Abstracts for Round Table (RT) Session 2: Advancements in Pharmaceutical Sciences
Moderators: Heather Frericks Schmidt and Jayshil Bhatt
Presentation 1
Particle Engineering of Amorphous Solid Dispersions by Atomic Layer Coating
Dana Moseson, PhD, Senior Principal Scientist, Pfizer Inc.
Abstract:
Amorphous solid dispersions (ASDs) are a popular formulation strategy to improve bioavailability of poorly water-soluble drugs. To further ASD technology, fundamental understanding of processing variables, material properties, structure/critical quality attributes (CQAs), and product performance must be generated. Atomic layer coating was investigated as a particle engineering strategy to influence physical stability, dissolution, and manufacturability challenges of ASDs. Atomic layer deposition was used to apply aluminum and zinc oxide coatings of 5-25 nm on ASD particles prepared from varying chemistry, particle attributes, and coating properties, which were subsequently stored at accelerated temperature and humidity. While the uncoated particles underwent surface crystallization in 1-2 weeks, crystallization was inhibited in the coated particles for longer time periods, demonstrating the broad applicability of coating to stabilize amorphous formulations. Non-sink dissolution studies suggest that the atomic layer coating does not hinder dissolution performance for HPMCAS-based ASDs. However, for PVPVA-based ASDs, due to the competing kinetics of hydration and gelation, release rates were slowed. Through formulating the coated ASD particles into a disintegrating tablet, accelerated hydration kinetics were observed, and drug release was rescued. Additionally, improved powder flow and hygroscopicity were observed.
Bio:
Dr. Dana Moseson is a Senior Principal Scientist working in the Formulation and Process Design group of the Drug Product Design department at Pfizer in Groton, CT, where she specializes in the formulation design, characterization, and manufacturing of early-stage clinical drug products using amorphous solid dispersion technology. She has over 12 years of industry experience developing formulations for early phase NCEs. Dana received a PhD in Industrial and Physical Pharmacy from Purdue University, where her research under Professor Lynne Taylor focused on the thermodynamic and kinetic aspects of hot melt extrusion processing to produce ASDs, as well as investigating the in vitro biopharmaceutics implications of residual crystallinity in ASDs. During her postdoctoral research, she investigated the physical stability and dissolution performance implications of atomic layer coating on amorphous solid dispersion particles. She has authored more than 25 publications on amorphous solid dispersion formulation design, hot melt extrusion processing design, crystallization, particle engineering, characterization, and in vitro dissolution performance of supersaturating formulations, and has presented at numerous scientific meetings and conferences. She is an associate editor of AAPS Open and serves on the editorial advisory board of Molecular Pharmaceutics.
Presentation 2
Application of an Interdisciplinary Approach to Form Selection
Darren Reid, PhD, Director of Synthetics Enabling Technologies, Amgen Inc.
Abstract:
Selecting the solid-state form of an active pharmaceutical ingredient (API) in drug development is key to determining the final performance of the drug substance and drug product. Form selection requires an interdisciplinary approach to discover, monitor, and evaluate the solid-state characteristics, biopharmaceutical properties, stability, and processability of form candidates. The importance of aligning critical material attributes with the desired target product profile to ensure drug safety and efficacy will be discussed. The form selection strategy is dependent on factors related to the administration route, dosage form, and therapeutic indication, and an interdisciplinary framework with four prioritized sets of target attributes for oral delivery: solid-state properties, biopharmaceutical performance, stability, and processability will be presented with a focus on form selection to support immediate-release oral medications. The interdisciplinary form selection process will be demonstrated through case studies highlighting how each set of target attributes were evaluated leading to the selection of ideal forms for development.
Bio:
Darren Reid joined Amgen’s Preformulation group as a Scientist in 2004 and held roles of increasing responsibility. Currently he is Director of the Synthetics Enabling Technologies group in Pre-Pivotal Drug Product and is responsible for synthetics Dev-Molecule Assessment and form selection, end-to-end solid state process support, and synthetics formulation development for preclinical and parenteral FIH studies. Before joining Amgen, Darren received his Ph.D. in physical organic chemistry from McMaster University and held Postdoctoral positions at the University of Calgary and Pfizer, developing approaches to assess oxidative stability. He has co-authored over 30 external articles, reviews, and book chapters, and several patents/applications, including for the LUMAKRAS(R) commercial form. His research interests include drug stability, developability assessment, and formulation strategies. Darren is a founding steering committee member for Lhasa Ltd.’s Zeneth drug degradation prediction program and an active member of ACS and AAPS.
Presentation 3
Polymeric Mesoscale Nanoparticles Selectively Target Gene Therapies to the Kidneys
Ryan Williams, PhD, Assistant Professor, Biomedical Engineering, The City University of New York
Abstract:
The last decade has seen a rapid expansion of the clinical utility of gene therapies. Many of these are focused on liver diseases, with a few exceptions. This is in large part due to the relative abundance of gene therapy carriers that target the liver and other accessible sites. However, there has been very limited success in the development of kidney-targeted gene therapy carriers to treat renal diseases. Here, we focused on the development of a non-viral gene delivery tool composed of FDA-approved polymeric materials to treat chronic kidney diseases.
