Session Two: Drug Delivery

Beat Flühmann

Vifor Pharma Ltd, Switzerland; NBCD Working Group, Lygature, Netherlands

Beat Flühmann is a Pharmacist by training and holds a PhD in molecular biology from ETH Zürich, Switzerland on “Structural analysis and characterization of cell surface receptors” and an MBA from the University of St. Gallen Switzerland. He was working in various positions in the field of pharmaceuticals and functional nutrition. Dr. Flühmann led a global multidisciplinary research and development team at Roche/DSM nutritional products developing novel compounds for the prevention and treatment of diabetes. Previously at Vifor Pharma Ltd, Dr. Flühmann was in the field of anemia therapy acting as Global Brand Director for intravenous iron preparations defining global strategic product plans across all functions (medical, marketing, market research, regulatory, life cycle management, logistics) and ensuring the operational execution. In his current position at Vifor Pharma Ltd Dr. Flühmann is Global Lead Nanomedicines. His main interest is in the translational science, namely the regulatory aspects of nanomedicines, and their follow-on products as well as the specific aspects that need to be considered in evaluation, selection and handling of nanomedicines in clinical practice. He is a Steering Committee Member of the Non-Biological Complex Drugs Working Group hosted at Lygature, a not for profit organization. The mission of the Non-Biological Complex Drugs Working Group is to work on appropriate and harmonized science-based approval and post-approval standards for Non-Biological Complex Drugs to ensure patient benefit and safety.

Dr Flühmann's presentation is kindly sponsored by Vifor Pharma.

Title of Research Sharing: Clinical Experience with Parenteral Iron Nanomedicines: Importance of Well-Controlled Manufacturing & Regulatory Process

Abstract of Research Sharing:  EMA has authorized 5 different originator intravenous iron-based nano-colloidal medicinal products and 26 follow-on products also referred as nanosimilars for the treatment of iron deficiency and/or iron deficiency anemia. To overcome the well-known toxicity of iron(II) and iron(III) salts, nanoparticles consisting of a core of polynuclear ferric hydroxide and a variety of different carbohydrates stabilizing the iron core were developed for the use in parenteral iron products. In a number of in vivo models it was demonstrated that not only nanoparticles composed of different carbohydrates but also nanoparticles of the same composition but from different manufacturers can have different biological profiles. Here we analyzed all available comparative clinical studies (28) and real world evidence such as retrospective studies (32), meta  analyses  and  pharmacovigilance data,  comparing  different  intravenous  iron-based nano-colloidal products. we found differences in  efficacy in  15  studies,  safety profiles in  26  studies  and laboratory parameters in 18 studies. We further identified in head-to-head studies comparing iron sucrose products from two manufacturers differences in efficacy and safety profiles.By today, not all critical quality attributes (CQA) responsible for these observed differences are known. Taken together this set of data is providing evidence that the nanoparticle’s physicochemical characteristics determined by the particle composition or even by the manufacturing process only can affect the clinical efficacy and safety profile of these products. As a consequence any change in manufacturing such as scale up, raw material sourcing, change of manufacturing equipment or site etc poses a substantial challenge and needs also to be addressed by adequate measure from regulatory authorities.

 

Jiong-Wei Wang

Jiong-Wei Wang obtained his Ph.D. in Medicine from Leiden University Medical Centre, The Netherlands. He did his postdoctoral training in University Medical Centre Utrecht and the National University of Singapore. Dr Wang is currently an Assistant Professor in the Department of Surgery at Yong Loo Lin School of Medicine and a Principal Investigator in the Cardiovascular Research Institute at the National University Heart Centre of Singapore. He also holds a joint appointment in the Department of Physiology at the National University of Singapore. Dr Wang's research focuses on cardiovascular immunology, extracellular vesicles and advanced drug delivery in cardiovascular disease.

