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Journal of Pharmaceutical Sciences
Journal Prestige (SJR): 0.984
Citation Impact (citeScore): 3
Number of Followers: 149  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0022-3549 - ISSN (Online) 1520-6017
Published by Elsevier Homepage  [3162 journals]
  • Impact of Superdisintegrants and Film Thickness on Disintegration Time of
           Strip Films Loaded With Poorly Water-Soluble Drug Microparticles
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Lu Zhang, Marie Aloia, Barbara Pielecha-Safira, Honghao Lin, Prarthana Manoj Rajai, Kuriakose Kunnath, Rajesh N. Davé Although strip films are a promising platform for delivery of poorly water-soluble drug particles via slurry casting, the effect of critical material attributes, for example, superdisintegrants (SDIs) on critical quality attributes, including film disintegration time (DT), remains underexplored. A 2-level factorial design is considered to examine the impact of the SDI type (sodium starch glycolate and croscarmellose sodium), their amount, and film thickness. SDIs were used with hydroxypropyl methylcellulose (E15LV) and glycerin solutions along with viscosity matching. Fenofibrate, a model poorly water-soluble drug, was micronized and surface modified via fluid energy milling. Significant decreases in film DT, measured using 3 different methods, were observed due to the addition of SDIs. Percentage reduction in DT was a strong function of SDI amount, and thinner films disintegrated faster. Films with either higher SDI concentrations (>9%) or films under 80 μm, exhibited fast DT (80% in 10 min). All films achieved good content uniformity, except for those with the lowest amount of SDI, attributed to insufficient viscosity and thickness nonuniformity due to the SDI. Finally, all films achieved adequate mechanical properties, notwithstanding minor negative impact of SDIs.
       
  • Simultaneous Retrodialysis by Calibrator for Rapid In Vivo Recovery
           Determination in Target Site Microdialysis
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Yichao Yu, Hardik Chandasana, Taran Sangari, Christoph Seubert, Hartmut Derendorf Concentrations in the interstitial tissue space are of clinical interest for many antibiotics and can be directly measured by microdialysis. Quantitative microdialysis strongly depends on reliable recovery estimates obtained from a suitable calibrator. Cefazolin (CFZ) is frequently used as a prophylactic antibiotic to prevent surgical site infections. This study aimed to develop a reliable and rapid calibration technique for CFZ microdialysis using cefuroxime (CFR) as a calibrator, which is applied simultaneously in the opposite direction via retrodialysis. Liquid chromatography-tandem mass spectrometry method was used for the measurement of both CFZ and CFR in microdialysate. Results from in vitro microdialysis experiments confirmed that CFR does not interfere with physicochemical properties of CFZ, and the loss of CFR is proportional to the gain of CFZ in microdialysis studies. Therefore, the validated bioanalytical assay is suitable to be applied in clinical microdialysis study of CFZ where microdialysis probes are simultaneously calibrated by retrodialysis of CFR. This approach shortens the overall sampling time of in vivo microdialysis studies significantly since calibration and sampling can be performed simultaneously and not in sequence as usually done. It also eliminates the necessary washout period if probe calibration is carried out before the actual sampling time.
       
  • Prediction of Human Brain Penetration of P-glycoprotein and Breast Cancer
           Resistance Protein Substrates Using In Vitro Transporter Studies and
           Animal Models
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Bo Feng, Angela C. Doran, Li Di, Mark A. West, Sarah M. Osgood, Jessica Y. Mancuso, Christopher L. Shaffer, Larry Tremaine, Jennifer Liras Four P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrates with human cerebrospinal fluid (CSF) concentrations and preclinical neuropharmacokinetics were used to assess in vitro–in vivo extrapolation of brain penetration in preclinical species and the ability to predict human brain penetration. Unbound brain (Cb,u), unbound plasma (Cp,u), and CSF compound concentrations (CCSF) were measured in rats and nonhuman primates (NHPs), and the unbound partition coefficients (Cb,u/Cp,u and CCSF/Cp,u) were used to assess brain penetration. The results indicated that for P-gp and BCRP dual substrates, brain penetration was severally impaired in all species. In comparison, for P-gp substrates that are weak or non-BCRP substrates, improved brain penetration was observed in NHPs and humans than in rats. Overall, NHP appears to be more predictive of human brain penetration for P-gp substrates with weak or no interaction with BCRP than rat. Although CCSF does not quantitatively correspond to Cb,u for efflux transporter substrates, it is mostly within 3-fold higher of Cb,u in rat and NHP, suggesting that CCSF can be used as a surrogate for Cb,u. Taken together, a holistic approach including both in vitro transporter and in vivo neuropharmacokinetics data enables a better estimation of human brain penetration of P-gp/BCRP substrates.
       
  • Probing the Amorphous State of Pharmaceutical Compounds Within Mesoporous
           Material Using Pair Distribution Function Analysis
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Alfonso E. Garcia-Bennett, Michael Lau, Nicholas Bedford Pharmaceutical compounds with poor solubility are loaded within mesoporous materials to understand the effect of mesoscale confinement on their dissolution behavior. Structural and calorimetric characterization is combined with atomic pair distribution function analysis probing the interactions between the silica surface and the loaded amorphous compound. While different degrees of amorphism are not identifiable from X-ray diffraction data or calorimetric techniques, the atomic pair distribution function analysis can help identify local ordering of the drug molecules. Together with a list of drug descriptors such as crystallization properties, molecular size, and glass transition temperature, the behavior of encapsulated compounds and their release kinetics may be rationalized. Dissolution experiments confirm that different release rates can be achieved with small differences in mesopore design, such as the presence of micropores in Santa Barbara Amorphous-15 and loading amount.
       
  • Self-Assembly of α-Cyclodextrin and β-Cyclodextrin: Identification and
           Development of Analytical Techniques
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): André Rodrigues Sá Couto, Alexey Ryzhakov, Thorsteinn Loftsson Recently, it has been shown that cyclodextrins (CDs) self-assemble in aqueous solutions to form aggregates. Such aggregation can give rise to formation of particulate matter in aqueous solutions. However, the analytical methodology available to detect and quantify these aggregates is still quite inadequate. Here, 5 different methods for evaluation of CD aggregate formation and determination of the critical aggregation concentration are evaluated: osmometry, viscosity, surface tension, dynamic light scattering, and permeability studies. Both the viscosity and surface tension methods applied were inadequate for aggregate detection, whereas the osmometry method can be used to study CD aggregation but with some limitations. Dynamic light scattering has also some limitations although it can be applied to detect CD aggregates and to estimate their hydrodynamic diameter. Overall, permeation studies proved to be the best method to detect and determine critical aggregation concentration. These results suggested that β-cyclodextrin (βCD) has higher tendency to aggregate than α-cyclodextrin (αCD). Filtration of αCD and βCD solutions affected the aggregate size distribution by breaking larger aggregates in to smaller ones that then reassembled to regenerate the larger ones upon storage. The osmolality studies showed that in aqueous αCD and βCD solutions, solute-solute interactions are favored over solute-solvent interactions with consequent CD aggregate formation.
       
  • Mechanism and Structural Factors of Lipid and Surfactant in the Formation
           of Self-Emulsified Nanoemulsion
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Pulkit Khatri, Jun Shao The study aims to elucidate the mechanism and the role of the molecular structure of surfactants and lipids in the formation of oil-in-water (o/w) self-emulsified nanoemulsions (SENs). The hypothesis is that the overall change of Gibb's free energy (ΔGf) during the mixing of the lipid and surfactant, the formation of the interface between the lipid nanodroplets and water, and the dispersion of the lipid nanodroplets into the water are the determinants of the formation of SEN, which are the result of the intermolecular interactions between the excipients involved. Various lipids and surfactants of different structures were studied for the possible formation of SEN. The results demonstrate that the formation of SEN requires (1) enough hydrophobic attractions between the surfactant molecule and the lipid molecule, which can break up the lipid-lipid and surfactant-surfactant intermolecular binding forces and (2) the surfactant to be able to associate with enough water molecules which can effectively cover the lipid droplets' surface to prevent coalescence.
       
  • Merits and Limitations of Dynamic Vapor Sorption Studies on the Morphology
           and Physicochemical State of Freeze-Dried Products
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Claudia Kunz, Henning Gieseler The goal of the present study was to assess the applicability of dynamic vapor sorption analysis of freeze-dried products. Water vapor sorption profiles of intact and ground cakes were recorded to determine the relevance of powder handling. Grinding prior to measurements appeared to be related with a more rapid uptake of water vapor and crystallization. Crystallization may be prevented when analyzing intact cakes. More hygroscopic materials appeared to require a longer time to achieve a constant mass. The specific surface area of different freeze-dried products was calculated from the sorption isotherms using water, organic solvents, and krypton. The specific surface areas calculated for mannitol with water and ethanol was in good agreement with krypton data. False high values were obtained from water vapor sorption of the investigated amorphous materials. The results were slightly improved by the application of vacuum. For trehalose and sucrose, no sorption and thus faulty results were detected with the studied organic solvents. The degree of crystallinity of mannitol within a binary formulation could not be determined by dynamic vapor sorption. Differences in sorption and crystallization tendencies of mannitol and sucrose that were freeze-dried separately and in a binary mixture were considered as the root cause.
       
  • Development, Characterization, and In Vitro Testing of Co-Delivered
           Antimicrobial Dry Powder Formulation for the Treatment of Pseudomonas
           aeruginosa Biofilms
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Tania F. Bahamondez-Canas, Silvia Ferrati, Daniel F. Moraga-Espinoza, Hugh D.C. Smyth Pseudomonas aeruginosa is an opportunistic bacteria responsible for recurrent lung infections. Previously, we demonstrated that certain materials improved the activity of tobramycin (Tob) against P. aeruginosa biofilms in vitro. We aimed to develop prototype dry powder formulations comprising Tob and a mixture of excipients and test its aerodynamic properties and antimicrobial activity. First, we evaluated different combinations of excipients with Tob in solution against P. aeruginosa biofilms. We selected the compositions with the highest activity, to prepare dry powders by spray drying. The powders were characterized by morphology, bulk density, water content, and particle size distributions. Finally, the antimicrobial activity of the powders was tested. The combinations of Tob (64 μg/mL) with l-alanine and l-proline (at 10 and 20 mM; formulations 1 and 2, respectively) and with l-alanine and succinic acid (at 20 mM; formulation 3) showed the highest efficacies in vitro and were prepared as dry powders. Formulation 1 had the best aerodynamic performance as indicated by the fine particle fraction and the best in vitro activity against P. aeruginosa biofilms. Formulation 3 represents a good candidate for further optimization because it demonstrated good dispersibility potential and optimization of the particle size distribution may achieve high delivery efficiencies.
       
  • Formulation Development, Optimization, and In Vitro–In Vivo
           Characterization of Natamycin-Loaded PEGylated Nano-Lipid Carriers for
           Ocular Applications
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Akash Patil, Prit Lakhani, Pranjal Taskar, Kai-Wei Wu, Corinne Sweeney, Bharathi Avula, Yan-Hong Wang, Ikhlas A. Khan, Soumyajit Majumdar The present study aimed at formulating and optimizing natamycin (NT)-loaded polyethylene glycosylated nano-lipid carriers (NT-PEG-NLCs) using Box-Behnken design and investigating their potential in ocular applications. Response surface methodology computations and plots for optimization were performed using Design-Expert® software to obtain optimum values for response variables based on the criteria of desirability. Optimized NT-PEG-NLCs had predicted values for the dependent variables which are not significantly different from the experimental values. NT-PEG-NLCs were characterized for their physicochemical parameters; NT's rate of permeation and flux across rabbit cornea was evaluated, in vitro, and ocular tissue distribution was assessed in rabbits, in vivo. NT-PEG-NLCs were found to have optimum particle size (
       
  • Development of Coprocessed Chitin-Calcium Carbonate as Multifunctional
           Tablet Excipient for Direct Compression
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Mohammad Chaheen, Noelia M. Sanchez-Ballester, Bernard Bataille, Ahmad Yassine, Emmanuel Belamie, Tahmer Sharkawi Owing to the increasing interest in multifunctional excipients for tableting, coprocessing of individual excipients is regularly used to produce excipients of improved multifunctionality superior to individual excipients or their physical mix. The use of chitin as an excipient in tablet formulation is limited because of certain drawbacks such as poor flowability and low true density. The objective of this work is to improve these properties through coprocessing of chitin with calcium carbonate (CaCO3) by precipitating CaCO3 on chitin particles using different methods. In addition, optimization of the coprocessed chitin was carried out to improve the excipient's properties. Physicochemical (CaCO3 content, true density, X-ray diffraction, infrared spectroscopy, and scanning electron microscopy) and functional testing (swelling force, flowability, tensile strength, deformation mechanism, and disintegration time) were used to characterize the coprocessed product. Results showed that the calcite CaCO3 polymorph is precipitated on the chitin surface and that it interacts with chitin at carbonyl- and amide-group level. In addition, the coprocessed excipient has an improved true density and powder flowability, with CaCO3 forming single layer on the chitin particles surface. Tableting studies showed that the coprocessed powder exhibited an intermediate deformation behavior between CaCO3 (most brittle) and chitin (most plastic). Tablets showed acceptable tensile strength and rapid disintegration (2-4 s). These results show the potential use of coprocessed chitin-CaCO3 as a multifunctional excipient for fast disintegration of tablets produced by direct compression.
       