We optimized the formulation of kidney-targeted polymeric mesoscale nanoparticles (MNPs) to maximize the encapsulation of siRNA and mRNA gene therapies for kidney diseases. Specifically, we designed a two-step mixture-nanoprecipitation formulation to design MNPs composed of poly-lactic-co-glycolic polyethylene glycol di-block (PLGA-PEG) polymer. Several MNP formulations loading a luciferase reporter mRNA were evaluated for their ability to target the kidneys. Similarly, several MNP formulations loaded with siRNAs that target inflammatory cytokines (IL-6, IL-1B, TNFa) were evaluated in both mouse and rat models of chronic kidney disease. We evaluated blood and urine markers of renal function in both models, as well as performed a histological assessment of renal inflammation.
We optimized mesoscale nanoparticles for maximal siRNA and mRNA therapy loading while maintaining a 300 – 400 nm polymeric MNP diameter. In healthy immunocompetent hairless mice, we found that MNPs specifically localize to the kidneys and deliver functional luciferase reporter mRNA via in vivo bioluminescence imaging. In both mouse and rat chronic kidney disease models (UUO and DSS, respectively), we administered inflammatory cytokine-silencing siRNA-loaded MNPs. These studies demonstrated substantial therapeutic efficacy and reduction of inflammation from kidney-targeted siRNA delivery as measured by renal fibrosis and injury markers. MNPs localize to the kidneys with up to 26-fold specificity compared to other organs, therefore there is little to no off-target delivery or toxicity.
We anticipate further pre-clinical development of both mRNA and siRNA-targeted delivery to the kidneys for chronic kidney diseases will result in a highly specific novel therapy with minimal off-target effects, a first-in-class indication for extrahepatic gene delivery.
Bio:
Dr. Williams is an Assistant Professor of Biomedical Engineering in The City College of New York Grove School of Engineering. He was an American Heart Association Postdoctoral Fellow at Memorial Sloan Kettering Cancer Center in the Cancer Nanomedicine Lab of Dr. Daniel Heller from 2013 until August 2019. Dr. Williams earned a PhD in Pharmaceutical Sciences from West Virginia University in 2013 and a BA in Biology from the University of Virginia in 2008. At CCNY, Dr. Williams’ lab focuses on the design and characterization of nanotechnologies for implantable optical diagnostics and targeted drug delivery systems. The lab has been recognized for its work through an NIH NIGMS R35 MIRA award and an Oak Ridge Associated Universities Junior Faculty Award.
Moderators: Heather Frericks Schmidt and Jayshil Bhatt
Presentation 1
Particle Engineering of Amorphous Solid Dispersions by Atomic Layer Coating
Dana Moseson, PhD, Senior Principal Scientist, Pfizer Inc.
Abstract:
Amorphous solid dispersions (ASDs) are a popular formulation strategy to improve bioavailability of poorly water-soluble drugs. To further ASD technology, fundamental understanding of processing variables, material properties, structure/critical quality attributes (CQAs), and product performance must be generated. Atomic layer coating was investigated as a particle engineering strategy to influence physical stability, dissolution, and manufacturability challenges of ASDs. Atomic layer deposition was used to apply aluminum and zinc oxide coatings of 5-25 nm on ASD particles prepared from varying chemistry, particle attributes, and coating properties, which were subsequently stored at accelerated temperature and humidity. While the uncoated particles underwent surface crystallization in 1-2 weeks, crystallization was inhibited in the coated particles for longer time periods, demonstrating the broad applicability of coating to stabilize amorphous formulations. Non-sink dissolution studies suggest that the atomic layer coating does not hinder dissolution performance for HPMCAS-based ASDs. However, for PVPVA-based ASDs, due to the competing kinetics of hydration and gelation, release rates were slowed. Through formulating the coated ASD particles into a disintegrating tablet, accelerated hydration kinetics were observed, and drug release was rescued. Additionally, improved powder flow and hygroscopicity were observed.
Bio:
Dr. Dana Moseson is a Senior Principal Scientist working in the Formulation and Process Design group of the Drug Product Design department at Pfizer in Groton, CT, where she specializes in the formulation design, characterization, and manufacturing of early-stage clinical drug products using amorphous solid dispersion technology. She has over 12 years of industry experience developing formulations for early phase NCEs. Dana received a PhD in Industrial and Physical Pharmacy from Purdue University, where her research under Professor Lynne Taylor focused on the thermodynamic and kinetic aspects of hot melt extrusion processing to produce ASDs, as well as investigating the in vitro biopharmaceutics implications of residual crystallinity in ASDs. During her postdoctoral research, she investigated the physical stability and dissolution performance implications of atomic layer coating on amorphous solid dispersion particles. She has authored more than 25 publications on amorphous solid dispersion formulation design, hot melt extrusion processing design, crystallization, particle engineering, characterization, and in vitro dissolution performance of supersaturating formulations, and has presented at numerous scientific meetings and conferences. She is an associate editor of AAPS Open and serves on the editorial advisory board of Molecular Pharmaceutics.