 

 

Title of Research Sharing: Liposomes for Drug Delivery in Cardiovascular Disease

Abstract of Research Sharing:  Cardiovascular disease remains the top killer accounting for one third of deaths worldwide. Of these, myocardial infarction (or heart attack), mostly due to blood clot following atherosclerotic plaque rupture, and the associated complications are the most common cause of death in cardiovascular disease worldwide. In Singapore, for instance, more than 8000 myocardial infarction patients are admitted to hospitals per year. However, pharmacological treatment of cardiovascular disease is often limited by insufficient drug concentrations in the atherosclerotic plaques or damaged myocardium while also systemic side effects can occur. On the other hand, nanomedicine, such as the clinically most successful liposomes, may bring new hope to cardiovascular disease field. Our group have recently reported that liposomes could selectively accumulate in the ischemic myocardium and deliver berberine, a natural compound extracted from barberry, specially to the injured heart. While berberine has been long known for its anti-inflammatory and anti-oxidant activities in both preclinical and clinical studies, its poor water solubility and side effects on digestive system following high dose oral intake limit its clinical application. The targeted delivery approach via liposomes, surprisingly, markedly increases its local drug concentration in the heart and results in a remarkable treatment efficacy that is evidenced by improvement in heart function. Another example is fish oil supplements that are recommended for patients with cardiovascular disease by the American Heart Association. It is known that high dose intake of fish oil may cause certain side effects such as nausea. Our latest study shows that long-circulating liposomes are able to deliver fish oil bioactive components to atherosclerotic lesions along the blood vessels, and therefore slow down the progression of atherosclerosis in preclinical animal models. Given that atherosclerosis is the primary cause of heart disease and stroke, we expect this liposomal fish oil formulation will reduce the risk of major adverse cardiovascular events to a significant level. Taken together, our studies highlight the potential of long circulating liposomes for improving pharmacological treatment in cardiovascular disease.

Yong Loo Lin School of Medicine, National University of Singapore, Singapore

 

Siddharth Jhunjhunwala

Centre for BioSystems Science and Engineering, Indian Institute of Science, India

Siddharth Jhunjhunwala is an Assistant Professor at the Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru. He is currently a DBT-Wellcome India Alliance Intermediate Fellow, and in the past has been awarded the Ramanujan Fellowship and the R.I. Mazumdar young investigator position at IISc. In collaboration with numerous colleagues, Siddharth has published over 40 journal articles and has been awarded 2 international patents. His primary research interest is in the field of Immuno-engineering.

Title of Research Sharing: Drug Delivery Systems to Heal Diabetic Foot Ulcers

Abstract of Research Sharing:  Foot ulcers are a common problem in individuals who have type-2 diabetes. Unlike wounds in non-diabetic individuals, a large number of ulcers in diabetic individuals do not heal. Current treatment strategies heal only about 65% of early-stage ulcers, with the remaining ulcers progressively worsening and eventually resulting in amputations. Hence, new strategies to improve the healing of these wounds are required. Our approach to addressing the non-healing ulcer issue focuses on modulating immune responses at the ulcer site, which we hypothesize will promote healing. In this presentation, I will elaborate on our work that characterizes the phenotype and function of immune cells in diabetic individuals and at the site of foot ulcers. Our data show that immune cell phenotype and function are dysregulated in individuals with non-healing diabetic foot ulcers. Based on the immuno-phenotyping data, we have been developing drug-delivering bandages that modulate immune responses at the ulcer site. In a diabetic mouse model, these immuno-modulatory bandages show improvements in wound healing, which will be discussed.

 
 

Enrico Mastrobattista

Department of Pharmaceutical Sciences, Pharmaceutics division, Utrecht University, The Netherlands

Enrico Mastrobattista obtained his Ph.D. in Advanced Drug Delivery from Utrecht University in 2001 and spent over two years as a Marie Curie postdoctoral fellow in the MRC-Laboratory of Molecular Biology in Cambridge (UK). He currently leads a research group that develops biomimetic drug delivery systems for the targeted delivery of therapeutic proteins, peptides and nucleic acids.