  • Development of a New Punch Head Shape to Replicate Scale-Up Issues on a
           Laboratory Tablet Press III: Replicating Sticking Phenomenon Using the SAS
           Punch and Evaluation by Checking the Tablet Surface Using 3-D Laser
           Scanning Microscope
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Manabu Ito, Shigeru Aoki, Jumpei Uchiyama, Keisuke Yamato Sticking is a common observation in the scale-up stage on the punch tip using a commercial tableting machine. The difference in the total compression time between a laboratory tableting machine and a commercial one is considered one of the main root causes of scale-up issues in the tableting processes. The proposed “Size Adjusted for Scale-up punch” can be used to adjust the consolidation and dwell times for commercial tableting machine. As a result, the sticking phenomenon is able to be replicated at the pilot scale stage. As reported in this article, the quantification of sticking was done using a 3-D laser scanning microscope to check the tablet surface. It was shown that the sticking area decreased with the addition of magnesium stearate in the formulation, but the sticking depth was not affected by the additional amount of magnesium stearate. It is proposed that the use of a 3-D laser scanning microscope can be applied to evaluate sticking as a process analytical technology tool, and so sticking can be monitored continuously without stopping the machine.
       
  • Bioadhesive Chitosan-Coated Cationic Nanoliposomes With Improved Insulin
           Encapsulation and Prolonged Oral Hypoglycemic Effect in Diabetic Mice
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Thanaa I. Shalaby, Wessam M. El-Refaie Oral administration of insulin is hampered by the lack of carriers that can efficiently achieve high encapsulation, avoid gastric degradation, overcome mucosal barriers, and prolong the hypoglycemic effect. Chitosan (CS)-coated insulin-loaded cationic liposomes have been developed and optimized for improved oral delivery. Liposomes were prepared cationic to improve insulin encapsulation. CS was selected as a mucoadhesive coat to prolong the system's residence and absorption. The performance of CS-coated liposomes compared with uncoated liposomes was examined in vitro, ex vivo, and in vivo in streptozotocin-induced diabetic mice. Free uncoated liposomes showed high positive zeta potential of +58.8 ± 2.2 mV that reduced (+29.9 ± 1.4 mV) after insulin encapsulation, confirming the obtained high entrapment efficiency of 87.5 ± 0.6%. CS-coated liposomes showed nanosize of 439.0 ± 12.3 nm and zeta potential of +60.5 ± 1.9 mV. In vitro insulin release was limited to 18.9 ± 0.35% in simulated gastric fluid, whereas in simulated intestinal fluid, 73.33 ± 0.68% was released after 48 h from CS-coated liposomes. Ex vivo intestinal mucoadhesion showed increased tissue residence of CS-coated liposomes compared with uncoated liposomes. A striking reduction in the glucose level was observed 1 h after oral administration of CS-coated liposomes and maintained up to 8 h (p
       
  • Retina Compatible Interactions and Effective Modulation of Blood Ocular
           Barrier P-gp Activity by Third-Generation Inhibitors Improve the Ocular
           Penetration of Loperamide
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Karthik Yadav Janga, Akshaya Tatke, Surabhi Shukla, Surya P. Lamichhane, Bharathi Avula, XiangDi Wang, Monica M. Jablonski, Ikhlas A. Khan, Soumyajit Majumdar Effective drug delivery to the deeper ocular tissues remains an unresolved conundrum mainly due to the expression of multidrug resistance efflux proteins, besides tight junction proteins, in the blood ocular barriers (BOBs). Hence, the purpose of the current research was to investigate the ability of the third-generation efflux protein inhibitors, elacridar (EQ), and tariquidar (TQ), to diminish P-glycoprotein (P-gp) mediated efflux transport of loperamide (LOP), a P-gp substrate, across the BOB in Sprague Dawley rats. Initially, Western blot analysis confirmed the expression of P-gp in the iris-ciliary bodies and the retina choroid in the wild type rats. Next, the ocular distribution of LOP, in the presence and absence of EQ/TQ (at 2 doses), was evaluated. The significantly higher aqueous humor/plasma (DAH) and vitreous humor (VH)/plasma (DVH) distribution ratios of LOP in the rats pretreated with EQ or TQ demonstrated effective inhibition of P-gp activity in the BOB. Interestingly, the modulation of P-gp activity by EQ/TQ was more pronounced at the lower dose. The normal functioning and architecture of the retina, as indicated by electroretinography studies, confirmed the cytocompatibility of LOP and EQ/TQ interactions at the doses tested.
       
  • Superparamagnetic Iron Oxide–Loaded Lipid Nanocarriers Incorporated in
           Thermosensitive In Situ Gel for Magnetic Brain Targeting of Clonazepam
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Haidy Abbas, Hanan Refai, Nesrine El Sayed The objective of the study was to target clonazepam to the brain through the intranasal olfactory mucosa using nanolipid carriers loaded with superparamagnetic iron oxide nanoparticles (SPIONs) to allow nanocarrier guidance and retention with an external magnetic field. For improved delivery, the nanolipid carriers were incorporated in a thermosensitive mucoadhesive in situ gel. Different nanolipid carriers including solid lipid nanoparticles and nanostructured lipid carriers (NLC) were prepared and characterized with respect to particle size, zeta potential, entrapment efficiency, and in vitro release. The NLC composed of 3 solid lipids (Compritol® 888, stearic acid, and glyceryl monostearate) and 2 liquid oils (oleic acid and glyceryl monooleate) showed the most satisfactory characteristics and was loaded with SPION (NLC/SPION). Both formulae (NLC and NLC/SPION) were incorporated in an optimized thermosensitive mucoadhesive in situ system composed of 15% pluronic 127 and 0.75% sodium alginate and evaluated for the anticonvulsant action in chemically induced convulsive Swiss Albino mice. The treatment of animals with NLC/SPION significantly prolonged the onset times for convulsion and considerably protected the animals from death. One can thus hope for the emergence of a new intranasal treatment of epilepsy with consequent decrease in peripheral side effects of clonazepam.
       
  • The Repurposing of Ivermectin for Malaria: A Prospective
           Pharmacokinetics-Based Virtual Clinical Trials Assessment of Dosing
           Regimen Options
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Raj Badhan, Zaril Zakaria, Olusola Olafuyi Ivermectin has demonstrated many successes in the treatment of a range of nematode infections. Considering the increase in malaria resistance, attention has turned toward ivermectin as a candidate for repurposing for malaria. This study developed and validated an ivermectin physiology-based pharmacokinetic model in healthy adults (20-50 years), pediatric (3-5 years/15-25 kg) subjects, and a representative adult malaria population group (Thailand). Dosing optimization demonstrating a twice-daily dose for 3- or 5-day regimens would provide a time above the LC50 of more than 7 days for adult and pediatric subjects. Furthermore, to address the occurrence of CYP450 induction that is often encountered with antiretroviral agents, simulated drug-drug interaction studies with efavirenz highlighted that a 1-mg/kg once-daily dose for 5 days would counteract the increased ivermectin hepatic clearance and enable a time above LC50 of 138.8 h in adults and 141.2 h in pediatric subjects. It was also demonstrated that dosage regimen design would require consideration of the age-weight geographical relationship of the subjects, with a dosage regimen for a representative Thailand population group requiring at least a single daily dose for 5 days to maintain ivermectin plasma concentrations and a time above LC50 similar to that in healthy adults.
       
  • Effect of Freeze Dryer Design on Heat Transfer Variability Investigated
           Using a 3D Mathematical Model
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Bernadette Scutellà, Erwan Bourlès, Artemio Plana-Fattori, Fernanda Fonseca, Denis Flick, Ioan-Cristian Trelea, Stephanie Passot During the freeze-drying process, vials located at the border of the shelf usually present higher heat flow rates that result in higher product temperatures than vials in the center. This phenomenon, referred to as edge vial effect, can lead to product quality variability within the same batch of vials and between batches at different scales. Our objective was to investigate the effect of various freeze dryer design features on heat transfer variability. A 3D mathematical model previously developed in COMSOL Multiphysics and experimentally validated was used to simulate the heat transfer of a set of vials located at the edge and in the center of the shelf. The design features considered included the vials loading configurations, the thermal characteristics, and some relevant dimensions of the drying chamber geometry. The presence of the rail in the loading configuration and the value of the shelf emissivity strongly impacted the heat flow rates received by the vials. Conversely, the heat transfer was not significantly influenced by modifications of the thermal conductivity of the rail, the emissivity of the walls, or the geometry of the drying chamber. The model developed turned out to be a powerful tool for cycle development and scale-up.
       
  • Container Closure Integrity Testing of Prefilled Syringes
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Sarah S. Peláez, Hanns-Christian Mahler, Anja Matter, Atanas Koulov, Satish K. Singh, Oliver Germershaus, Roman Mathaes Prefilled syringes (PFSs) are increasingly preferred over vials as container closure systems (CCSs) for injectable drug products when facilitated or self-administration is required. However, PFSs are more complex compared to CCSs consisting of vial, rubber stopper, and crimp cap. Container closure integrity (CCI) assurance and verification has been a specific challenge for PFSs as they feature several sealing areas. A comprehensive understanding of the CCS is necessary for an appropriate CCI assessment as well as for packaging development and qualification. A comprehensive CCI assessment of 6 different PFSs from 3 different manufacturers (including 1 polymeric PFS) was conducted using helium leak testing. PFS components were manipulated to systematically assess the contribution of the different sealing areas to CCI, namely rigid needle shield (RNS)/needle, RNS/tip cone, and the individual ribs of a syringe plunger. The polymeric PFS required an equilibrium measurement for accurate container closure integrity testing. The different sealing areas and a single plunger rib were shown to provide adequate CCI. Acceptable tip cap movement until the point of CCI failure was estimated. The assessment of acceptable tip cap movement demonstrated the importance of considering the RNS/tip cone seal design to ensure CCI of the PFS upon post assembly possesses and shipment.
       
  • Predictive Modeling of Micellar Solubilization by Single and Mixed
           Nonionic Surfactants
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Shaoxin Feng, Nathaniel D. Catron, Alan (Donghua) Zhu, John M. Lipari, Jianwei Wu, Yi Gao, Geoff G.Z. Zhang Micellar solubilization is an important concept in the delivery of poorly water-soluble drugs. The rational selection of the type and the amount of surfactant to be incorporated in a formulation require comprehensive solubility studies. These studies are time and material demanding, both of which are scarce, especially during late discovery and early development stages. We hypothesized that, if the solubilization mechanism or molecular interaction is similar, the solubilization capacity ratio (a newly defined parameter) is dictated by micellar structures, independent of drugs. We tested this hypothesis by performing solubility studies using 8 commonly used nonionic surfactants and 17 insoluble compounds with diverse characteristics. The results show a striking constant solubilization capacity ratio among the 8 nonionic surfactants, which allow us to develop predictive solubility models for both single and mixed surfactant systems. The vast majority of the predicted solubility values, using our developed models, fall within 2-fold of the experimentally determined values with high correlation coefficients. As expected, systems involving ionic surfactant sodium dodecyl sulfate, used as a negative control, do not follow this trend. Deviations from the model, observed in this study or envisioned, were discussed. In conclusion, we have established predictive models that are capable of predicting solubility in a wide range of nonionic micellar solutions with only 1 experimental measurement. The application of such a model will significantly reduce resource and greatly enhance drug product development efficiency.
       
  • Urea Improves Stability of Inactivated Polio Vaccine Serotype 3 During
           Lyophilization and Storage in Dried Formulations
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Wei Qi, Scott Orgel, Alain Francon, Theodore W. Randolph, John F. Carpenter Stable formulations of inactivated polio vaccine (IPV) could reduce cold-chain requirements and increase distribution of the vaccine to developing countries. Recently, significant improvement in thermal stability of IPV vaccines has been achieved by including urea in lyophilized formulations. In the present study, we investigated the effects of urea on recovery of potency of IPV after lyophilization and storage at 37°C and the correlation of potency recovery with key biophysical properties of IPV. By dynamic light scattering and transmission light microscopy, we found that loss of potency appeared to be due to agglomeration of virus particles during lyophilization and that moderate concentrations (e.g., 0.4 M) of urea reduced agglomeration and improved potency recovery. In addition, the relative thermal stability of the viron proteins was assessed after rehydration with temperature-dependent intrinsic fluorescence. Lyophilization of formulations without urea and postdrying storage resulted in reduced apparent melting temperatures in rehydrated samples. In formulations with urea, the rehydrated samples had thermal transitions and melting temperatures that were similar to those observed in aqueous control samples. Overall, the results indicated that in IPV formulations, urea improved potency recovery by inhibiting viron particle agglomeration and reducing denaturation of viron proteins.
       
