapsules: A new platform for oral drug delivery system
Time : 11:45-12:15
Biography:
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.
Abstract:
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).
- Smart Drug Delivery Systems | Pharmaceutical Nanotechnology | Drug Delivery Technology | Drug Targeting and Design | Major Challenges in Drug Delivery | Recent Advances in Drug Delivery
Location: Greenspring4
Session Introduction
Marina A Dobrovolskaia
Nanotechnology Characterization Lab, USA
Title: Immunological properties of nanotechnology-based complex drug formulations and challenges in their preclinical characterization
Biography:
Marina A Dobrovolskaia
Abstract:
Delivery of drugs, antigens and imaging agents benefits from using nanotechnology carriers. Successful translation of nanoformulations into clinic involves a thorough assessment of their safety profiles, which among other end-points, includes evaluation of immunotoxicity. This presentation will discuss current knowledge and experiences from the US Nanotechnology Characterization Laboratory to highlight most prominent pieces of nanoparticle-immune system puzzle and discuss achievements, disappointments and lessons learned from past ten years of preclinical immunological characterization of nanomaterials. I will present translational case studies to highlight common challenges in the preclinical characterization of nanotechnology carriers and nanoparticle based complex drug formulations. The presentation will focus on areas such as structure-activity relationships, effects on blood coagulation system, activation of complement, effects on the immune cell function, endotoxin detection and quantification, nanoparticle interference with traditional immunological tests, and applicability of traditional in vivo immune function tests to engineered nanomaterials.
Biography:
Dr. Qing Li is a scientist at Medimmune, and her research focuses on antibody discovery, tissue specific drug delivery, and ADC development. Dr. Li received her PhD in chemistry from University of Minnesota, where she developed a novel method of engineering and preparation of Chemically Self-assembled Antibody Nanorings (CSANs) that can be used for drug delivery, imaging and cell surface engineering. Dr. Li completed post-doctoral training in Dr. Brent Iverson and Dr. George Georgiou’s lab at the University of Texas, Austin, where she co-developed a yeast-surface-display based high-throughput screening method of protease evolution for altered specificity and activity.
Abstract:
PEGylation has been widely used to improve pharmacokinetics of biologics. We have evaluated the effects of PEG size, shape and conjugation methods on the PEGylated diabodies. We modified diabody with PEGs of different molecular weight and shape, and applied different conjugation methods. We also measured hydrodynamic size of PEGylated diabodies with multi-angle light scattering. We found the pharmacokinetic properties of modified diabody significantly improved when Rh increased up to 6nm. In addition, PEGylation significantly reduced the non-specific binding of the diabody conjugates. Understanding the impact of PEGylation on pharmacokinetic and biophysical properties would help develop PEGylated diabody as therapeutics
Maslov M Y
Tufts University School of Medicine, USA
Title: Myocardial drug distribution following epicardial drug delivery: Potential impact of cardiac capillary perfusion in a swine model
Biography:
Mikhail Maslov has done his PhD and has been in biomedical research for 20 years. He is an expert in local myocardial drug delivery, infusion systems, cardiovascular pharmacology, heart failure and hemorheology. He has investigated myocardial pharmacokinetics and pharmacodynamics following epicardial drug delivery and evaluated role of compromised myocardial energy metabolism in the development of heart failure. He has contributed to the global pre-clinical studies of Entresto, a new drug designed to treat heart failure.
Abstract:
Statement of the Problem: Optimal therapeutic concentrations of antiarrhythmic, inotropic, angiogenic and regenerative agents in the heart can exceed the toxic threshold for other organs. Local epicardial drug delivery (LEDD) to the left ventricle aims to overcome this limitation. However, the global myocardial drug distribution following LEDD is vague. Myocardial drug distribution following LEDD is governed by diffusive, convective forces, and blood flow. We aimed to characterize the three-dimensional (transmural, longitudinal and circumferential) myocardial pharmacokinetics by site-specific point-source and distributed-source release of epinephrine, a model small hydrophilic drug, to the epicardial surface in a large animal model.
Methodology & Theoretical Orientation: A living swine model was used to evaluate epinephrine deposition and distribution in the heart following LEDD using biocompatible polymeric point-source release and alternatively distributed-source release.
