Day 2 :
Keynote Forum
Michael Chorny
University of Pennsylvania, USA
Keynote: Codrug-impregnated nanocarriers as an experimental therapy for aggressive neuroblastoma
Time : 09:00-09:40
Biography:
Michael Chorny is an Associate Professor in the Department of Pediatrics from University of Pennsylvania and the Children’s Hospital of Philadelphia (CHOP). He has received his Doctoral training in Pharmaceutical Sciences at the Hebrew University of Jerusalem and is pursuing his Post-doctoral studies at CHOP. In 2009, he joined the Faculty of Perelman School of Medicine at the University of Pennsylvania. His research focuses on development and evaluation of biodegradable nanocarriers for targeted delivery of drugs, gene vectors and cells for cardiovascular disease applications and cancer therapy.
Abstract:
Camptothecin derivatives are a family of potent small-molecule topoisomerase I inhibitors with a broad spectrum of activity against adult and pediatric cancers. Safety, metabolic stability and therapeutic efficacy of camptothecin can be greatly improved by formulation and delivery in biodegradable nanocarriers. In our studies, we evaluated an experimental delivery strategy integrating nanocarriers with novel, in situ activatable codrug of a potent camptothecin (SN-38) and redox-silent tocol mitocans. Reversibly hydrophobized codrug constructs stably encapsulated in sub-100 nm sized nanoparticles (NP) were comparatively examined in orthotopic xenograft models of aggressive neuroblastoma (NB), the most common solid tumor in infants responsible for 15% of all childhood cancer deaths. NP loaded with a phenolic ester codrug were found to be most effective against both chemo-naïve and chemoresistant NB cells (IMR-32 and BE (2)-C cells derived at diagnosis and during relapse after chemotherapy, respectively) in conditions modeling different levels of exposure experienced by NB cells in the tumor environment. Slowly activatable codrug with phenolic carbonate and aliphatic ester designs were notably less efficient. In a model of previously untreated disease, phenolic ester codrug-loaded nanocarriers administered weekly for four weeks induced rapid regression and completely inhibited regrowth of orthotopic tumors over a 180-day period. The same codrug/ nanocarriers formulation tested against chemoresistant NB potently suppressed tumor growth and extended animal survival up to seven weeks, in contrast to a marginal and transient effect of a clinically used SN-38 precursor, irinotecan. Our experimental results in preclinical NB models faithfully reproducing key features of aggressive disease provide evidence that camptothecinmitocan codrug can be rationally designed as a therapeutic cargo for nanocarriers-based therapy of high-risk NB. Integrated codrug/nanocarriers-based delivery is a promising experimental treatment strategy for pediatric and adult solid tumors not responding to standard therapies.
Keynote Forum
Michael Chorny
University of Pennsylvania, USA
Keynote: Codrug-impregnated nanocarriers as an experimental therapy for aggressive neuroblastoma
Time : 09:05-09:45
Biography:
Michael Chorny is an Associate Professor in the Department of Pediatrics from University of Pennsylvania and the Children’s Hospital of Philadelphia (CHOP). He has received his Doctoral training in Pharmaceutical Sciences at the Hebrew University of Jerusalem and is pursuing his Post-doctoral studies at CHOP. In 2009, he joined the Faculty of Perelman School of Medicine at the University of Pennsylvania. His research focuses on development and evaluation of biodegradable nanocarriers for targeted delivery of drugs, gene vectors and cells for cardiovascular disease applications and cancer therapy.
Abstract:
Camptothecin derivatives are a family of potent small-molecule topoisomerase I inhibitors with a broad spectrum of activity against adult and pediatric cancers. Safety, metabolic stability and therapeutic efficacy of camptothecin can be greatly improved by formulation and delivery in biodegradable nanocarriers. In our studies, we evaluated an experimental delivery strategy integrating nanocarriers with novel, in situ activatable codrug of a potent camptothecin (SN-38) and redox-silent tocol mitocans. Reversibly hydrophobized codrug constructs stably encapsulated in sub-100 nm sized nanoparticles (NP) were comparatively examined in orthotopic xenograft models of aggressive neuroblastoma (NB), the most common solid tumor in infants responsible for 15% of all childhood cancer deaths. NP loaded with a phenolic ester codrug were found to be most effective against both chemo-naïve and chemoresistant NB cells (IMR-32 and BE (2)-C cells derived at diagnosis and during relapse after chemotherapy, respectively) in conditions modeling different levels of exposure experienced by NB cells in the tumor environment. Slowly activatable codrug with phenolic carbonate and aliphatic ester designs were notably less efficient. In a model of previously untreated disease, phenolic ester codrug-loaded nanocarriers administered weekly for four weeks induced rapid regression and completely inhibited regrowth of orthotopic tumors over a 180-day period. The same codrug/ nanocarriers formulation tested against chemoresistant NB potently suppressed tumor growth and extended animal survival up to seven weeks, in contrast to a marginal and transient effect of a clinically used SN-38 precursor, irinotecan. Our experimental results in preclinical NB models faithfully reproducing key features of aggressive disease provide evidence that camptothecinmitocan codrug can be rationally designed as a therapeutic cargo for nanocarriers-based therapy of high-risk NB. Integrated codrug/nanocarriers-based delivery is a promising experimental treatment strategy for pediatric and adult solid tumors not responding to standard therapies.