His main areas of expertise are drug delivery, pharmaceutical biotechnology and nanobiotechnology with a focus on the intracellular delivery of nucleic acids and genetic vaccines. Prof. Mastrobattista has published over 120 articles in scientific journals, contributed to several book chapters in pharmaceutical biotechnology and holds several patents to his name. A total of 14 PhD students obtained their doctorate under his direct supervision. In addition, he served as the scientific coordinator of IMI COMPACT, a public-private partnership with a total budget of 30M€ in which 132 scientists from industry, SMEs and academia work together to find solutions for the delivery problem of biopharmaceuticals (www.compact-research.org). In 2013 he was awarded the prestigious Galien research price, The Netherlands, for his research on drug delivery (www.galenusprijs.nl). In addition, he is a board member of the Netherlands Society of Gene & Cell Therapy (www.nvgct.nl).

Title of Research Sharing: Nanovaccines for Cancer Immunotherapy

Abstract of Research Sharing:  Cancer immunotherapy relies on the ability of our adaptive immune system to discriminate between healthy cells and their malignantly-transformed counterparts. Tumor-specific T cell epitopes play a critical role in this discrimination that can be used to develop tumor-specific cancer vaccines. These vaccines should not only deliver these epitopes in sufficient quantity to professional antigen presenting cells, they should also provide the necessary co-stimulatory signals to evoke effective tumor-specific responses in an often immunosuppressive tumor microenvironment. In this presentation I give several examples of biomimetic delivery systems at the (sub)micron scale that have been developed for tumor vaccination. I discuss the structural features of such nanovaccines and highlight some preclinical data showing proof-of-concept that such nanovaccines have therapeutic potential.

 

Kannan Rangaramanujam

Wilmer Eye Institute, Johns Hopkins School of Medicine, United States of America

Kannan Rangaramanujam is the Arnall Patz distinguished professor of ophthalmology and co-director of center for nanomedicine at the Wilmer Eye Institute at Johns Hopkins School of Medicine. He obtained his Ph.D. in Chemical Engineering from California Institute of Technology and followed with a postdoctoral stint at the University of Minnesota (Chemistry / Chemical Engineering). His research interests are in the field of translational nanomedicine centered on a unique hydroxyl dendrimer platform technology. His team has developed approaches to target and manipulate injured glia/macrophages specifically from systemic administration. Targeted therapies for neuroinflammation and angiogenesis are being developed with this approach, with significant implications for addressing unmet needs in many CNS, systemic and ocular disorders as well as cancer (e.g. ARDS, childhood cerebral adrenoleukodystropy, cerebral palsy, age-related macular degeneration, diabetic retinopathy, brain tumors, immunotherapy, neuroimaging).  Dr. Rangaramanujam is an author of >75 patents (issued and pending, licensed), more than 120 peer-reviewed publications, and is supported by significant NIH and federal funding (>$35M over 10 years). He has won several recognitions, including fellowship of the American Institute of Medical and Biological Engineers (AIMBE) and the NSF CAREER award. He is the co-founder and chief technology officer of Ashvattha Therapeutics Inc., a Hopkins spinoff that is translating his team’s patented dendrimer technologies to the clinic, with a lead product in early clinical trials for a pediatric brain disorder.

Title of Research Sharing: Glia-Directed Nanomedicines: Engineering Neuroinflammation for Novel Central Nervous System (CNS) Therapies