  • Application of Empirical Phase Diagrams for Multidimensional Data
           Visualization of High-Throughput Microbatch Crystallization Experiments
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Marieke E. Klijn, Jürgen Hubbuch Protein phase diagrams are a tool to investigate the cause and consequence of solution conditions on protein phase behavior. The effects are scored according to aggregation morphologies such as crystals or amorphous precipitates. Solution conditions affect morphologic features, such as crystal size, as well as kinetic features, such as crystal growth time. Commonly used data visualization techniques include individual line graphs or phase diagrams based on symbols. These techniques have limitations in terms of handling large data sets, comprehensiveness or completeness. To eliminate these limitations, morphologic and kinetic features obtained from crystallization images generated with high throughput microbatch experiments have been visualized with radar charts in combination with the empirical phase diagram method. Morphologic features (crystal size, shape, and number, as well as precipitate size) and kinetic features (crystal and precipitate onset and growth time) are extracted for 768 solutions with varying chicken egg white lysozyme concentration, salt type, ionic strength, and pH. Image-based aggregation morphology and kinetic features were compiled into a single and easily interpretable figure, thereby showing that the empirical phase diagram method can support high-throughput crystallization experiments in its data amount as well as its data complexity.
       
  • High-Throughput In-Use and Stress Size Stability Screening of Protein
           Therapeutics Using Algorithm-Driven Dynamic Light Scattering
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Ashwinkumar A. Bhirde, Meng-Jung Chiang, Ramesh Venna, Serge Beaucage, Kurt Brorson Stability of therapeutic proteins (TPs) is a critical quality attribute that impacts both safety and efficacy of the drug. Size stability is routinely performed during and after biomanufacturing. Dynamic light scattering (DLS) is a commonly used technique to characterize hydrodynamic size of the TPs. Herein, we have developed a novel method to evaluate in-use and thermal stress stability of TPs using algorithm-driven high-throughput DLS. Five marketed TPs were tested under the guidance of customized algorithms. The TPs were evaluated at relevant temperature conditions as well as under dilution and thermal stress for size stability. We found that the TPs were stable under the in-use conditions tested; however, sample loss due to evaporation can lead to large protein aggregates. A combined assessment of autocorrelation function and photos of sample well could be useful in formulation screening. Dilution of TPs also has an impact on the hydrodynamic size. Thermal stress experiments showed the importance of using different data processing methods to access size distribution. Polydispersity index was useful in evaluating sample heterogeneity. Herein, we show that algorithm-driven high-throughput DLS can provide additional supportive information during and after biomanufacturing and the potential to be used in a quality control environment.
       
  • Phosphatidylserine Is Not Just a Cleanup Crew but Also a Well-Meaning
           Teacher
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Fiona Y. Glassman, Jennifer L. Schneider, Radha Ramakrishnan, Robert K. Dingman, Murali Ramanathan, Richard B. Bankert, Sathy V. Balu-Iyer Phosphatidylserine (PS) exposure during apoptosis leads to silent clearance of cells without adverse immune reactions to self-proteins. Given the biological functions of PS in cellular cleanup and global immunosuppression, we hypothesized that administration of PS-protein complexes would reduce immunogenicity. Here, we report that exposing Pompe disease mice to acid alpha glucosidase (rhGAA) with PS or immunosuppressant dexamethasone resulted in lower anti-rhGAA antibodies than in animals receiving rhGAA alone. However, upon rechallenge with rhGAA, only PS-rhGAA pre-exposed mice displayed a durable hyporesponsiveness even after PS administration was ceased. Thus, pre-exposure of antigens administered together with PS were not silently cleared, but the immune system acquired memory about the antigen that averted mounting of a response during rechallenge. In hemophilia A mice, PS hyporesponsiveness toward Factor VIII was reversed by administration of function-blocking antibody against the PS receptor T-cell immunoglobulin and mucin 4, implicating this receptor in PS's effect. Moreover, pre-exposure of myelin oligodendrocyte glycoprotein peptide with PS delayed the onset and reduced the severity of experimental autoimmune encephalomyelitis. These observations suggest that PS's function in apoptosis is not limited to silent antigen clearance without immune responses toward self-proteins but shows that PS reduces immune response during rechallenge to several antigens that also involves initiation of antigen tolerance.
       
  • Pushing the Limits of Molecular Crystal Structure Determination From
           Powder Diffraction Data in High-Throughput Chemical Environments
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Elena A. Kabova, Charles D. Blundell, Kenneth Shankland Crystal structure determination from powder diffraction data (SDPD) using the DASH software package is evaluated for data recorded using transmission capillary, transmission flat plate, and reflection flat plate geometries on a selection of pharmaceutical compounds. We show that transmission capillary geometry remains the best option when crystal structure determination is the primary consideration and, as expected, reflection flat plate geometry is not recommended for SDPD because of preferred orientation effects. However, the quality of crystal structures obtained from transmission plate instruments can be excellent, and the convenience factor for sample preparation, throughput, and retrieval is higher than that of transmission capillary instruments. Indeed, it is possible to solve crystal structures within an hour of a polycrystalline sample arriving in the laboratory, which has clear implications for making small-molecule crystal structures more routinely available to the practicing laboratory medicinal chemist. With appropriate modifications to crystal structure determination software, it can be imagined that SDPD could become a rapid turn-around walk-up analytical service in high-throughput chemical environments.
       
  • Characterization of Aptamer BC 007 Substance and Product Using Circular
           Dichroism and Nuclear Magnetic Resonance Spectroscopy
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Hardy Weisshoff, Katrin Wenzel, Sarah Schulze-Rothe, Heike Nikolenko, Hanna Davideit, Niels-Peter Becker, Peter Göttel, G. Susan Srivatsa, Margitta Dathe, Johannes Müller, Annekathrin Haberland Possible unwanted folding of biopharmaceuticals during manufacturing and storage has resulted in analysis schemes compared to small molecules that include bioanalytical characterization besides chemical characterization. Whether bioanalytical characterization is required for nucleotide-based drugs, may be decided on a case-by-case basis. Nucleotide-based pharmaceuticals, if chemically synthesized, occupy an intermediate position between small-molecule drugs and biologics. Here, we tested whether a physicochemical characterization of a nucleotide-based drug substance, BC 007, was adequate, using circular dichroism (CD) spectroscopy. Nuclear magnetic resonance confirmed CD data in one experimental setup. BC 007 forms a quadruplex structure under specific external conditions, which was characterized for its stability and structural appearance also after denaturation using CD and nuclear magnetic resonance. The amount of the free energy (ΔG0) involved in quadruplex formation of BC 007 was estimated at +8.7 kJ/mol when dissolved in water and +1.4 kJ/mol in 154 mM NaCl, indicating structural instability under these conditions. However, dissolution of the substance in 5 mM of KCl reduced the ΔG0 to −5.6 kJ/mol due to the stabilizing effect of cations. These results show that positive ΔG0 of quadruplex structure formation in water and aqueous NaCl prevents BC 007 from preforming stable 3-dimensional structures, which could potentially affect drug function.
       
  • A Refined Developability Classification System
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Julian Rosenberger, James Butler, Jennifer Dressman In 2010, the Developability Classification System (DCS) was proposed. The DCS was designed to close the gap between the biopharmaceutics classification system, which is aimed at guiding regulatory decisions about well-characterized drugs, and the need for early evaluation of drug candidates with respect to their suitability for oral delivery. The DCS applied solubility in fasted state simulated intestinal fluid to estimate intestinal solubility, assessed the compensatory nature of permeability and solubility during oral absorption and provided a way of estimating the critical the particle size at which dissolution becomes rate-limiting to absorption. Building on this framework, a refined developability classification system (rDCS) is now proposed. The rDCS is stratified into standard investigations applied to all candidates, and customized investigations. Standard investigation of solubility and permeability can be performed according to in-house methods, and the results compared with standard data sets of fasted state human intestinal fluid solubility and human effective jejunal permeability, which have been generated specifically for rDCS. Customized investigations are triggered when there is potential for supersaturation/precipitation (weak bases; salts of weak acids) and to assess dissolution versus permeation limited absorption. In addition, the rDCS offers facile visualization of the results, enabling pragmatic comparison of drug candidates and formulation approaches.
       
  • Postproduction Handling and Administration of Protein Pharmaceuticals and
           Potential Instability Issues
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): M. Reza Nejadnik, Theodore W. Randolph, David B. Volkin, Christian Schöneich, John F. Carpenter, Daan J.A. Crommelin, Wim Jiskoot The safety and efficacy of protein pharmaceuticals depend not only on biological activity but also on purity levels. Impurities may be process related because of limitations in manufacturing or product related because of protein degradation occurring throughout the life history of a product. Although the pharmaceutical biotechnology industry has made great progress in improving bulk and drug product manufacturing as well as company-controlled storage and transportation conditions to minimize the level of degradation, there is less control over the many factors that may subsequently affect product quality after the protein pharmaceuticals are released and shipped by the manufacturer. Routine handling or unintentional mishandling of therapeutic protein products may cause protein degradation that remains unnoticed but can potentially compromise the clinical safety and efficacy of the product. In this commentary, we address some potential risks associated with (mis)handling of protein pharmaceuticals after release by the manufacturer. We summarize the environmental stress factors that have been shown to cause protein degradation and that may be encountered during typical handling procedures of protein pharmaceuticals in a hospital setting or during self-administration by patients. Moreover, we provide recommendations for improvements in product handling to help ensure the quality of protein pharmaceuticals during use.
       
  • Factors Influencing the Retention of Organic Solvents in Products
           Freeze-Dried From Co-Solvent Systems
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): Claudia Kunz, Henning Gieseler Controlling residual solvent levels is a major concern in pharmaceutical freeze-drying from co-solvent systems. This review provides an overview of the factors influencing this process and estimates their potential to reduce residual solvents in freeze-dried products. Decreased solvent contents are potentially correlated with the lower solid content, complete excipient crystallization, higher water solubility, and smaller molecular sizes of the solvent. Although no general rule can be derived for the selection of appropriate freezing conditions, the freezing stage appears to play a major role in subsequent volatile retention. In contrast, diverse secondary drying conditions do not appear to impact the amount of solvent retained in lyophilisates, and modification of this stage is thus not assumed to be expedient. Co-solvents are strongly entrapped in an amorphous product matrix as soon as the local moisture content decreases below a certain level. Thus, the moisture content in the dried product layer adjacent to the sublimation interface might be a key factor. Therefore, extension of the high moisture content period during the primary drying phase as well as a postlyophilization humidification of the dried products are presumably promising approaches to promote solvent release.
       
  • Editorial Advisory Board
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s):
       
  • Spectral Reflectance Measurement of Evaporating Chemical Films: Initial
           Results and Application to Skin Permeation
    • Abstract: Publication date: August 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 8Author(s): H. Frederick Frasch, Larry Lee, Ana M. Barbero The present study has 2 aims. First, the method of spectral reflectance was used to measure evaporation rates of thin (∼25-300 μm) films of neat liquid volatile organic chemicals exposed to a well-regulated wind speed u. Gas-phase evaporation mass transfer coefficient (kevap) measurements of 10 chemicals, 9 of which were measured at similar u, are predicted (slope of log-log data = 1.01; intercept = 0.08; R2 = 0.996) by a previously proposed mass transfer correlation. For one chemical, isoamyl alcohol, the dependence of kevap on u0.52 was measured, in support of the predicted exponent value of ½. Second, measured kevap of nicotine was used as an input in analytical models based on diffusion theory to estimate the absorbed fraction (Fabs) of a small dose (5 μL/cm2) applied to human epidermis in vitro. The measured Fabs was 0.062 ± 0.023. Model-estimated values are 0.066 and 0.115. Spectral reflectance is a precise method of measuring kevap of liquid chemicals, and the data are well described by a simple gas-phase mass transfer coefficient. For nicotine under the single exposure condition measured herein, Fabs is well-predicted from a theoretical model that requires knowledge of kevap, maximal dermal flux, and membrane lag time.
       