Findings: LEDD via point-source release, and to a greater extent via distributed-source release, generated transmural epinephrine gradients directly beneath the site of application, longitudinally down the length of the heart and around the circumference toward the lateral and inferior walls, but not towards the interventricular septum. In both cases these gradients extended further than might be predicted from simple diffusion. Drug distribution away from the release source, down the axis of the left ventricle, and selectively towards the left heart follows the direction of capillary perfusion away from the anterior descending and circumflex arteries, suggesting a role for the coronary circulation in myocardial drug deposition and clearance. The role of the coronary vasculature is further suggested by the elevated drug levels in the coronary sinus effluent.
Conclusions: The coronary vasculature significantly shapes the distribution within the myocardium following LEDD in large animal models. Optimal design of epicardial drug delivery systems must consider these underlying bulk capillary perfusion currents within the tissue to deliver drug to tissue targets.
Maura Murphy
iCeutica Operations LLC, USA
Title: Bioavailability enhancement using submicron particles
Biography:
Maura Murphy is a formulation development scientist, specializing in solid dosage form development of poorly soluble small molecules. She graduated from the University of Texas with a BS in Pharmacy, and the University of Maryland at Baltimore with a PhD in Pharmaceutical Sciences. She has nearly 20 years of product development experience, having worked at Schering-Plough, Genzyme, Vertex, and Pharmaceutics International before her current position as the Senior Director of R&D at iCeutica
Abstract:
Statement of the Problem: Many compounds exhibit low oral bioavailability due to poor dissolution in-vivo. The poor dissolution is typically due to low water solubility, and improving oral bioavailability of poorly soluble compounds has been a focus of formulation development for many years. Advancements which have been successful include particle size reduction, SEDDS, and amorphous solid dispersions.
Objective: The objectives of this session are to review the current tools available for oral bioavailability enhancement with a focus on particle size reduction, and to introduce a new tool, SoluMatrix Fine Particle Technology™.
Methodology: Drug substance particles can be milled to the submicron size utilizing wet media milling or dry attritor milling. With the dry milling method, the drug substance is milled with excipients and media to produce a free-flowing powder containing submicron particles of the drug substance.
Findings and Conclusions: Multiple case studies demonstrate that submicron particles can improve dissolution and the pharmacokinetics of orally administered poorly soluble drugs. Benefits included increased oral bioavailability, reduction in food effect, more rapid absorption, and thermodynamic stability.
Nina Mezu-Nwaba
United States Food and Drug Administration, USA
Title: Future of biomarkers in drugs, biologics, and device development: A US FDA initiative
Biography:
Dr. Nina Mezu-Nwaba is a Captain with the United States Public Health Service and a Senior Compliance Officer in the Center for Devices and Radiological Health (CDRH) at the Food and Drug Administration. She has over 20 years of clinical, retail, and regulatory experience, with expert knowledge in OB/GYN, Gastroenterology, Surgical and Urology products. Dr. Mezu-Nwaba has been with the FDA for over 17 years and has held positions at the Office of Generic Drugs, the Center for Drug Evaluation and Research, CDRH Office of Device Evaluation, and CDRH Office of Surveillance and Biometrics. She obtained her Doctor of Pharmacy from the University of Maryland at Baltimore, a Masters in Biomedical Science from Georgetown University, and a Masters in Public Health from the Johns Hopkins Bloomberg School of Public Health. Dr. Mezu-Nwaba has represented the FDA in Berlin, Puerto Rico, and the U.S. as the Liaison for International Standards committees. She actively participates in community health outreach, mentoring, as well as international humanitarian missions. Dr. Mezu-Nwaba seeks to bridge gaps in health-disparities through voluntary service with the Commissioned Corps, Health and Human Services, MI Foundation in Nigeria, Rotary Club, and serving the USPHS in Indian Health Reservations and other U.S. locations.
Abstract:
Statement of the Problem: Biomarkers are a core part of medical treatment used in diagnosing, detecting, and treating diseases. However, some nonspecific biomarkers may pose challenges due to poor predictive value for forecasting subsequent clinical course in patients with suspected infections, adverse events, and disease state progression. The purpose of this study is to review the evidence for biomarkers and their role in diseases, describe the future direction of biomarkers, and support the Biomarker Qualification Program, which was established to support the United States Food and Drug Administration (FDA), Center for Drug Evaluation and Research’s (CDER's) work with external stakeholders to develop biomarkers that aid in the drug development process.