Presentation 2
Application of an Interdisciplinary Approach to Form Selection
Darren Reid, PhD, Director of Synthetics Enabling Technologies, Amgen Inc.
Abstract:
Selecting the solid-state form of an active pharmaceutical ingredient (API) in drug development is key to determining the final performance of the drug substance and drug product. Form selection requires an interdisciplinary approach to discover, monitor, and evaluate the solid-state characteristics, biopharmaceutical properties, stability, and processability of form candidates. The importance of aligning critical material attributes with the desired target product profile to ensure drug safety and efficacy will be discussed. The form selection strategy is dependent on factors related to the administration route, dosage form, and therapeutic indication, and an interdisciplinary framework with four prioritized sets of target attributes for oral delivery: solid-state properties, biopharmaceutical performance, stability, and processability will be presented with a focus on form selection to support immediate-release oral medications. The interdisciplinary form selection process will be demonstrated through case studies highlighting how each set of target attributes were evaluated leading to the selection of ideal forms for development.
Bio:
Darren Reid joined Amgen’s Preformulation group as a Scientist in 2004 and held roles of increasing responsibility. Currently he is Director of the Synthetics Enabling Technologies group in Pre-Pivotal Drug Product and is responsible for synthetics Dev-Molecule Assessment and form selection, end-to-end solid state process support, and synthetics formulation development for preclinical and parenteral FIH studies. Before joining Amgen, Darren received his Ph.D. in physical organic chemistry from McMaster University and held Postdoctoral positions at the University of Calgary and Pfizer, developing approaches to assess oxidative stability. He has co-authored over 30 external articles, reviews, and book chapters, and several patents/applications, including for the LUMAKRAS(R) commercial form. His research interests include drug stability, developability assessment, and formulation strategies. Darren is a founding steering committee member for Lhasa Ltd.’s Zeneth drug degradation prediction program and an active member of ACS and AAPS.
Presentation 3
Polymeric Mesoscale Nanoparticles Selectively Target Gene Therapies to the Kidneys
Ryan Williams, PhD, Assistant Professor, Biomedical Engineering, The City University of New York
Abstract:
The last decade has seen a rapid expansion of the clinical utility of gene therapies. Many of these are focused on liver diseases, with a few exceptions. This is in large part due to the relative abundance of gene therapy carriers that target the liver and other accessible sites. However, there has been very limited success in the development of kidney-targeted gene therapy carriers to treat renal diseases. Here, we focused on the development of a non-viral gene delivery tool composed of FDA-approved polymeric materials to treat chronic kidney diseases.
We optimized the formulation of kidney-targeted polymeric mesoscale nanoparticles (MNPs) to maximize the encapsulation of siRNA and mRNA gene therapies for kidney diseases. Specifically, we designed a two-step mixture-nanoprecipitation formulation to design MNPs composed of poly-lactic-co-glycolic polyethylene glycol di-block (PLGA-PEG) polymer. Several MNP formulations loading a luciferase reporter mRNA were evaluated for their ability to target the kidneys. Similarly, several MNP formulations loaded with siRNAs that target inflammatory cytokines (IL-6, IL-1B, TNFa) were evaluated in both mouse and rat models of chronic kidney disease. We evaluated blood and urine markers of renal function in both models, as well as performed a histological assessment of renal inflammation.
We optimized mesoscale nanoparticles for maximal siRNA and mRNA therapy loading while maintaining a 300 – 400 nm polymeric MNP diameter. In healthy immunocompetent hairless mice, we found that MNPs specifically localize to the kidneys and deliver functional luciferase reporter mRNA via in vivo bioluminescence imaging. In both mouse and rat chronic kidney disease models (UUO and DSS, respectively), we administered inflammatory cytokine-silencing siRNA-loaded MNPs. These studies demonstrated substantial therapeutic efficacy and reduction of inflammation from kidney-targeted siRNA delivery as measured by renal fibrosis and injury markers. MNPs localize to the kidneys with up to 26-fold specificity compared to other organs, therefore there is little to no off-target delivery or toxicity.
We anticipate further pre-clinical development of both mRNA and siRNA-targeted delivery to the kidneys for chronic kidney diseases will result in a highly specific novel therapy with minimal off-target effects, a first-in-class indication for extrahepatic gene delivery.
Bio:
Dr. Williams is an Assistant Professor of Biomedical Engineering in The City College of New York Grove School of Engineering. He was an American Heart Association Postdoctoral Fellow at Memorial Sloan Kettering Cancer Center in the Cancer Nanomedicine Lab of Dr. Daniel Heller from 2013 until August 2019. Dr. Williams earned a PhD in Pharmaceutical Sciences from West Virginia University in 2013 and a BA in Biology from the University of Virginia in 2008. At CCNY, Dr. Williams’ lab focuses on the design and characterization of nanotechnologies for implantable optical diagnostics and targeted drug delivery systems. The lab has been recognized for its work through an NIH NIGMS R35 MIRA award and an Oak Ridge Associated Universities Junior Faculty Award.