- Pharmaceutical Packaging and Logistics | Regulatory Authority Compliance | Clinical Trials and Pharmacovigilance | Pharmacoeconomics | Pharmaceutical Manufacturing, Scale Up and Tech Transfer | QC & QA: Quality Control and Quality Assurance
Location: Philadelphia, USA
Chair
Freddie Ann Hoffman
Heterogeneity LLC, USA
Co-Chair
Michael Chorny
University of Pennsylvania, USA
Session Introduction
Hongbin Wang
California Northstate University, USA
Title: Complement peptide C4a mitigates LPS-induced endothelium disruption, cytokine production, ERK activation, and [Ca2+] influx from human moncytes- A new therapeutic intervention for endotoxin shock
Time : 10:55:11:30
Biography:
Hongbin Wang received his PhD in 2010 from the University of Pennsylvania and Post-doctoral training from University of Pennsylvania Perelman School of Medicine. Now, he is an Assistant Professor of Pharmacology in the Department of Pharmaceutical and Biomedical Sciences at the California Nothstate University College of Pharmacy. He has published more than 40 papers in peer reviewed journals.
Abstract:
Activation of the complement cascade is a major effector of the inflammatory response. Cleavage of complement components in the course of activation produces low-molecular-weight peptides, including C3a, C4a, and C5a. Both C3a and C5a have potent anaphylatoxin properties. Our recent study idnetified that C4a mediates effector functions through binding to proteaseactivated receptors (PAR) 1 and PAR4. Early study demonstrated that animals with complement C4 deficiency were reported to be more susceptable to endotoxic shock, suggesting that C4 protects animals from endotoxic effects. However, the molecular mechanism for C4 protective effect on endotoxin shock in animals is poorly understood. We propose that C4 activation peptide, C4a, possiblly through binding to PAR1/4 on platelets, monocytes, and endothelial cells, inhibits LPS-induced platelet aggregation, IL-1β and TNFα cytokine production from monocytes, and endothelium permeability to achieve C4 protective effects in endotoxin shock animal models. In the present study, we found that pretreatment with C4a to human primary monocytes can significantly inhibit LPS-induced IL-1β and TNFα production. Moreover, LPS-induced ERK phosphorylation and [Ca2+] influx were significantly inhibited by the pretreatment of C4a. Our experiments also revealed that C4a significantly decreased endothelium permeability when human endothelial cells were cultured in the presence of LPS, indicating under endotoxemia condition, C4a prevents endothelium disruption. Our data provide deeper insight into the mechanism of C4’s protective effect on endotoxic shock and would provide a valuable resource for the wider scientific community to generate future therapeutic interventions for the treatment of clinical endotoxemia.
Aysu Yurdasiper Erdem
Ege University, Turkey
Title: Characterization and aerolization properties of Carrageenan dry powder inhalers containing ibuprofen
Time : 11:30:12:05
Biography:
Aysu Yurdasiper Erdem obtained her BSc and MSc degrees from Faculty of Pharmacy at Ege University, Izmir, Turkey respectively, followed by a PhD Degree from Department of Pharmaceutical Technology, Ege University. She has studied as a PhD Student with TUBITAK Scholarship in Cardiff University, Welsh School of Pharmacy, Cardiff, UK. Her work is focused on dry powder inhalers, dermal delivery (topical, transdermal drug systems), controlled release formulations (nanoparticles, microparticles) for drug delivery. She is Editor in Chief of American Journal of Drug Delivery and Therapeutics, also Editor on the Editorial Board of several international journals. She has filed a national patent on dry powder inhaler formulation. She has been working as a Researcher in Department of Pharmaceutical Technology, Ege University. Her current research interests focus on development of novel nanomedicine including polymers and in vitro-in vivo evaluation for treatment of asthma.
Abstract:
Statement of the Problem: Delivery via the lung represents a unique opportunity to circumvent the prostaglandin independent mucosal injury associated with the oral administration of NSAIDs, as it eliminates the direct GI exposures to these drugs. Furthermore, the pulmonary drug delivery route usually decreases the dose requirements by 10 to 20 folds. Additionally, a slower rate of respiratory decline is shown in cystic fibrosis patients on high, oral doses of IBU in comparison to placebo. Dry powder inhalation is the most versatile way of pulmonary administration of API. It allows numerous formulation variations and many different dry powder inhaler (DPI) devices to design a drug product matching therapeutic needs. The purpose of the present research was to formulate IBU dry powder inhalers (DPI) containing Carrageenan as a natural polymer and to indicate appropriate excipient and polymer to improve the aerodynamic properties of the DPI formulations.