  • How Well Do Low- and High-Concentration Protein Interactions Predict
           Solution Viscosities of Monoclonal Antibodies'
    • Abstract: Publication date: Available online 12 July 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Mahlet A. Woldeyes, Wei Qi, Vladimir I. Razinkov, Eric M. Furst, Christopher J. Roberts Protein-protein interactions (PPI) and solution viscosities were measured at low and high protein concentrations under a range of formulation conditions for four different monoclonal antibodies (MAbs). Static light scattering (SLS) was used to quantify the osmotic second virial coefficient (B22) and the zero-q limit static structure factor (Sq=0), versus protein concentration (c2) from low to high c2. Dynamic light scattering (DLS) was used to measure the collective diffusion coefficient (DC) as a function of c2, and to determine the protein interaction parameter (kD). SLS and DLS were combined to determine the hydrodynamic factor (Hq=0), which accounts for changes in hydrodynamic PPI as a function of c2. The net PPI ranged from strongly repulsive to attractive interactions, via changes in buffer pH, ionic strength, and choice of MAb. Multiple-particle-tracking micro-rheology and capillary viscometery were used to measure MAb solution viscosities under the same solution conditions. In most cases, even large and qualitative changes in PPI did not result in significant changes in protein solution viscosity. This highlights the complex nature of PPI and how they influence protein solution viscosity, and raises questions as to the validity of using experimental PPI metrics such as kD or B22 as predictors of high viscosity.
       
  • Dietary induced obesity and changes in the biodistribution and metabolism
           of amiodarone in the rat
    • Abstract: Publication date: Available online 12 July 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Ali Abdussalam, Marwa Al-Agili, Hamdah M. Al Nebaihi, Patrick R. Mayo, Raniah Q. Gabr, Dion R. Brocks The metabolism and biodistribution of the antiarrhythmic drug amiodarone was assessed in male Sprague-Dawley rats given either normal chow or high fat and/or high fructose diets for 14 weeks. After the feeding period, microsomes were prepared from liver and intestine and the metabolism of amiodarone to desethylamiodarone was determined. Intrinsic clearance was reduced by hepatic microsomes isolated from rats given high calorie diets. In intestinal microsomes there was no change or a small increase in metabolic rate in obese rats. A biodistribution study was also undertaken in a group of Control and high fat+high fructose-fed rats. Excess calories led to a significant increase in plasma amiodarone compared to normal chow-fed Control animals. A population pharmacokinetic analysis of amiodarone confirmed that its oral clearance was reduced. In plasma there was a decrease in the metabolite to drug ratio. Some tissue:plasma ratios of amiodarone in high calorie-fed rats were aligned with a decrease in plasma unbound fraction. It is concluded that the findings reinforced those of a recent report where we found decreases in expressions of enzymes involved in amiodarone dealkylation, in showing greater exposure and lower oral clearance, and generally decreases in liver microsomal metabolism of amiodarone after high calorie diets.
       
  • Freeze-Drying from Organic Co-Solvent Systems, Part 2: Process
           Modifications to Reduce Residual Solvent Levels and Improve Product
           Quality Attributes
    • Abstract: Publication date: Available online 12 July 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Claudia Kunz, Sonja Schuldt-Lieb, Henning Gieseler The use of co-solvent systems can benefit the freeze-drying process and product performance. In this study, cycle designs were applied based on existing recommendations for water-based formulations. Modifications thereof and the influence on the process (e.g., drying times) and product quality attributes (e.g., product appearance, residual solvent) were tested for various co-solvent systems. It was found that fast freezing was associated with the formation of large crystals for 50 mg/g polyvinylpyrrolidone in 40% 1,4-dioxane (w/w), resulting in a 7% reduction of primary drying. The application of high shelf temperatures during primary drying for 50 mg/g polyvinylpyrrolidone in 70% tert-butanol was feasible, resulting in shorter primary drying times but high residual solvent levels (7.7%). Most notable was that the inclusion of an evaporation step after freezing improved the product appearance for low melting co-solvents (10% ethanol and 10% acetone). No ice or solvent nucleation occurred in the case of 50 mg/g mannitol in 50% N,N-dimethylacetamide during the normal freezing stage. Instead, the solution viscosity significantly increased after cooling to low shelf temperatures, followed by product evaporation (rather than sublimation) during the drying phase and failure to form a product cake after drying. The application of annealing enabled nucleation and sublimation.
       
  • Improving Dissolution Properties by Polymers and Surfactants: A Case Study
           of Celastrol
    • Abstract: Publication date: Available online 12 July 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Jun Zha, Qi Zhang, Meiqi Li, Jian-Rong Wang, Xuefeng Mei Two polymorphs of celastrol were discovered and fully characterized by XRPD, TGA and DSC. The single crystal structures of form I and the isostructural solvate of form II were disclosed by SCXRD. The apparent solubility and wettability of the both two crystalline forms were determined. It was found that surfactant can significantly improve the solubility of celastrol up to more than 104 times. Tween 80 and SDS largely improved the wettability of the two crystals. Form I shows better wettability than form II in all the buffer solutions with polymers and surfactants. Compared to form II,form I exhibits higher solubility in CMC and PVP media but much lower solubility in tween 80 and SDS solutions. An investigation of wettability and solubility mechanism was fully explored and a hypothesis was proposed to understand the abnormal solubility differences.
       
  • Quantification of moisture induced cohesion in pharmaceutical mixtures
    • Abstract: Publication date: Available online 12 July 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Raj Mukherjee, Koyel Sen, Lauren Fontana, Chen Mao, Bodhisattwa Chaudhuri Moisture-induced flow variabilities in pharmaceutical blends lead to multiple impediments during manufacturing of solid dosage formulations. Processing and storage humidity conditions both govern the moisture contents of the pharmaceutical mixtures and bear significant impact on the final product quality. In this study, experimentally validated Discrete Element Method (DEM) based computational models along with statistical formalism have been implemented to develop a predictive tool for moisture induced cohesion in binary and tertiary mixtures. V-blending was applied to prepare the pharmaceutical blends, and mixing characterization was performed using a Raman PhAT probe. Optimum fill volume was established for the mixing conditions to minimize static charging due to blender wall interactions on the pharmaceutical powders. A Simplex Centroid (Augmented) design for three component system was implemented to predict and quantify the non-linear behavior of moisture-induced cohesion between the pharmaceutical powders based on their systematic hopper discharge studies (experiments and simulations). A methodical implementation of these quantification tools was hence performed to validate a design space that enables an approach to the appropriate selection of blend concentrations that achieve minimum mixture flow variability across different humidity conditions.
       
  • Long-term stability and reversible thermal unfolding of antibody structure
           at low pH: case study
    • Abstract: Publication date: Available online 12 July 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Harumi Fukada, Kouhei Tsumoto, Tsutomu Arakawa, Daisuke Ejima We have here observed that the differential scanning calorimetry (DSC) profiles and melting temperatures of a humanized antibody were unchanged over a 10-year span when stored at 4°C and at different pH values, even at pH 2.7. This is somewhat surprising, as this particular antibody undergoes conformational changes below pH 4.0. DSC analysis showed that melting of the antibody at pH 2.7 was highly reversible, suggesting a possibility that the observed reversibility is at least in part responsible for a 10-year stability at low pH. Conversely, it showed thermal unfolding followed by aggregation at higher pH.
       
  • Physical characterization and stabilization of a lentiviral vector against
           adsorption and freeze-thaw
    • Abstract: Publication date: Available online 12 July 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Ozan S. Kumru, Yu Wang, C.Wayne R. Gombotz, Brenna Kelley-Clarke, Witold Cieplak, Tae Kim, Sangeeta B. Joshi, David B. Volkin A replication-deficient lentiviral vector encoding the tumor antigen gene NY-ESO-1 was characterized in terms of vector morphology, particle size range, concentration and zeta potential employing a variety of physical methods. Environmentally stressed vector samples were then evaluated in terms of viral vector particle size and concentration by nanoparticle tracking analysis (NTA). These NTA stability results correlated reasonably well with a qPCR assay for quantitation of viral genome copy number (r2=0.80). Approximately 40 pharmaceutical excipients were examined for their ability to stabilize the vector against exposure to an adsorptive container surface (glass) as well as freeze-thaw cycling using NTA as the screening method. Stabilizing additives that inhibit viral vector particle loss under these conditions included proline, lactose and mannitol. Several candidate frozen liquid formulations that contained a combination of these lead excipients and various buffering agents were further evaluated for their ability to stabilize the viral vector. The additional benefit of lowering the Tris buffer concentration was observed. This study highlights the use of physical particle assays such as NTA for initial screening of stabilizing excipients to minimize vector loss due to container adsorption and freeze-thaw cycling to facilitate early formulation development of viral vector candidates in frozen liquid formulations.
       
  • Submicron size particles of a murine monoclonal antibody are more
           immunogenic than soluble oligomers or micron size particles upon
           subcutaneous administration in mice
    • Abstract: Publication date: Available online 10 July 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Grzegorz Kijanka, Jared S. Bee, Samuel A. Korman, Yuling Wu, Lorin K. Roskos, Mark A. Schenerman, Bram Slütter, Wim Jiskoot Protein aggregates are one of several risk factors for undesired immunogenicity of biopharmaceuticals. However, it remains unclear which features determine whether aggregates will trigger an unwanted immune response. The aim of this study was to determine the effect of aggregates’ size on their relative immunogenicity. A monoclonal murine IgG1 was stressed by exposure to low pH and elevated temperature followed by stirring to obtain aggregates widely differing in size. Aggregate fractions enriched in soluble oligomers, submicron size particles and micron size particles were isolated via centrifugation or size-exclusion chromatography and characterized physicochemically. The secondary and tertiary structures of aggregates were altered in a similar way for all the fractions, while no substantial chemical degradation was observed. Development of anti-drug antibodies was measured after subcutaneous administration of each enriched fraction to BALB/c mice. Among all tested fractions, the most immunogenic was the one highly enriched in submicron size particles (∼100-1000 nm). Fractions composed of micron size (> 1 μm to 100 μm) particles or soluble oligomers (< 100 nm) were not immunogenic under the dosing regimen studied in this work. These results show that aggregate size is an important factor for protein immunogenicity.
       
  • Pharmacokinetic and Pharmacodynamic Evaluation of Different PEGylated
           Human Interleukin-11 Preparations in Animal Models
    • Abstract: Publication date: Available online 10 July 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Kuo-Ming Yu, Johnson Yiu-Nam Lau, Manson Fok, Yuk-Keung Yeung, Siu-Ping Fok, Tsan-Lin Hu, Yuan-Jang Tsai, Qui-Lim Choo Treating thrombocytopenia induced by chemotherapy remains an unmet-medical need. The use of recombinant human interleukin-11 (rhIL-11) requires repeated injections and induces significant fluid retention in some patients. Modification of human interleukin-11 with chemically inert polyethylene glycol polymer (PEG) may extend the peripheral circulation half-life leading to an improved pharmacokinetic and pharmadynamic profile. In this study, a number of rhIL-11 PEG conjugates were created to determine the optimal approach to prolong circulating half-life with the most robust pharmacological effect. The lead candidate was found to be a single 40-kDa Y-shaped PEG linked to the N-terminus, which produced a long-lasting circulating half-life, enhanced efficacy and alleviated side-effect of dilutional anemia in healthy rat models. This candidate was also shown to be effective in myelosuppressive rats in preventing the occurrence of severe thrombocytopenia whilst ameliorating dilutional anemia, compared to rats receiving daily administration of unmodified rhIL-11 at the same dose. These data indicated that a single injection of the selected modified rhIL-11 for each cycle of chemotherapy regimen is potentially feasible. This approach may also be useful in treating patients of acute radiation syndrome when frequent administration is not feasible in a widespread event of a major radiation exposure.
       
  • Assessment of Patient Exposure to Leachables from Lyophilized Drug
           Formulations Following Reconstitution, Storage, and Administration via
           Polymeric Packaging/Delivery Systems
    • Abstract: Publication date: Available online 10 July 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Steven A. Zdravkovic It has been demonstrated that lyophilized drug formulations have an increased propensity to leach substances from the rubber stoppers comprising their primary packaging system when compared to aqueous liquid formulations stored in the same manner. Unfortunately, patient exposure to leachables originating in lyophilized drug products is not known. To that end, the goal of this study was to assess patient exposure to these leachables after reconstitution, storage, and administration of the lyophilized drug. To achieve this goal, several leachables present in two commercial lyophilized drug products were quantified after contact with PVC and non-PVC medication bags as well as an infusion set for durations of 15 minutes to 7 days at refrigerated and/or ambient temperature. The results obtained from this study showed that the bag’s material of construction and the drugs formulation did not impact the mass of the leachables administered. Conversely, the mass of each leachable administered to the patient was reduced or eliminated as the contact duration with the IV bag and the temperature increased. However, for shorter contact durations, refrigerated storage, and/or higher molecular weight compounds, the patient would be exposed to a majority of the leachables originating from the vial.
       