Findings: Biomarkers are applicable in drug, biologic, and device development and are regulated by the FDA. Biomarkers such as troponin have their place in early detection of cardiac injury. Other well established applications of biomarkers include blood pressure, pulse oximetry, creatinine clearance, hemoglobin A1C, which are crucial for baseline therapy assessment. Non-specific biomarkers, such as WBC, D-dimers, C-reactive protein and criteria to diagnose sepsis have also played a part in improving therapy. The importance of including biomarkers in drug, device and biologic development derives from its potential innovative benefit in targeted patient care and personalized medicine.
Conclusion & Significance: Emerging studies have evaluated biomarkers for critical conditions, such as early detection of sepsis or assessment of oxygen levels for predicting retinopathy in premature neonates. Biomarkers can aid as useful means towards monitoring medical device treatment outcomes as well. Further research is needed for evaluation of current therapy and detection of early stages of cancer. Other findings can contribute to the encouragement of novel biomarkers development for future medicinal and research use.
Ahmed Alalaiwe
Prince Sattam Bin Abdulaziz University, Saudi Arabia
Title: The oral bioavailability behavior of AuNPs conjugated with Chitosan
Biography:
Ahmed Alalaiwe has his expertise in evaluation of nano metals bioavailability. His open and contextual evaluation model based on IVIVC creates new pathways for improving new drug delivery systems. He has built this model after years of experience in research, evaluation, teaching and administration both in hospital and education institutions. He is currently a Vice-Dean for Preparatory Deanship in Prince Sattam Bin Abdulaziz University, Saudi Arabia beside his wok duty in researching/teaching in College of Pharmacy at the same university.
Abstract:
The unique properties of gold nanoparticles (AuNPs) such as their controllable size, shape and surface chemistry among other metal alloys make them highly attractive models in many medical purposes. Due to the ease to functionalize, AuNPs could be coupled with different surface chemistry to be used as drug delivery systems (DDS), biological senses and biomedical imaging. In this project, we graft 3 nm AuNPs with chitosan as an enhanced oral absorption agent and investigate the AuNPs bioavailability behavior after an oral dose in rats. The syntheses of these particles are prepared using citrate method. In vitro characterization will be conducted using Transmission Electron Microscopy and Dynamic Light Scattering techniques. While detection of AuNPs in biological samples will be quantified using ICP-MS. Finally, the data will be assessed using a phoenix software to obtain the pharmacokinetic parameters.
Sameer Alshehri
University of Nebraska Medical Center, USA
Title: Investigation of BBN-HPMA conjugates for targeting Gastrin Releasing-Peptide (GRPR) Receptor
Biography:
Sameer Alshehri has received his MS degree in pharmaceutics from Massachusetts College of Pharmacy and Health Sciences University, Boston in 2015. He then started his PhD studies at University of Nebraska Medical Center in Pharmaceutical Sciences. Since then he has been actively participating in research-related radiopharmaceuticals. His main focus is designing targeted HPMA copolymers for treatment and imaging of bombesin receptor-expressing tumors such as prostate cancer
Abstract:
Background: Compared to small radiolabeled bombesin (BBN) peptide conjugates, targeting efficacy of macromolecular conjugates modified with BBN analogues in tumors expressing gastrin releasing-peptide receptor (GRPR) is largely unexplored. Our goal was to investigate the targeting efficacy of BBN-conjugated polymeric system in vitro and in vivo.