Materials & Methods: Trehalose and leucine were dissolved in Carrageenan solution. IBU was added into the solution. The mixture was then sprays and dried with constant stirring using a Büchi Nanospray dryer B-90. The formulations were analyzed by thermogravimetry (Perkin Elmer 4000). The in vitro aerosolization performance was investigated using next generation impactor (Copley). In vitro dissolution studies were done with paddle over disc method USP apparatus 2.
Results & Discussion: Encapsulation efficiency and the Carr’s Index increased with increasing Carrageenan. The highest encapsulation efficiency value was 78.6±2.9. On the other hand, the process yield decreased with increasing carrageenan. The lowest process yield value was 71.16±1.7%. The fine particle fractions of the formulations were over 37.8±3.2% thanks to the nanospray dryer. The release of IBU was nearly complete within 8 hours with 1:1 drug: polymer.
Conclusions: In this study, IBU DPI containing carrageenan was obtaining with good process yield, aerolization properties and low cohesively.
Imeda Rubashvili
Tbilisi State University, Georgia
Title: Validation of sampling procedures and quantitative determination HPLC method of Alprazolam residues for cleaning validation
Time : 12:05:12:40
Biography:
Imeda Rubashvili is an Assistant Professor, a Scientific Researcher at Ivane Javakhishvili Tbilisi State University and the Head of Validation Department of Pharmaceutical Company “Aversi-Rational” Ltd. He has published more than 30 scientific papers and participated in more than 30 international scientific conferences. He is the Member of the Council of Young Scientists of the Georgian National Academy of Sciences.
Abstract:
Cleaning validation is a critical analytical responsibility of quality assurance system in pharmaceutical industry and ensures the efficiency of the cleaning routine procedure used in production which means that it is capable and effective in removing active pharmaceutical ingredient residues from the manufacturing equipment surfaces below a predetermined level and to prevent cross-contamination of next product. The aim of this study was to validate swab and rinse sampling procedures and demonstrate the applicability of developed HPLC method for quantitative estimation of alprazolam residues in cleaning control samples collected from pharmaceutical equpment surfaces after manufacturing of alprzolam 1 mg uncoated tablets.The swab and rinse sampling procedures were developed in order to obtain a suitable recovery (>90 %). The known amounts of alprazolam are spiked onto representative surfaces, which are dried, sampled and analyzed using the validated HPLC method. Additionally, the robustness of sampling procedures was assessed. For swab sampling the surface (sampling area - 5 × 5 cm2) was successively wiped with one micro polyester swab (3×2.5×10 mm) moistened with diluent – methanol. The method was developed using LC system “Ag 1260 Infinity” and Prodigy C8(2) 250 × 4.0 mm, 5 μm column with a mobile phase - a mixture of methanol, phosphate buffer pH 3.0 and acetonitrile (10 : 45 : 45 v/v); The flow rate – 1.4 ml/min; The detector wavelength - 220 nm; The injection volume – 20 μL; The column temperature – 300C. The method was validated with respect to robustness, system suitability test, specificity, linearity-range, accuracy, precision (intra-day and inter day), limit of detection (LOD) and quantitation (LOQ). The stability of alprazolam solutions was also studied. These studies were performed in accordance with established ICH Q2 guideline. The calibration curve is linear r2=1.00000 over a concentration range 0.025 – 10 μg/mL; LOD - 0.005 μg/mL and LOQ - 0.025 μg/mL.
Adella Aparna
Vaagdevi College of Pharmacy, India
Title: Enhancement of solubility and bioavailability of Clopidogrel by selfnanoemulsifying drug delivery system
Time : 13:50-14:25
Biography:
Abstract:
A self-nanoemulsifying drug-delivery system (SNEDDS) has been explored to improve the solubility and dissolution profile of poorly soluble drug clopidogrel. Different formulations were prepared using different oils, surfactants and cosurfactants. A pseudo ternary phase diagram was constructed to identify the self-micro emulsification region. Further, the resultant formulations were investigated for clarity, phase separation, drug content, % transmittance, globule size, freeze-thaw, in vitro dissolution studies, particle size analysis and zeta potential. On the basis of particle size, zeta potential and dissolution profile and other studies, F6 was found to be the best formulation of clopidogrel SNEDDS. The particle size of the emulsion is a crucial factor in self-emulsification performance because it determines the rate and extent of drug release as well as absorption. The average particle size of clopidogrel SNEDDS for transparent micro-emulsions should be less than 50nm. The particle size of the optimized SNEDDS formulation was found to be 5.2 nm and zeta potential was found to be -29 mV which comply with the requirement of the zeta potential for stability. The faster dissolution from SNEDDS may be attributed to the fact that in this formulation, the drug is a solubilized form and upon exposure to dissolution medium results in small droplet that can dissolve rapidly. The % release from optimized SNEDDS formulation F6 was highest (98.93%) and faster than other SNEDDS formulations and pure drug substance indicating influence of droplet size on the rate of drug dissolution. FTIR data revealed no physicochemical interaction between drug and excipients. Thus clopidogrel with SNEDDS formulation may be used for the improvement of solubility and dissolution rate in the effective management of heart disease.