  • Imaging techniques to characterize cake appearance of freeze-dried
           products
    • Abstract: Publication date: Available online 10 July 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Christina Haeuser, Pierre Goldbach, Joerg Huwyler, Wolfgang Friess, Andrea Allmendinger Pharmaceutically elegant lyophilisates are highly desirable implying a stable and robust freeze-drying process. In order to ensure homogenous and intact cake appearance after process scale-up and transfer, characterization of lyophilisates during formulation and cycle development is required. The present study investigates different imaging techniques to characterize lyophilisates on different levels. Cake appearance of freeze-dried BSA formulations with different dextran/sucrose ratios was studied by visual inspection, 3D laser scanning, polydimethylsiloxane (PDMS) embedding, scanning electron microscopy (SEM), and micro-computed tomography (μ-CT). The set of techniques allowed a holistic evaluation of external cake appearance and internal structure providing complementary information at macroscopic and microscopic scale. In comparison to state of the art technologies like visual inspection or SEM, 3D laser scanning and μ-CT provided quantitative information allowing comparison of visual cake appearance. In particular μ-CT enables a global, qualitative, and quantitative characterization of external and internal cake structure with a single measurement detecting heterogeneities of lyophilisates. We even demonstrated the use of non-invasive μ-CT for qualitative imaging of internal cake structure through the glass vial. Providing meaningful characterization of the entire lyophilisate, μ-CT can serve as a powerful tool during development of freeze-drying cycles, process scale-up, and transfer.
       
  • Preparation and characterization of Poloxamer 407 solid dispersions as an
           alternative strategy to improve benznidazole bioperformance
    • Abstract: Publication date: Available online 10 July 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Analía Simonazzi, Carolina Davies, Alicia G. Cid, Elio Gonzo, Luis Parada, José M. Bermúdez :Benznidazole, the first line drug for Chagas disease treatment, presents a low solubility, limiting the possibilities for its formulation. In this work, solid dispersions´ technology was exploited to increase benznidazole kinetic solubility and dissolution rate, seeking for an improvement in its bioperformance. A physical mixture (PM) and a solid dispersion (SD) using Poloxamer 407 as carrier were prepared and characterized. Dissolution tests were performed and data were analyzed with the lumped model, which allowed to calculate different parameters of pharmaceutical relevance. A bioactivity assay was also carried out to probe the SD anti-trypanocidal activity. Among the most relevant results, the initial dissolution rate of the benznidazole SD was near 3, 4 and about 400-fold faster than the PM, a commercial formulation (CF) and an extracted benznidazole, respectivley. The times needed for an 80% of drug dissolution were 3.6 (SD), 46.4 (PM), and 238.7 min (CF); while the dissolution efficiency values at 30 minutes were 85.2 (SD), 71.2 (PM), and 65.0% (CF). Survival curves suggested that using Poloxamer 407 as carrier did not alter the anti-trypanocidal activity of benznidazole. These results allow to conclude that SDs can be an effective platform for immediate release of benznidazole in an oral administration.
       
  • Effects of Hydrogen Bond Acceptor Ability of Solvents on Molecular
           Self-Assembly of Sulfadiazine Solvates
    • Abstract: Publication date: Available online 10 July 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Xia Zhang, Chang Wang, Ling Zhou, Wenchao Yang, Lina Zhou, Ying Bao, Meijing Zhang, Baohong Hou, Zhao Xu, Qiuxiang Yin The solvate formation of sulfadiazine was systematically studied in the four selected solvents with the aids of experiment and simulation methods. The intermolecular interactions between solute and solvent molecules in different solid states were analyzed and compared through their single crystal structures, and the solution behavior of sulfadiazine was discussed using molecular dynamics simulations. The results indicated that sulfadiazine was easy to form solvates with the solvents having strong hydrogen bond acceptor ability, which determined the formation of hydrogen bonding synthon. Furthermore, the sulfadiazine molecules conformation and packing were compared in various crystal structures. In addition, the desolvation processes of sulfadiazine solvates were studied to investigate the role of solvent in different solvate structures.
       
  • Pharmacokinetics and preventive effects of sulfo-albumin as a novel
           macromolecular hydrogen sulfide prodrug on carbon tetrachloride-induced
           hepatic injury
    • Abstract: Publication date: Available online 2 July 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Kosuke Sakai, Hidemasa Katsumi, Mayu Sugiura, Ayaka Tamba, Kentaro Kamano, Kiyo Yamauchi, Yosui Tamura, Toshiyasu Sakane, Akira Yamamoto Hydrogen sulfide (H2S) has been recently recognized as a gaseous signaling molecule that controls various biological activities. In the present study, we developed sulfo-albumin as a macromolecular H2S prodrug for therapeutic use, in which multi-sulfide groups (source of H2S) were conjugated with bovine serum albumin through a covalent linkage. In an in vitro study on H2S release in PBS solution, we found that H2S was released from sulfo-albumin in the presence of 5 mM glutathione (GSH), but not in its absence. Furthermore, sulfo-albumin was taken up by RAW 264.7 cells, and it released H2S in cells but not in plasma. These results indicate that H2S can be selectively released from sulfo-albumin in cells. 111In-labeled sulfo-albumin predominantly accumulated in the liver, dependent upon the number of sulfide groups, after intravenous injection in mice. In a carbon tetrachloride (CCl4)-induced acute liver injury mouse model, sulfo-albumin significantly suppressed the increase in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, which are indicators of hepatocyte injury, after intravenous injection. These findings indicate that sulfo-albumin is a promising compound for the treatment of hepatic injuries.
       
  • Using Computational Fluid Dynamics to Compare Shear Rate and Turbulence in
           the TIM-Automated Gastric Compartment With USP Apparatus II
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Matthew Hopgood, Gavin Reynolds, Richard Barker We use computational fluid dynamics to compare the shear rate and turbulence in an advanced in vitro gastric model (TIMagc) during its simulation of fasted state Migrating Motor Complex phases I and II, with the United States Pharmacopeia paddle dissolution apparatus II (USPII). A specific focus is placed on how shear rate in these apparatus affects erosion-based solid oral dosage forms. The study finds that tablet surface shear rates in TIMagc are strongly time dependant and fluctuate between 0.001 and 360 s−1. In USPII, tablet surface shear rates are approximately constant for a given paddle speed and increase linearly from 9 s−1 to 36 s−1 as the paddle speed is increased from 25 to 100 rpm. A strong linear relationship is observed between tablet surface shear rate and tablet erosion rate in USPII, whereas TIMagc shows highly variable behavior. The flow regimes present in each apparatus are compared to in vivo predictions using Reynolds number analysis. Reynolds numbers for flow in TIMagc lie predominantly within the predicted in vivo bounds (0.01-30), whereas Reynolds numbers for flow in USPII lie above the predicted upper bound when operating with paddle speeds as low as 25 rpm (33).
       
  • Confirmation of More Stable Polymorphic Form of Etoricoxib at Room
           Temperature
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Ting Zhang, Liping Wang, Ying Bao, Qi Yang, Lina Zhou, Hongxun Hao, Chuang Xie Polymorphic forms of etoricoxib have been reported in the literature, and form I was considered to be the most stable one. However, in this work, it was found that form I and form V are enantiotropic by differential scanning calorimetry analysis, solubility measurements, and solution-mediated polymorphic transformation experiments with form V being more stable than form I at room temperature. Thermodynamic transition temperature is determined as (353.45 ± 0.10) K. Besides, form V would transform to form I with the seeding effect of form I at high temperature below the melting point of form V. The crystal structure of form V was solved for the first time. The molecules in form V are linked by weak hydrogen bond C–H⋯O to form ring motif, which is nonexistent in form I.
       
  • Push-Pull Controlled Drug Release Systems: Effect of Molecular Weight of
           Polyethylene Oxide on Drug Release
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Takehisa Nakajima, Issei Takeuchi, Hiroyuki Ohshima, Hiroshi Terada, Kimiko Makino First, an elementary osmotic pump (EOP) with a simple structure was prepared using polyethylene oxide (PEO) and NaCl as an excipient, and the influence of the molecular weight (Mw) of PEO on drug release was investigated. In the dissolution test of EOP, it was observed that the gelated core tablet was pushed out through the orifice. The dissolution profile of EOP was sigmoidal, and despite the short time, a zero-order release region was observed. The gel swelling rate in the zero-order region was independent of the Mw of PEO. It was also found that higher the Mw of PEO, the larger the saturated swelling amount. Next, a push-pull pump (PPP) with almost identical formulation to that of EOP was prepared, and its drug release characteristics were investigated. PPPs were prepared by varying the combination of Mws of PEO in both layers, and their dissolution profiles were compared. It was found that PPP using a low-Mw PEO for the drug layer and PEO with a high-Mw in the push layer showed the longest dissolution profile of the linear region. The obtained findings suggested that the properties of PEO and its hydrogel play a crucial role in the drug release of PPP.
       
  • Mesoporous Pravastatin Solid Dispersion Granules Incorporable Into Orally
           Disintegrating Tablets
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Hojun Song, Cheol Moon, Beom-Jin Lee, Euichaul Oh Herein, we aimed to prepare porous granules of pravastatin and evaluate their applicability to orally disintegrating tablets (ODTs). Pravastatin solid dispersion granules (PSDGs-A) were prepared by dispersing pravastatin sodium in D-mannitol (the dispersion medium) in the presence of ammonium bicarbonate (the sublimation agent) using a spray-drying process. The PSDGs-A were round, irregularly shaped, mesoporous agglomerates with appropriate particle size, bulk density, and flowability for the tableting process. The mesopore formation in PSDGs-A resulted from the complete sublimation of ammonium bicarbonate during spray-drying and resulted in a notably high surface area. When the PSDGs-A were blended with ODT excipients and then directly compressed into ODTs (PSDGs-A-ODTs), they were readily incorporated into ODTs without tableting problems and had desirable ODT characteristics. They demonstrated rapid disintegration times because of the fast water uptake of mesoporous PSDGs-A caused by their high surface area. This rapid disintegration of PSDGs-A-ODTs was reflected also by their quick initial dissolution. The mesoporous PSDGs-A prepared with ammonium bicarbonate using the spray-drying process can be used to develop pravastatin ODTs. This spray-dried, mannitol-based solid dispersion of drugs using sublimation solids is a potential formulation technology for ODT product development.
       
  • Effect of the Dispersion States of Azone in Hydroalcoholic Gels on Its
           Transdermal Permeation Enhancement Efficacy
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Hui-lin Chen, Chen-chen Cai, Jun-yuan Ma, Mei-ling Yu, Mei-hui Zhao, Jian-bo Guo, Hui Xu The objective of this study was to investigate the effect of dispersion states of azone in gels on the transdermal permeation of levamisole hydrochloride (LH). LH hydroalcoholic gels containing azone of different dispersion states were prepared by varying the contents of azone and Tween 80, and the in vitro transdermal permeation of LH across excised rat skin was evaluated. Depending on the content of azone, mixed solvents, and solubilizer used, azone presented as dissolved molecules, solubilized in micelles, and fine or coarse emulsion droplets in gels. Dramatically increased transdermal permeation of LH within the azone contents between 0.25% and 0.75% indicated high transdermal enhancement efficiency of the molecular or micellar azone, and extra azone that existed as oil droplets did not fully exert transdermal penetration enhancement of LH. Although solubilizer (Tween 80) can greatly increase the solubility of azone, only small amount of Tween 80 (0.5%) in the gel significantly increased the steady-state flux of LH. Addition of extra amount of Tween 80 (>0.5%) reduced the amount of azone distributed in the skin, and thus decreased the transdermal drug permeation. The results partly elucidated the versatile effects of the dispersion states of azone on the transdermal permeation of hydrophilic drug from semisolid gels.
       
  • Fluorescence-Based High-Throughput Salt Screening
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Kazue Kimura, Saho Onishi, Kei Moriyama The present study reports a high-throughput screening method for the salt formation of amine-containing active pharmaceutical ingredients (APIs) based on fluorescence measurements. A free form amine API was alkynylated by a solid–vapor reaction using propargyl bromide, and a fluorescent compound was produced by a subsequent reaction using 9-azidomethylanthracene. In contrast, salts were inert to propargyl bromide; thus, no fluorescence was observed. Samples for salt screening were prepared by grinding haloperidol with various counter acids, and these mixtures were derivatized in a 96-well microplate to determine whether the salt formation had occurred between haloperidol and the counter acids. Samples that turned into fluorescent and nonfluorescent were confirmed to be free form and salt form, respectively, using powder X-ray diffraction and Raman spectroscopy. In conclusion, our method adequately functions as an indicator of the salt formation of amine APIs. Further, this method allows for the rapid evaluation of the salt formation of APIs using 96-well microplates without the need for special reagents or techniques; thus, it is valuable for the discovery of an optimal salt form of newly developed amine APIs in the pharmaceutical industry.
       