Methods: Four concentrations, 2, 5, 10 and 15 mol% of L-BBN peptide, were conjugated to HPMA copolymer. As a control, 10 mol% D-BBN-HPMA was synthesized. Using PC-3 human prostate cancer cell line, 1 hr cellular internalization studies for all conjugates and 4 hr cellular internalization studies as well as confocal imaging studies for the 10% L-BBN-HPMA and 10% D-BBN-HPMA were performed. Results: After 1 hr, cellular internalization studies showed high uptake of 10% L-BBN-HPMA by around 13.76% internalized activity compared to 0.61%, 3.58%, 6.00% and 9.35% for 2% L-BBN-HPMA, 5% L-BBN-HPMA, 10% D-BBN-HPMA and 15% L-BBN-HPMA, respectively. Similarly, after 4 hr, 10% L-BBN-HPMA showed higher internalized radioactivity (16.96%) compared to 10% D-BBN-HPMA (9.59%).The confocal imaging study showed higher fluorescent signal for 10% L-BBN-HPMA compared to 10% D-BBN-HPMA by two folds. Surprisingly, biodistribution studies showed higher retention in liver and spleen for all conjugates except 2% L-BBN-HPMA. Interestingly, the retention in spleen was found to be directly proportional to the concentration of peptide/polymer.
Conclusion: The results indicate that incorporating of BBN peptides in the HPMA copolymer construct enhances the internalization into PC-3 cells, with 10% molar concentration being the optimum concentration. However, due to high retention in liver and spleen, further modifications to the construct are needed.
Biography:
Abstract:
We present cyclic thiolsulfi nates as the fi rst tool to permanently modify thiol pairs while transiently binding lone thiols. This tool can be tuned to enable “click” coupling of cyclic thiosulfi nates and dithiols, in vivo thiol-pair selective probes and pharmacological chaperones, a less toxic alternative to current di-ene crosslinkers for creating biopolymers, active transport of cargo
across the cell membrane. 1,2-dithiane-1-oxide was synthesized, administered in human blood, human cell lines, and to an ALS mouse model, and shown to selectively crosslink the dithiol pair (8 Å distance) of Cu/Zn-superoxide dismutase (SOD1) by our proposed mechanism, stabilizing its quaternary structure. Salient characteristics of cyclic thiosulfi nate chemistry include: 1) binding one (lone) thiol reversibly, but crosslinking thiols indefi nitely; 2) crosslinking is driven by the enthalpies of disulfi de bond and water formation; 3) attributes of click chemistry including orthogonality with common protein functional groups, high reaction yields, compatibility with aqueous solvents, and much higher ring strain-dependence than molecules comprised only of period 2 elements.
- Routes of Drug Administration | Novel Drug Delivery Systems | Peptide and Protein Drug Delivery | Drug Targeting and Design | Nucleic Acid Based Drug Delivery
Location: Greenspring4
Session Introduction
Srinivasa R Raghavan
University of Maryland, USA
Title: Nature-inspired multilayered capsules based on stimuli-responsive polymers: A new design for the multi-step release of drugs
Biography:
Srinivasa R Raghavan is the Patrick and Marguerite Sung Professor in the Department of Chemical and Biomolecular Engineering at the University of Maryland, College Park (UMD). He received his B Tech and PhD in Chemical Engineering from the Indian Institute of Technology, Madras, and North Carolina State University, respectively. His research on self-assembly, nanostructured fluids and soft materials has resulted in more than 150 publications and 20 US patents. He has received several national and University-wide awards for his teaching and his research (including the CAREER award from the National Science Foundation in 2004 and UMD Invention of the Year in 2009). He is also the scientific co-founder of three startup companies based on technologies invented in his laboratory.
Abstract:
Diverse structures in nature such as eggs, embryos, body parts like the spinal disc, plant seeds, and the onion all have a common structural motif, which is the presence of multiple concentric layers. Individual layers are often composed of distinct materials because the layers serve different purposes. The creation of these structures in nature (morphogenesis) typically proceeds by the initial formation of an inner layer or core, followed by a first shell, and a further progression outwards to add more shells. Here, we draw inspiration from natural morphogenesis to create multilayered polymer capsules by an “inside-out” technique. First, an aqueous gel core is loaded with an initiator. This core is placed in a solution of monomer 1, whereupon a shell of polymer 1 grows around the core. Thereafter, this core-shell structure is loaded with fresh initiator and placed in a solution of monomer 2, which causes a concentric shell of polymer 2 to form around the first shell. This process can be repeated further to obtain multiple layers of distinct polymers. Each polymeric shell grows outward from the surface of the previous shell; thus, the thickness of a given shell steadily increases with time and can be controlled. A highlight of this technique is the ability to juxtapose different polymers next to each other among the concentric layers in an onion-like capsule. For example, layers of a non-responsive polymer can be placed next to either a temperature-responsive or a pH-responsive polymer. By varying the location of the stimuli-responsive layer(s), we demonstrate that the release of solutes (e.g., drugs) from the capsule can be made to follow unique multi-step release profiles as the stimulus is varied.