Abstract of Research Sharing:  Inflammation, mediated by reactive microglia / macrophages, plays a key role in many systemic, neurological and ocular disorders. Therefore, targeted, localized, and ‘appropriate reprogramming’ of reactive macrophages can have a significant impact on many disorders, offering potent therapeutic strategies for unmet needs. However, targeted delivery of drugs to specific cells at remote sites of injury is a challenge. We take advantage of the selective, intrinsic, pathology-dependent, reactive microglia/macrophage uptake of dendrimers (tree-like nanoparticles, 4nm in size, with no targeting moieties) in >30 models of CNS, ocular, and systemic disorder models in six species (mouse to primates). Building on such selective uptake, we have designed dendrimer-drug conjugates which have shown significant promise for translation. We show that appropriate manipulation of reactive glia/macrophages can have dramatic impact on inflammation, oxidative stress, excitotoxicity, neurobehavior and cognition in many models. These results not only provide unique insights into the role of macrophages on disease and repair,  but also offer opportunities for developing potent therapies for unmet needs,  from childhood disorders such as cerebral palsy and autism, to disorders affecting the elderly such as COVID-related injuries, age-related macular degeneration, and Alzheimer’s Disease. Examples of the promise of this approach and efforts towards clinical translation will be discussed. Potential of this approach in rheumatology will be highlighted.

Girdhari Roy

Birla Institute of Technology and Science Pilani, Hyderabad Campus, India

Girdhari Roy is pursuing his Ph.D in pharmaceutical sciences from BITS Pilani, Hyderabad campus under the supervision of Prof. V. Vamsi Krishna Venuganti. Prior to his Ph.D, he worked in the pharmaceutical industry for 2 years. At present, he is looking for opportunities where he can utilize his educational qualification and industrial experience to support commercialization of products.

Title of Research Sharing: Development of Microneedle Devices for Ophthalmic Drug Delivery

Abstract of Research Sharing:  Ophthalmic drug delivery using conventional delivery systems such as eye drop solution, suspension, etc., is always a challenge for the pharmaceutical scientist. Poor ocular tissue permeability and less retention time on the ocular surface decrease the ocular bioavailability. Several invasive approaches were employed to overcome the poor bioavailability issues using intrastromal, intravitreal injection, ocular implant etc. However, the limitations such as retinal detachment, pain at the injection site, and poor patient compliance decrease its popularity. So, there is a need to develop a drug delivery system that can overcome the limitation of both topically applied formulation and invasive drug delivery methods. Our study investigated the role of polymeric microneedle (MN) based drug delivery device to deliver the therapeutics in a minimally invasive manner. The MN's placement on the eye globe is always a challenge, here we have designed a microneedle corneal device (MCD) device, which mimics the shape of the commercially available contact lens. The 25 MNs are centrally located into the concave portion of the MCD. The MCD was prepared using micromolding techniques. The micromolding technique can significantly contribute to industrial applicability, where the same mold can be used multiple times to produce MCP. The effectiveness of the MCD to deliver a various range of drug molecules was investigated using in-vitro, ex-vivo, and in-vivo models in the excised human cornea, excised porcine eye globe, and the male New Zeeland white rabbit, respectively. Further, we have also investigated the safety, sterility, and irritation potential of the polymeric microneedle using Hen's Egg Test – Chorioallantoic Membrane (HET-CAM), microbial growth study, and MTT assay using human corneal epithelial cell lines. The SEM image of the MCD reveals the uniform distribution of MNs on the concave portion of the device. The polymeric MN of MCD gets dissolved within a minute post-application on the cornea. The ex-vivo and in-vivo study reveals its effectiveness in delivering  the  therapeutics  more  effectively  than  topically applied formulation. The  HET- CAM study shows the MCD prepared using dissolving polymer did not cause any irritation. Similarly, the MTT assay reveals its safety during the application. We can conclude that the polymer-based dissolvable microneedle corneal device can be a better alternative to deliver the therapeutics in the eye in a minimally invasive manner.

 
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The conference is organised by the Pharmaceutical Innovation & Research Centre (PIRC) of NUS Department of Pharmacy, NUS Faculty of Science, in partnership with Covate Pharma, the Society for Pharmaceutical Dissolution Science (SPDS), the Controlled Release Society (CRS), A*Star CoRE-Net.

Explain My Research: NUS meets industry was initialized by the NUS Faculty of Science Industry Committee. 

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