  • Biophysical Properties and Heating-Induced Aggregation of
           Lysine-Conjugated Antibody-Drug Conjugates
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Aditya V. Gandhi, Keith J. Arlotta, Hsiao-Nung Chen, Shawn C. Owen, John F. Carpenter The commercially available antibody-drug conjugate (ADC) product, Kadcyla® is synthesized using a 2-step reaction, wherein the linker is conjugated to native lysines on the mAb in step 1, followed by drug conjugation to the linker-modified antibody in step 2. In our study, we synthesized a lysine-conjugated ADC (Syn-ADC) on the same trastuzumab scaffold as Kadcyla® using a 1-step reaction. Mass spectrometry of both products revealed a subpopulation of Kadcyla® containing free linkers conjugated to the mAb, but not conjugated to the drug, which were absent in the 1-step reaction ADC product. Differential scanning calorimetry thermograms showed that the drug and linker conjugation significantly reduced the thermal stability and energies of activation for the denaturation of the CH2 domain of the ADCs. The heating induced aggregation events started as early as ∼57°C and ∼45°C for Kadcyla® and Syn-ADC, respectively, compared with 71°C for Herceptin®. The colloidal stability measurements clearly showed that the hydrophobic drug payload on ADCs significantly reduced the repulsive interprotein interactions when compared to the unconjugated antibody under formulation buffer conditions (pH 6.0). Attaching hydrophobic drug and linker moieties onto the antibody lowered the thermal and colloidal stabilities and increased the aggregation propensity of the ADCs.
       
  • Protein Nanoparticles Promote Microparticle Formation in Intravenous
           Immunoglobulin Solutions During Freeze-Thawing and Agitation Stresses
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Neha N. Pardeshi, Chen Zhou, Theodore W. Randolph, John F. Carpenter In this study, we investigated the potential roles of nanoparticles (1000 nm) in protein formulations under some pharmaceutically relevant stress conditions. Exposure of intravenous immunoglobulin solutions to the interface-associated stresses of freeze-thawing or agitation resulted in relatively large increases in microparticle concentrations, which depended directly on the levels of pre-existing nano- and submicron particles. Thus, agglomeration of nanoparticles and submicron particles appears to play a role in microparticle formation under these stresses. In contrast, increases in microparticle concentrations during quiescent incubation at elevated temperatures were independent of the initial nano- and submicron particle concentrations in solution.
       
  • A Platform for Preparing Homogeneous Proteinaceous Subvisible Particles
           With Distinct Morphologies
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Malthe Møhl Schack, Eva Horn Møller, John F. Carpenter, Thomas Rades, Minna Groenning Regulatory authorities and scientific communities are increasingly attentive to the known and universal presence of small particulates in biological drug products. The underlying concern is that these particulates may cause unwanted formation of antidrug antibodies in patients. Pharmacological studies, however, have to date not succeeded in unambiguously identifying risk-prone particle properties. This lack of success may be partly due to a lack of available, well-defined, homogenous particle material. Protein particles arising from stress of protein drug products are by nature often highly heterogeneous in size, morphology, and structure of the constituent protein in the particles. Here, we present simple and pharmaceutically relevant stress conditions to produce 8 different highly homogenous micrometer-sized protein particles from human insulin, representing very different morphologies and conformation of the constituent protein molecules in the particles generated. Insulin's self-association patterns were varied by formulation approaches to create diverse starting materials. The resulting collection of homogenous particles underlines that the particle formation is not necessarily a random process but a consequence of formulation and specific stress condition. Owing to the inherent homogenicity of these populations, the particle materials can act as a standard platform for further studies on insulin subvisible particles in drug products.
       
  • Simple and Robust N-Glycan Analysis Based on Improved 2-Aminobenzoic Acid
           Labeling for Recombinant Therapeutic Glycoproteins
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Yeong Ran Jeong, Sun Young Kim, Young Sam Park, Gyun Min Lee N-glycans of therapeutic glycoproteins are critical quality attributes that should be monitored throughout all stages of biopharmaceutical development. To reduce both the time for sample preparation and the variations in analytical results, we have developed an N-glycan analysis method that includes improved 2-aminobenzoic acid (2-AA) labeling to easily remove deglycosylated proteins. Using this analytical method, 15 major 2-AA–labeled N-glycans of Enbrel® were separated into single peaks in hydrophilic interaction chromatography mode and therefore could be quantitated. 2-AA–labeled N-glycans were also highly compatible with in-line quadrupole time-of-flight mass spectrometry (MS) for structural identification. The structures of 15 major and 18 minor N-glycans were identified from their mass values determined by quadrupole time-of-flight MS. Furthermore, the structures of 14 major N-glycans were confirmed by interpreting the MS/MS data of each N-glycan. This analytical method was also successfully applied to neutral N-glycans of Humira® and highly sialylated N-glycans of NESP®. Furthermore, the analysis data of Enbrel® that were accumulated for 2.5 years demonstrated the high-level consistency of this analytical method. Taken together, the results show that a wide repertoire of N-glycans of therapeutic glycoproteins can be analyzed with high efficiency and consistency using the improved 2-AA labeling–based N-glycan analysis method.
       
  • Determination of Interaction Parameters for Reversibly Self-Associating
           Antibodies: A Comparative Analysis
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Mandi M. Hopkins, Cherie L. Lambert, Jared S. Bee, Arun Parupudi, David L. Bain Monoclonal antibodies (mAbs) represent a major class of biotherapeutics and are the fastest growing category of biologic drugs on the market. However, mAb development and formulation are often impeded by reversible self-association (RSA), defined as the dynamic exchange of monomers with native-state oligomers. Here, we present a comparative analysis of the self-association properties for 5 IgG mAbs, under matched conditions and using orthogonal methods. Concentration-dependent dynamic light scattering and sedimentation velocity studies revealed that the majority of mAbs examined exhibited weak to moderate RSA. However, because these studies were carried out at mAb concentrations in the mg/mL range, we also observed significant nonideality. Noting that nonideality frequently masks RSA and vice versa, we conducted direct boundary fitting of the sedimentation velocity data to determine stoichiometric binding models, interaction affinities, and nonideality terms for each mAb. These analyses revealed equilibrium constants from micromolar to millimolar and stoichiometric models from monomer-dimer to isodesmic. Moreover, even for those mAbs described by identical models, we observed distinct kinetics of self-association. The accuracy of the models and their corresponding equilibrium constants were addressed using sedimentation equilibrium and simulations. Overall, these results serve as the starting point for the comparative dissection of RSA mechanisms in therapeutic mAbs.
       
  • Analytical Comparability Assessments of 5 Recombinant CRM197 Proteins From
           Different Manufacturers and Expression Systems
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): John M. Hickey, Vishal M. Toprani, Kawaljit Kaur, Ravi P.N. Mishra, Akshay Goel, Natalia Oganesyan, Andrew Lees, Robert Sitrin, Sangeeta B. Joshi, David B. Volkin Cross-reacting material 197 (CRM197), a single amino acid mutant of diphtheria toxoid, is a commonly used carrier protein in commercial polysaccharide protein conjugate vaccines. In this study, CRM197 proteins from 3 different expression systems and 5 different manufacturers were obtained for an analytical comparability assessment using a wide variety of physicochemical and in vitro antigenic binding assays. A comprehensive analysis of the 5 CRM197 molecules demonstrate that recombinant CRM197's expressed in heterologous systems (Escherichia coli and Pseudomonas fluorescens) are overall highly similar (if not better in some cases) to those expressed in the traditional system (Corynebacterium diphtheriae) in terms of primary sequence/post-translational modifications, higher order structural integrity, apparent solubility, physical stability profile (vs. pH and temperature), and in vitro antigenicity. These results are an encouraging step to demonstrate that recombinant CRM197 expressed in alternative sources have the potential to replace CRM197 expressed in C diphtheriae as a source of immunogenic carrier protein for lower cost polysaccharide conjugate vaccines. The physicochemical assays established in this work to monitor the key structural attributes of CRM197 should also prove useful as complementary characterization methods (to routine quality control assays) to support future process and formulation development of lower cost CRM197 carrier proteins for use in various conjugate vaccines.
       
  • Exploring a Kinetic Model Approach in Biopharmaceutics: Estimating the
           Fraction Absorbed of Orally Administered Drugs in Humans
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Po-Chang Chiang, Jia Liu, Peter Fan, Harvey Wong Increasing costs of research and development in the pharmaceutical industry has necessitated a growing interest in the early prediction of human pharmacokinetics of drug candidates. Of growing interest is the need to understand oral absorption, the most common route of small molecule drug administration. The fraction of dose absorbed (%Fa) is considered a critical yet challenging parameter to predict. A kinetic model has been developed and tested to provide an early prediction of the fraction dose absorbed in humans. Unlike the traditional plug-flow model, this model assumes first-order kinetics to estimate the amount of drug present in the stomach and small intestine as a function of time and calculates the amount of drug released and absorbed during the transit. Other variables can be included in calculation as a function of time to better mimic the physiological condition with this approach. Absorption efficiency is assigned along with %Fa to give a quantitative estimate of the limiting factor for oral absorption. The model was tested with literature and in-house compounds. It was found that this model gives a good prediction of human %Fa with a correction coefficient (R2) of 0.8 and greater between predicted and reported %Fa for all compounds.
       
  • Extrapolation of the Hepatic Clearance of Drugs in the Absence of Albumin
           In Vitro to That in the Presence of Albumin In Vivo: Comparative
           Assessement of 2 Extrapolation Models Based on the Albumin-Mediated
           Hepatic Uptake Theory and Limitations and Mechanistic Insights
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Patrick Poulin, Sami Haddad The extrapolation of hepatic clearance (CL) from data determined in an in vitro assay in the absence of albumin (ALB) to that in the presence of ALB in liver in vivo was often inaccurate using traditional in vitro-to-in vivo extrapolation (IVIVE) methods for drugs binding to the ALB. It is recognized that considering an ALB-facilitated hepatic uptake phenomenon in the IVIVE can improve the extrapolation. Therefore, the present study provides a comparison of 2 existing models that account for the ALB-facilitated hepatic uptake phenomenon in the IVIVE of CL. These models assume an interaction of the ALB-bound drug complex with the hepatocyte membrane that enhanced the dissociation of the drug from ALB to result in increased unbound intracellular drug levels available for metabolism or transporter-mediated elimination. One model refers to the old facilitated-dissociation model (FDM), which is based on a binding isotherm and necessitates knowing the specific input parameters of the interaction (i.e., relative capacity of the interaction, dissociation constant, number of binding sites, and ALB concentration). The other model is based on the same theory but is recent and more speculative although it presumes that each interaction between the ALB-drug complex and the hepatocyte surface would at all times enhance and deliver the dissociated bound drug moiety into the hepatocytes and therefore, has the advantage to use less binding information. Consequently, this second model simply consists of adjusting the unbound fraction determined in plasma in vitro of each drug (fup-adjusted) with the real differential of ALB concentration between the plasma and liver in vivo to estimate the corresponding differential of ALB-drug complex also assumed available to deliver the unbound drug moiety for hepatic uptake in vivo versus in vitro. Application of these 2 models (FDM and fup-adjusted) significantly improved the IVIVEs of CL of drugs, and hence, the next step was to compare these 2 models with the same data set. Recently published data on the hepatic uptake of 2 organic anions, namely 1-anilino-8-naphthalene sulfonate and pitavastatin, provide all binding information. As expected, the results indicate that these 2 models are conceptually and mathematically equivalent as well as they successfully predicted the experimentally determined ratios of the unbound intrinsic CL (CLint) in the presence of ALB in vivo to that in the absence of ALB in vitro. However, the 2 models were equivalent particularly for pitavastatin because its ALB-drug complex showed a relevant capacity of interaction and dissociation with the hepatocyte membrane. Conversely, for 1-anilino-8-naphthalene sulfonate, the model of fup-adjusted overestimated the ratio of unbound CLint by contrast to the FDM model because its ALB-drug complex demonstrated a significantly lower capacity of interaction with the membrane. The rational is simply because the model of fup-adjusted presumably assumed an important facilitated-uptake phenomenon for each drug, whereas the FDM model was derived from binding data specific to each drug. Overall, these 2 models are complementary, and all contribute toward achieving the same objective of quantifying the ALB-facilitated uptake phenomenon; however, the FDM model is more specific, but its application necessitates collecting more binding data compared with the model of fup-adjusted that can be used prospectively to predict the maximal effect of the facilitated-hepatic uptake in IVIVE.
       
  • Microdosing Cocktail Assay Development for Drug–Drug Interaction
           Studies
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Cynthia M. Chavez-Eng, Ryan W. Lutz, Dina Goykhman, Kevin P. Bateman Methodology for analysis of a microdosing drug cocktail designed to evaluate the contribution of drug transporters and drug metabolizing enzymes to disposition was developed using liquid chromatography–mass spectrometry–based detection. Fast and sensitive methods were developed and qualified for the quantification of statins (pitavastatin, pitavastain lactone, rosuvastatin, atorvastatin, 2-hydroxy, and 4-hydroxy atorvastatin), midazolam, and dabigatran in human plasma. Chromatographic separation was accomplished using reversed-phase liquid chromatography or hydrophilic interaction liquid chromatography with gradient elution and detection by tandem mass spectrometry in the positive ionization mode using electrospray ionization. The lower limit of quantitation (LLOQ) for the statins assay was 1 pg/mL for the 6 analytes with a linear range from 1 to 1000 pg/mL processing 250 μL plasma sample. The midazolam assay LLOQ was 0.5 pg/mL with a linear range of 0.5 to 1000 pg/mL. For the dabigatran assay, the LLOQ was 10 pg/mL with a linear range of 10 to 5000 pg/mL processing 100 μL plasma sample. The intraday and interday precision and accuracy of the assays were within acceptable ranges, and the assays were successfully applied to support a study where a microdose cocktail was dosed to healthy human subjects for simultaneous assessment of clinical drug-drug interactions mediated by major drug transporters and CYP3A.
       