L A Avila
Auburn University, USA
Title: Delivery of lethal dsRNAs in insect diets by branched amphiphilic peptide capsules
Biography:
Currently I am an Assistant Professor at Auburn University. A primary focus of my research is the design of innovative nanomedicines for the treatment of different human diseases. Additionally, I am investigating new methods for gene silencing in insect models, by adding dsRNA associated with peptide nanoparticles to their diet. Gene silencing by feeding dsRNA in insects has great potential as a tool for pest management because it can reduce the off-target effect and slow down resistance development to chemical insecticides.
Abstract:
In this study we inhibited expression of two insect genes, BiP and Armet, through the
ingestion of dsRNA complexed with Branched Amphipathic Peptide Capsules (BAPCs). The dsRNA- BAPCs complexes were added to the diets of two insect species from two Orders: Acyrthosiphon pisum and Tribolium castaneum. The gene transcripts tested (BiP and Armet) are part of the unfolded protein response (UPR) and suppressing their translation resulted in lethality. For Acyrthosiphon pisum, ingestion of <10 ng of BiP-dsRNA associated with BAPCs led to the premature death of the aphids (t1/2 = 4 - 5 days) compared to ingestion of the same amounts of free BiP-dsRNA (t1/2 = 11-12 days). Tribolium castaneum was effectively killed by ingestion (by larvae only) using a combination of BiP-dsRNA and Armet-dsRNA complexed with BAPCs (75% of the subjects, n = 30) died as larvae or during eclosion (the emergence of adults from pupae). Feeding the two dsRNA alone resulted in fewer deaths (30% with n = 30). These results show that complexation of dsRNA with BAPCs greatly enhances the oral delivery of dsRNA over dsRNA alone in the diet. This approach provides a simpler method of delivering dsRNA compared to microinjection for studying in vivo protein function and for developing novel strategies for pest management.
Abdullah Mahmud
Nanotechnology Characterization Lab, USA
Title: CCK-B targeted PEG-poly (L-Lysine) polyplex micelle for the effective delivery of gastrin siRNA to the pancreatic cancer
Biography:
Abdullah Mahmud is a Scientist at the nanotechnology characterization laboratory (NCL) of U S Frederick National Laboratory for Cancer Research, Frederick, working on the development of nanotechnology based formulations for cancer therapeutics. He possess 8+ years of experience working in the chemistry-biology interface utilizing chemistry principles to address the formulation and delivery challenges of novel cancer therapeutics including nucleic acid therapeutics, chemotherapeutics and biologics. His areas of expertise include pharmaceutical sciences, formulation and drug delivery, and physicochemical characterization with extensive laboratory experience in functional modification of polymer, liposome and lipid chemistry and analytical method development. He possesses several patents and publications in the field of nanotechnology based drug delivery. Prior to Join NCL, he was a Post-doctoral Researcher with Prof. Dennis Discher at the University of Pennsylvania. He received his PhD in Pharmaceutical Sciences, specializing in polymer based drug delivery from the University of Alberta, Canada.
Abstract:
Introduction: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with late detection, rapid progression, high metastasis rate and poor treatment options culminating in the worst 5-year survival of all gastrointestinal malignancies. Two of the major obstacles in treating PDAC are the inefficient delivery of therapeutic agents to the tumor and profound drug resistance that necessitates development of novel delivery and treatment strategies. One such novel approach is the targeted delivery of gene therapies to PDAC. The cholecystokinin-B (CCK-B) receptor and its ligand gastrin are both overexpressed in PDAC, and contribute to PDAC development and proliferation through an autocrine mechanism. We have developed a novel gastrin targeted polyethylene glycol-block-poly (L-Lysine) (PEG-PLL) polyplex (Ga-polyplex), selective for the CCK-B receptor, in order to deliver gastrin siRNA (Figure 1) to PDAC and disrupt proliferation.
Methods: The targeted polyplex micelle (Ga-polyplex) was prepared by complexing gastrin-10 (Ga-10) conjugated PEG-poly (L-lysine) polymer, Ga-PEG-PLL, with gastrin siRNA (Figure1). Ga-polyplex was characterized for hydrodynamic size and stability in serum. The Ga-polyplex was then assessed for targeting ability, gastrin mRNA knockdown, and tumor growth inhibition, both in vitro and in vivo.
Results: The Ga-polyplex micelle formation was confirmed from its monodisperse hydrodynamic size (~44.3 nm). The Ga-polyplex demonstrated 7h serum stability, selective tumor uptake, superior mRNA knockdown and tumor growth inhibition compared to untargeted and scrambles siRNA polyplex both in vitro and in PDAC bearing mice. Furthermore, the targeted gastrin siRNA polyplex micelle prevented metastasis in pancreatic tumor bearing mice.
Conclusion: The CCK-B receptor targeted polyplex micelle was successfully developed, characterized and evaluated for selective delivery of gastrin siRNA to the PDAC. This targeted platform has tremendous potential for oligonucleotide therapeutic delivery to pancreatic cancer.
Blessing Aderibigbe
University of Fort Hare, South Africa
Title: Physicochemical properties and in vitro cytotoxicity evaluation of polymer-drug conjugates for combination therapy
Biography:
Blessing Aderibigbe research is focused on the design of polymer-based drug delivery for combination therapy. She has years of experience in research and teaching in education institutions. She is currently a Senior Lecturer in the Department of Chemistry, University of Fort Hare, South Africa.
Abstract:
Polymer-drug conjugates are potential therapeutics suitable for combination therapy for the treatment of selected diseases that are characterized by drug resistance such as cancer, malaria etc. In this study, different polymer-drug conjugates containing either anticancer or antimalarial drugs were prepared. The physicochemical properties of the conjugates were evaluated. The scanning electron microscopy images of the conjugates revealed a combination of spherical, interwoven and strip shaped morphologies. In vitro drug release revealed sustained mechanism and the cytotoxic effects of the conjugates was selective when compared to the free drugs. The results obtained suggest that the design of the conjugates influences their biological activity and hence, are potential therapeutics for combination therapy.
Emilia Barcia
Universidad Complutense, Spain
Title: Multiparticulate drug delivery systems for Parkinson´s disease
Biography:
Emilia Barcia is PhD in Pharmaceutics from the Universidad Complutense de Madrid (UMC), Spain. Her current position is Chairman of the Department of Pharmaceutics at the School of Pharmacy (UMC) and Full Professor. Her main research interests are focused on the development of new controlled drug delivery systems for neurodegenerative disorders as well as population pharmacokinetics studies. She belongs to SPLC-CRS (Spanish-Portuguese Local Chapter of the Controlled Release Society) and to SEFIG (Spanish Society of Pharmaceutics) and has directed more than 12 doctoral thesis and published more than 50 scientific research articles.
Abstract:
Ropinirole (RP) is a specific D2 and D3 dopamine receptor agonist indicated for the treatment of Parkinson’s disease (PD) both as monotherapy and in combination with L-dopa in the advanced stages of the disease. New biodegradable RP multiparticulate systems are developed and characterized both in vitro and in vivo. Microparticles were prepared by the solvent-evaporation technique using PLGA (poly-D,L-lactide-co-glycolide acid) resomers 502 and 502H as polymers. Several formulations were prepared with increasing amounts of RP (40, 80 and 120 mg). Mean encapsulation efficiency of RP was >79% in all cases. In vitro release of RP exhibited zero-order kinetics for 2 and 3 weeks for formulations prepared with PLGA 502H and PLGA 502, respectively. The formulation selected was prepared with 120 mg RP and exhibited constant release of the drug for three weeks (K0= 78.23 µg/day).