  • Japan-Specific Key Regulatory Aspects for Development of New
           Biopharmaceutical Drug Products
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Kashappa Goud Desai, Hirokazu Obayashi, James D. Colandene, Douglas P. Nesta Japan represents the third largest pharmaceutical market in the world. Developing a new biopharmaceutical drug product for the Japanese market is a top business priority for global pharmaceutical companies while aligning with ethical drivers to treat more patients in need. Understanding Japan-specific key regulatory requirements is essential to achieve successful approvals. Understanding the full context of Japan-specific regulatory requirements/expectations is challenging to global pharmaceutical companies due to differences in language and culture. This article summarizes key Japan-specific regulatory aspects/requirements/expectations applicable to new drug development, approval, and postapproval phases. Formulation excipients should meet Japan compendial requirements with respect to the type of excipient, excipient grade, and excipient concentration. Preclinical safety assessments needed to support clinical phases I, II, and III development are summarized. Japanese regulatory authorities have taken appropriate steps to consider foreign clinical data, thereby enabling accelerated drug development and approval in Japan. Other important topics summarized in this article include: Japan new drug application-specific bracketing strategies for critical and noncritical aspects of the manufacturing process, regulatory requirements related to stability studies, release specifications and testing methods, standard processes involved in pre and postapproval inspections, management of postapproval changes, and Japan regulatory authority's consultation services available to global pharmaceutical companies.
       
  • Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms:
           Proguanil Hydrochloride
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Gerlinde F. Plöger, Bertil Abrahamsson, Rodrigo Cristofoletti, Dirk W. Groot, Peter Langguth, Mehul U. Mehta, Alan Parr, James E. Polli, Vinod P. Shah, Tomokazu Tajiri, Jennifer B. Dressman Literature data relevant to the decision to waive in vivo bioequivalence testing for the approval of generic immediate release solid oral dosage forms of proguanil hydrochloride are reviewed. To elucidate the Biopharmaceutics Classification System (BCS) classification, experimental solubility and dissolution studies were also carried out. The antimalarial proguanil hydrochloride, effective via the parent compound proguanil and the metabolite cycloguanil, is not considered to be a narrow therapeutic index drug. Proguanil hydrochloride salt was shown to be highly soluble according to the U.S. Food and Drug Administration, World Health Organization, and European Medicines Agency guidelines, but data for permeability are inconclusive. Therefore, proguanil hydrochloride is conservatively classified as a BCS class 3 substance. In view of this information and the assessment of risks associated with a false positive decision, a BCS-based biowaiver approval procedure can be recommended for orally administered solid immediate release products containing proguanil hydrochloride, provided well-known excipients are used in usual amounts and provided the in vitro dissolution of the test and reference products is very rapid (85% or more are dissolved in 15 min at pH 1.2, 4.5, and 6.8) and is performed according to the current requirements for BCS-based biowaivers.
       
  • Nonlinear Protein Binding: Not What You Think
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Amelia N. Deitchman, Ravi Shankar Prasad Singh, Hartmut Derendorf Nonlinear protein binding is traditionally thought of as an increasing fraction unbound with increasing total drug concentration. In the past several years, research into the protein binding of several tetracyclines has shown that an unexpected and counterintuitive phenomenon has been observed, specifically that of decreasing unbound drug fraction with increasing total concentrations of drug over certain concentration ranges. Although several studies of tigecycline have shown the importance calcium and its chelation may play in the protein-drug interaction, the potential clinical implications and relevance have not been explored. Here, we define typical and atypical nonlinear protein binding, overview protein binding theory, and discuss theoretical implications on pharmacokinetics. Using tigecycline as an example, in silico simulations and calculations show how when atypical nonlinear protein binding is not accounted for free drug exposure, and drug tissue penetration may be overestimated. It is important to revisit the impacts of nonlinearity in protein binding on clinical pharmacokinetics and pharmacodynamics, and ultimately, clinical efficacy. Although this phenomenon could potentially warrant clinical dose adjustment for certain compounds, it also presents a potential opportunity to exploit underlying mechanisms to develop new therapies and better understand molecular interactions of xenobiotics within the physiological system.
       
  • Role of Cyclodextrins in Nanoparticle-Based Drug Delivery Systems
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Haley Shelley, R. Jayachandra Babu Cyclodextrins (CDs) are cyclic oligosaccharides with unique hydrophobic interior surfaces. Three parent CDs, α-CD, β-CD, and γ-CD, are further chemically modified primarily to make them suitable for parenteral administration, and these are used for many pharmaceutical applications. CDs offer distinctive advantages due to their unique ability to form inclusion complexes with a variety of organic and inorganic lipophilic molecules. This attribute is promising for a wide range of fields such as drug delivery, cancer therapy, gene delivery, and biosensing. In recent years, CDs have become more commonly used functional materials in nanoparticle (NP)-based drug delivery. The properties of NPs can be advantageously modified by the inclusion of CDs or their derivatives. CD-conjugated NPs (CD-NPs) have many benefits such as improved drug solubility and serve as drug carriers to specific locations such as cancer cells, which reduces toxicity to normal cells. In addition, CDs can overcome the limitations of NPs such as low encapsulation efficiency and drug loading. This review will discuss the various uses of CDs as it applies to NP-based drug carriers. Specifically, how CDs enhance the characteristics of polymeric, magnetic, lipid, metallic, and mesoporous NPs are discussed.
       
  • Editorial Advisory Board
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s):
       
  • Evaluation of the Effects of Animal Growth and Previous Exposure on the
           Pharmacokinetics of Rituximab in Rats
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Hélène Chapy, Leonid Kagan With a long half-life, pharmacokinetic (PK) evaluation of monoclonal antibodies in rodents lasts multiple weeks during which the animals may grow significantly. We evaluated the impact of weight, age, and previous drug exposure on the PK of rituximab. Serum concentrations of rituximab were measured after intravenous and subcutaneous dosing in Sprague Dawley rats aged between 7 and 21 weeks and weighing between 200 and 600 g. The growth of rats during the study was incorporated into the model through the increase of the volumes of compartments in relation to the rats total body weight. The final model successfully captured all the data; and no difference was observed in the rituximab PK profiles between exposure naïve and redosed or young and older rats. Incorporating the rodent growth over the time course of the study into the PK model was shown to be important for providing a more physiological description of the disposition of rituximab, especially when young and rapidly growing animals are used. Redosing the same rats with monoclonal antibodies might be a viable strategy for reducing the use of laboratory animals in accordance with the 3R principles.
       
  • Translational Pharmacokinetic/Pharmacodynamic Characterization and
           Target-Mediated Drug Disposition Modeling of an Anti–Tissue Factor
           Pathway Inhibitor Antibody, PF-06741086
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Chuenlei Parng, Pratap Singh, Debra D. Pittman, Katherine Wright, Beth Leary, Sunita Patel-Hett, Swapnil Rakhe, James Stejskal, Marjorie Peraza, Dawn Dufield, John E. Murphy, Rob Webster Tissue factor pathway inhibitor (TFPI) exhibits multiple isoforms, which are known to present in multiple locations such as plasma, endothelium, and platelets. TFPI is an endogenous negative modulator of the coagulation pathway, and therefore, neutralization of TFPI function can potentially increase coagulation activity. A human monoclonal antibody, PF-06741086, which interacts with all isoforms of TFPI is currently being tested in clinic for treating hemophilia patients with and without inhibitors. To support clinical development of PF-06741086, pharmacokinetics (PK) and pharmacodynamics of PF-06741086 were characterized in monkeys. In addition, a mechanistic model approach was used to estimate PK parameters in monkeys and simulate PK profiles in human. The results show that PF-06741086 exhibited target-mediated drug disposition and had specific effects on various hemostatic markers including diluted prothrombin time, thrombin generation, and thrombin-antithrombin complex in monkeys after administration. The model-predicted and observed human exposures were compared retrospectively, and the result indicates that the exposure prediction was reasonable within less than 2-fold deviation. This study demonstrated in vivo efficacy of PF-06741086 in monkeys and the utility of a rational mechanistic approach to describe PK for a monoclonal antibody with complex target binding.
       
  • Improving Prediction of Metabolic Clearance Using Quantitative
           Extrapolation of Results Obtained From Human Hepatic Micropatterned
           Cocultures Model and by Considering the Impact of Albumin Binding
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Franck Da-silva, Xavier Boulenc, Hélène Vermet, Pauline Compigne, Sabine Gerbal-Chaloin, Martine Daujat-Chavanieu, Sylvie Klieber, Patrick Poulin The objective was to compare, with the same data set, the predictive performance of 3 in vitro assays of hepatic clearance (CL), namely, micropatterned cocultures (also referring to HepatoPac®) and suspension as well as monolayer hepatocytes to define which assay is the most accurate. Furthermore, existing in vitro-to-in vivo extrapolation (IVIVE) methods were challenged to verify which method is the most predictive (i.e., direct scaling method without binding correction, conventional method based either on the unbound fraction in plasma (fup) according to the free-drug hypothesis, or based on an fup value adjusted for the albumin [ALB]-facilitated hepatic uptake phenomenon). Accordingly, the role of ALB binding was specifically challenged, and consequently, the ALB production was monitored in parallel to the metabolic stability. The ALB concentration data were used to compare the in vitro assays and to adjust the value of fup of each drug to mimic the ALB-facilitated hepatic uptake phenomenon. The results confirmed that the direct and conventional IVIVE methods generally overpredicted and underpredicted the CL in vivo in humans, respectively. However, the underprediction of the conventional IVIVE method based on fup was significantly reduced from data generated with the HepatoPac® system compared with the 2 other in vitro assays, which is possibly because that system is producing ALB at a rate much closer to the in vivo condition in liver. Hence, these observations suggest that the presence of more ALB molecules per hepatocyte in that HepatoPac® system may have facilitated the hepatic uptake of several bound drugs because their intrinsic CL was increased instead of being decreased by the ALB binding effect. Accordingly, the IVIVE method based on the fup value adjusted for the ALB-facilitated uptake phenomenon gave the lowest prediction bias from the statistical analyses. This study indicated that the HepatoPac® system combined with the adjusted value of fup was the most reliable IVIVE method and revealed the importance of quantifying the in vitro-to-in vivo variation of ALB concentration to improve the CL predictions, which would help any future physiologically based pharmacokinetics modeling exercise.
       
  • Quantitative Estimation of Plasma Free Drug Fraction in Patients With
           Varying Degrees of Hepatic Impairment: A Methodological Evaluation
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Guo-Fu Li, Guo Yu, Yanfei Li, Yi Zheng, Qing-Shan Zheng, Hartmut Derendorf Quantitative prediction of unbound drug fraction (fu) is essential for scaling pharmacokinetics through physiologically based approaches. However, few attempts have been made to evaluate the projection of fu values under pathological conditions. The primary objective of this study was to predict fu values (n = 105) of 56 compounds with or without the information of predominant binding protein in patients with varying degrees of hepatic insufficiency by accounting for quantitative changes in molar concentrations of either the major binding protein or albumin plus alpha 1-acid glycoprotein associated with differing levels of hepatic dysfunction. For the purpose of scaling, data pertaining to albumin and α1-acid glycoprotein levels in response to differing degrees of hepatic impairment were systematically collected from 919 adult donors. The results of the present study demonstrate for the first time the feasibility of physiologically based scaling fu in hepatic dysfunction after verifying with experimentally measured data of a wide variety of compounds from individuals with varying degrees of hepatic insufficiency. Furthermore, the high level of predictive accuracy indicates that the inter-relation between the severity of hepatic impairment and these plasma protein levels are physiologically accurate. The present study enhances the confidence in predicting fu in hepatic insufficiency, particularly for albumin-bound drugs.
       
  • A Conformationally Gated Model of Methadone and Loperamide Transport by
           P-Glycoprotein
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Morgan E. Gibbs, Laura A. Wilt, Kaitlyn V. Ledwitch, Arthur G. Roberts P-glycoprotein (Pgp) is a multidrug resistance transporter that limits the penetration of a wide range of neurotherapeutics into the brain including opioids. The diphenylpropylamine opioids methadone and loperamide are structurally similar, but loperamide has about a 4-fold higher Pgp-mediated transport rate. In addition to these differences, they showed significant differences in their effects on Pgp-mediated adenosine triphosphate (ATP) hydrolysis. The activation of Pgp-mediated ATP hydrolysis by methadone was monophasic, whereas loperamide activation of ATP hydrolysis was biphasic implying methadone has a single binding site and loperamide has 2 binding sites on Pgp. Quenching of tryptophan fluorescence with these drugs and digoxin showed competition between the opioids and that loperamide does not compete for the digoxin-binding site. Acrylamide quenching of tryptophan fluorescence to probe Pgp conformational changes revealed that methadone- and loperamide-induced conformational changes were distinct. These results were used to develop a model for Pgp-mediated transport of methadone and loperamide where opioid binding and conformational changes are used to explain the differences in the opioid transport rates between methadone and loperamide.
       