Evaluation of the efficacy of the formulation selected was performed in an animal model of PD which was developed with the neurotoxin rotenone (RT). RT was given i.p. at a dose of 2 mg/kg/day for 45 days to male Wistar rats. The multiparticulate formulation was administered at two dose levels (7.5 mg/kg and 15 mg/kg) on days 15th and 30th. Moreover RP in solution was daily administered at 1 mg/kg from day 15th when the first symptoms of PD were observed. All treatments were given i.p. After 45 days all animals were sacrificed and brains removed. Brain immunochemistry (Nissl-staining, GFAP and TH immunohistochemistry) and behavioral testing (catalepsy, akinesia, rotarod and swim test) were performed along the study. The results obtained showed that animals receiving the multiparticulate formulation selected at a dose of 15 mg/kg significantly reverted PD-like symptoms, thereby confirming the potential therapeutic interest of this new biodegradable delivery system developed for ropinirole and destined to treat Parkinson´s disease.
Ding Lin
Central South University, China
Title: Ocular and plasmic dexamethasone distribution following controllable continuous subtenon drug delivery in rabbit
Biography:
Ding Lin
Abstract:
Aim: To examine the distribution of dexamethasone (DEX) in ocular and plasmic samples following CCSDD of dexamethasone disodium phosphate (DEXP) in rabbit.
Method: New Zealand white rabbits (n=6/time/group) were included in the experiments. There are three groups including controllable continuous sub-tenon drug delivery system (CCSDD) group, intravenous injection (IV) group and sub-conjunctival injection (SC) group. In the CCSDD group, trickled 0.3 ml initial doses of 5 mg/ml DEXP, and then perfused at a rate of 0.1 ml/h for 10 hours using a pump and administrated 1mg/Kg DEXP intravenously in IV group and 0.3ml of 5mg/ml DEXP into sub-conjunctive in SC group. At different time point within 24 hours, the blood samples and eye samples were collected. The DEX concentration was analyzed by Shimadzu LC–MS 2010 system.
Result: In the CCSDD group, high levels of DEX were observed in the ocular tissue immediately after the administration and were maintained at 12 hours. Even at 24 hours, the mean DEX concentration was 31.72 ng/ml and 22.40 ng/ml in aqueous and vitreous respectively. The maximum DEX in plasma was 321.81 ng/ml, 1798.44 ng/ml and 8441.26 ng/ml respectively in CCSDD, SC and IV group. Each ocular tissue peak DEX level is higher in CCSDD and SC group than IV group. Although there are a similar Cmax levels in ocular tissues in CCSDD and SC, the ocular tissues exclusion of iris exposure (AUC0-24) to DEX is higher and plasma exposure is lower in CCSDD than SC.
Conclusion: Controllable continuous sub-tenon drug delivery diffusion of DEX resulting in high levels in the ocular tissue and low levels in the plasma. Thus CCSDD is an effective method of delivering DEX into both anterior and posterior segments of the eye.
Soline PEERS
Ingénierie des Matériaux Polymères, France
Title: Study of delayed-release of carboxyfluorescein from liposome-loaded chitosan physical hydrogels
Biography:
Soline Peers is a second year PhD student in Lyon, France at Ingénierie des Matériaux Polymères laboratory. One research axes of this lab is the elaboration of materials for life science. As a Physico-Chimist with a strong interest in biology and improving health, she dedicates her work to materials in the service of mankind. Her research deals with improving drug delivery by the elaboration of originals systems to enhance drug-delayed release.
Abstract:
Statement of the Problem: The property of prolonged release for therapeutic agents from liposomes or biocompatible gels has widely been investigated during the last decade [1, 2]. To overcome classic issues that may be encountered with common drug delivery systems such as the “burst effect” or fast outside diffusion of drugs [3], an “hybrid” system composed of liposomes entrapped within a chitosan physical hydrogel [4] has been developed (Figure and is presented herein. It combines the advantages of both components recognized for the drug delivery applications.
Methodology & Theoretical Orientation: The elaboration process of this “hybrid” system consists in the addition of suspension of pre-formed phosphatitdylcholine liposomes entrapping a model molecule (carboxyfluorescein, CF) to a chitosan solution. The polymer gelation [4] was subsequently carried out according to experimental conditions optimized in this work. The release of this model molecule from “hybrid” system is assayed by fluorescence.
Findings: The release study of water soluble CF entrapped in liposomes, themselves incorporated in a chitosan hydrogel has confirmed the concept of delayed-release. Indeed, the CF release was found to be longer in the “drug-in-hydrogel” systems in comparison with the “drug-in-liposomes-in-hydrogels” ones.
Conclusion & Significance: These first results show that such a “hybrid” system could be a step forward in drug delivery for tissue engineering [6], regenerative medicine or wound healing applications. The next step of this work will be to study the impact of structural parameters of the chitosan (e.g., weight-average molecular weight or acetylation degree) and liposomes on the drug release and the interactions between the two components of this “hybrid” system. The influence of the nature, the charge and the molecular weight of the therapeutic agent could also be investigated.
Biography:
Mehran Ghiaci is a Professor of Chemistry at Isfahan University of Technology (Iran). He received his BS (1973) and MS (1974) in chemistry from Pars College (Iran). He received his PhD degree (1980) in Physical Organic Chemistry from University of California at Los Angeles (USA). His current research interests include physical organic chemistry, heterogeneous catalysts, organic synthesis, surface chemistry, chemical sensing and drug delivery.
Abstract:
Our main goal in presenting this methodology was to modify the conventional systemic delivery of drugs because such procedures may cause toxicity; for example, polymeric coatings may present some disadvantages such as limited chemical stability, local inflammatory reactions and so on. As a result, we thought that it could be interesting to embed bioactive compounds and biomolecules within inorganic coating such as TiO2, ZrO2, and SiO2. This type of coating increases drug passage time through its small and long pores forward intended fluid (whether in vitro or in vivo) and eliminates different stimuli such as (temperature, pH, ultrasonic irradiation,...) to remove the coating on the surface of drug carrier system. This could be very effective economically and time spent. Moreover, if such inorganic coatings have nanostructure properties, they improve cellular adhesion, enhances osteoblast proliferation, and increase biomineralization. In this talk, emphasis is placed on presenting the technique, and would like to explore it as a new methodology in drug delivery.
Pallavi Mangesh Patil
P.E. Society’s Modern College of Pharmacy, India
Title: Stability-indicating HPTLC method for simultaneous determination of Ketoprofen, methyl paraben and propyl paraben in gel formulation
Biography:
Dr Pallavi M.Patil has completed her PhD at the age of 34 years from Tamilnadu University and. She is the Assositant Profersor of Pharmaceutical Chemistry, a premier Modern College of Pharmacy, Nigdi Pune organization. .she has her expertise in development and validation parameter quantity evaluation and passion in improving the method optimisation which help in health and wellbeing. She has published more than 35 papers in reputed International Journals and also presented her research work in National and International conference and has been serving as an reviewer of repute Journals. Now I am staying at Albany New York for my research work and attending some of conference here.
Abstract:
Aim: A novel and quick HPTLC-densitometric method was developed for the simultaneous determination of Ketoprofen, Methyl Paraben, and Propyl Paraben.
Methods: Chromatographic separation of the drugs was performed on precoated silica gel 60 F254 Merck plates using Toluene:Ethyl acetate:Glacial acetic acid (6.5:2.5:1.0 v/v/v) as a mobile phase. A TLC scanner set at 265 nm was used of Ketoprofen, Methyl Paraben, Propyl Paraben respectively were validated according to ICH guidelines. Forced degradation conditions of hydrolysis (neutral, acidic and alkaline), oxidation, photolysis and thermal stress, as suggested in the ICH guideline Q1A (R2).
Results: The three drugs were satisfactorily resolved with Rf values of 0.33 - 0.05,0.54 - 0.05, 0.71 -0.05 for Ketoprofen, Methyl Paraben, Propyl Paraben respectively. Calibration curves were polynomial in the range 200-1000 ng/band, 200-1500 ng/band, 100 -600 ng/band, for Ketoprofen,Methyl Paraben, and Propyl Paraben respectively. Correlationcoefficient (r) values were 0.9917, 0.9927, 0.9906 Ketoprofen,Methyl Paraben, PropylParaben respectively. The percentage recovery ranges from 99 to 101%.
Conclusion: A low relative standard deviation (<2%) was found for both precision and robustness study showing that the proposed method was precise and robust. The methodhad an accuracy of 99.95%, 99.85% and 100.07 of Ketoprofen, Methyl Paraben, Propyl Paraben respectively were validated according to ICH guidelines. The drug showed instability in oxide , heat and UV light, while it remained stable in neutral conditions.
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