  • Quantitative Monitoring the Anti-Solvent Crystallization and Storage
           Process for Nandrolone by Near-Infrared Spectroscopy
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Xia Zeng, Xinnuo Xiong, Hongqin Yang, Bin Tang, Qiaohong Du, Quan Hou, Zili Suo, Hui Li A novel hydrate (SH2O) of nandrolone was prepared by anti-solvent methods. The crystallization processes with 2 schemes (A and B) were monitored by in-line near-infrared (NIR) spectroscopy. The amounts of SH2O in powder samples obtained by the anti-solvent crystallization and storage process were quantified by NIR combined with chemometrics methods. In-line NIR spectra from 4500 to 8000 cm−1 were chosen to capture physicochemical changes during the whole crystallization process. The combination of the principal component results with offline characterization (scanning electron microscopy, powder X-ray diffraction, NIR) data showed that both schemes yielded high purity SH2O products, but the crystallization speed of scheme B was significantly accelerated. It was demonstrated that in-line NIR spectroscopy combined with principal component analysis can be very useful to monitor in real time and control the anti-solvent crystallization process. Moreover, the solubility and the solid-state transformation of nandrolone under different storage conditions were investigated. The apparent solubility of SH2O was 2.19-2.44 times of Form I, and SH2O was relatively stable when stored at a high relative humidity and temperature below 25°C.
       
  • Powder Compression Properties of Paracetamol, Paracetamol Hydrochloride,
           and Paracetamol Cocrystals and Coformers
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Ann-Sofie Persson, Hamzah Ahmed, Sitaram Velaga, Göran Alderborn The objective was to study the relationship between crystal structure, particle deformation properties, and tablet-forming ability for the monoclinic form of paracetamol (PRA), 2 cocrystals and a salt crystal of PRA in addition to 2 coformers (oxalic acid and 4,4′-bipyridine). Thus, the structure–property–performance relationship was investigated. Analytical powder compression was used for determination of effective plasticity, as inferred from the Heckel yield pressure and the Frenning parameter, and the elastic deformation was determined from in-die tablet elastic recovery. The plasticity could not be linked to the crystal lattice structure as crystals containing zig-zag layers displayed similar plasticity as crystals containing slip planes. In addition, crystals containing slip planes displayed both high and low plasticity. The mechanical properties could not be linked to the tablet-forming ability as the tablet tensile strength, unexpectedly, displayed a tendency to reduce with increased plasticity. Furthermore, the elastic deformation could not explain the tablet-forming ability. It was concluded that no relationship between structure–property–performance for PRA and its cocrystals and salt could be established. Thus, it was indicated that to establish such a relationship, an improved knowledge of crystallographic structure and interparticle bonding during compaction is needed.
       
  • Long-Acting Profile of 4 Drugs in 1 Anti-HIV Nanosuspension in Nonhuman
           Primates for 5 Weeks After a Single Subcutaneous Injection
    • Abstract: Publication date: July 2018Source: Journal of Pharmaceutical Sciences, Volume 107, Issue 7Author(s): Lisa A. McConnachie, Loren M. Kinman, Josefin Koehn, John C. Kraft, Sarah Lane, Wonsok Lee, Ann C. Collier, Rodney J.Y. Ho Daily oral antiretroviral therapy regimens produce limited drug exposure in tissues where residual HIV persists and suffer from poor patient adherence and disparate drug kinetics, which all negatively impact outcomes. To address this, we developed a tissue- and cell-targeted long-acting 4-in-1 nanosuspension composed of lopinavir (LPV), ritonavir, tenofovir (TFV), and lamivudine (3TC). In 4 macaques dosed subcutaneously, drug levels over 5 weeks in plasma, lymph node mononuclear cells (LNMCs), and peripheral blood mononuclear cells (PBMCs) were analyzed by liquid chromatography–tandem mass spectrometry. Plasma and PBMC levels of the active drugs (LPV, TFV, and 3TC) were sustained for 5 weeks; PBMC exposures to LPV, ritonavir, and 3TC were 12-, 16-, 42-fold higher than those in plasma. Apparent T1/2z of LPV, TFV, and 3TC were 219.1, 63.1, and 136.3 h in plasma; 1045.7, 105.9, and 127.7 h in PBMCs. At day 8, LPV, TFV, and 3TC levels in LNMCs were 4.1-, 5.0-, and 1.9-fold higher than in those in PBMCs and much higher than in plasma. Therefore, 1 dose of a 4-drug nanosuspension exhibited persistent drug levels in LNMCs, PBMCs, and plasma for 5 weeks. With interspecies scaling and dose adjustment, this 4-in-1 HIV drug-combination could be a long-acting treatment with the potential to target residual virus in tissues and improve patient adherence.
       
  • Dehydration Study of Piracetam Co-crystal Hydrates
    • Abstract: Publication date: Available online 30 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Xiangmin Liao, Ninglin Zhou A hydrate of co-crystal of Piracetam and 3,5-dihydroxybenzoic acid (35DHBA) was obtained via crystallization from water. Single crystal X-ray data shows that Piracetam/3,5-dihydroxybenzoic acid tetrahydrate (P35TH) crystallizes in the triclinic system with a P1 space group. The physicochemical properties of co-crystal hydrate were characterized using powder X-ray diffractometry (XRD), differential scanning calorimetry (DSC), thermogravimetric analyzer (TGA) and Fourier Transform Infrared spectroscopy (FTIR). The dehydration kinetics of P35TH was monitored at various temperatures and heating rates by DSC and TGA. Activation energy of P35TH dehydration was obtained using temperature-ramp DSC, isothermal and non-isothermal TGA methods. Kinetic analysis of isothermal TGA data was fitted to various solid-state reaction models. Mechanistic models derived from isothermal dehydration kinetic data is best described as a two-dimensional diffusion mechanism. A correlation was noted between the dehydration behavior and the bonding environment of the water molecules in the crystal structure. This study is a good demonstration of complexity of co-crystal hydrate and their dehydration behavior.
       
  • Solid-state insight into the action of a pharmaceutical solvate:
           structural, thermal and dissolution analysis of indinavir sulfate
           ethanolate
    • Abstract: Publication date: Available online 28 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Chengcheng Zhang, Kortney M. Kersten, Jeff W. Kampf, Adam J. Matzger The crystal structure of indinavir sulfate, a pharmaceutical administered as an ethanol solvate, is presented, revealing a unique channel/ionic solvate structure to be characteristic of the compound. The properties of the material with regard to thermal treatment and water adsorption follow closely from the structure. The in situ amorphization of the pharmaceutical upon contacting liquid water is observed and highlights the unique dissolution enhancement of marketing the crystalline solvate dosage. Through survey of published crystal structures, an ambiguous sulfate/bisulfate ionization state is also observed in the crystal, which challenges the general understanding of the pharmaceutical. This study provides a solid-state insight into the function of a special multicomponent crystalline pharmaceutical form.
       
  • Thermodynamic Evaluation of the Interaction Driven by Hydrophobic Bonding
           in the Aqueous Phase
    • Abstract: Publication date: Available online 27 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Peng Yu, Dale Eric Wurster In the current study, the interaction between phenobarbital and activated carbons which is driven by hydrophobic bonding was evaluated. The Two-Mechanism Langmuir-Like Equation (TMLLE) was proposed to describe the isotherms for phenobarbital adsorbing to activated carbons. The parameters in the TMLLE obtained from the non-linear fitting of isotherms were used in the calculations of the differential Gibbs free energy for the hydrophobic bonding-driven interaction. Two thermodynamic models, the Modified Crisp Model and the van’t Hoff Equation, were adopted to estimate the differential Gibbs free energy. And, comparing the differential Gibbs free energy obtained from the two thermodynamic relationships, it can be determined that an adsorbing phenobarbital molecule displaces 12 water molecules on the hydrocarbon surfaces of the activated carbons (hydrophobic bonding case). The difference between the estimates of the differential Gibbs free energy obtained by the Modified Crisp Model and by the van’t Hoff Equation provides a new experimental method to calculate the number of solvent molecules displaced by an adsorbing solute molecule. This is a completely general technique for the hydrophobic bonding-driven interaction, and is not limited to the systems studied. The calculated positive differential entropy confirmed that the adsorption process was entropy driven.
       
  • N-7-Guanine Adduct of the Active Monoepoxide of Prodrug Treosulfan: First
           Synthesis, Characterization, and Decomposition Profile under Physiological
           Conditions
    • Abstract: Publication date: Available online 27 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Michał Romański, Ulrich Girreser, Artur Teżyk, Franciszek K. Główka (2S,3S)-1,2:3,4-diepoxybutane (DEB) cross-links DNA guanines by forming the intermediate epoxy-adduct (EHBG). This process is presently considered a primary mechanism for the action of treosulfan (TREO), the prodrug that transforms to DEB via the monoepoxide intermediate EBDM. In this paper, the N-7-guanine adduct of EBDM (HMSBG) was synthesized for the first time and its stability was investigated at physiological in vitro conditions. To synthesize HMSBG, EBDM, formed in-situ from TREO, was treated with guanosine in glacial acetic acid at 60 oC followed by ribose cleavage in 1 M HCl at 80 oC. HMSBG was stable during the synthesis, which showed that a β-hydroxy group protects the sulfonate moiety against hydrolysis in acid environment. At pH 7.2 and 37 oC, HMSBG exclusively underwent first-order epoxidation to EHBG with a half-life of 5.0 h. EHBG further decomposed to trihydroxybutyl-guanine, chlorodihydroxybutyl-guanine (major products), phosphodihydroxy-guanine and a structural isomer (minor products). The isomeric derivative was identified as guanine with a fused seven-membered ring, which provided a new insight into the EHBG stability. To conclude, the exclusive conversion of HMSBG to EHBG indicates that EBDM might contribute to DNA cross-linking independently from DEB and play a more important role in the TREO action than expected before.
       
  • Amphotericin B-Loaded Plga Nanofibers: an Alternative Therapy Scheme for
           Local Treatment of Vulvovaginal Candidiasis
    • Abstract: Publication date: Available online 27 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Ramon Oliveira Souza, Tadeu Henrique de Lima, Rodrigo Lambert Oréfice, Marcelo Gonzaga de Freitas Araújo, Sandra Aparecida de Lima Moura, Juliana Teixeira Magalhães, Gisele Rodrigues da Silva Vulvovaginal candidiasis is an inflammation localized in the vulvovaginal area. It is mostly caused by Candida albicans. Its treatment is based on the systemic and/or local administration of antifungal drugs. However, this conventional therapy can fail owing to the resistance of the Candida species and noncompliance of patients. Amphotericin B-loaded PLGA nanofibers are single-use, antifungal, controlled drug delivery systems, and represent an alternative therapeutic scheme for the local treatment of vulvovaginal candidiasis. Nanofibers were characterized by analytical techniques, and with an in vitro drug delivery study. In vitro and in vivo fungicidal activity of amphotericin B released from nanofibers was evaluated using the agar diffusion method and an experimental murine model of vulvovaginal candidiasis, respectively. Analytical techniques showed that amphotericin B was physically mixed in the polymeric nanofibers. Nanofibers controlled the delivery of therapeutic doses of amphotericin B for eight consecutive days, providing effective in vitro antifungal activity and eliminated the in vivo vaginal fungal burden after three days of treatment and with only one local application. Amphotericin B-loaded PLGA nanofibers could be potentially applied as an alternative strategy for the local treatment of vulvovaginal candidiasis without inducing fungal resistance, yet ensuring patient compliance.
       
  • Liquid Droplet of Protein–Polyelectrolyte Complex for
           High-Concentration Formulations
    • Abstract: Publication date: Available online 27 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Ayumi Matsuda, Masahiro Mimura, Takuya Maruyama, Takaaki Kurinomaru, Mieda Shiuhei, Kentaro Shiraki The formulation of high-concentration protein solutions is a challenging issue for achieving subcutaneous administration. Previously, we developed a method of precipitation–redissolution using polyelectrolyte as a precipitant to produce protein solutions at high concentrations. However, the redissolution yield of proteins was insufficient. This study aims to optimize the solution conditions for practical applications by combining immunoglobulin G (IgG) and poly–L–(glutamic acid) (polyE). A systematic analysis of solution pH and polyE size conditions revealed that an acidic condition favors precipitation, while neutral pH values are more effective for the redissolution. We find that the optimal size for polyE ranged from 15,000 to 50,000. This slight modification in the procedure in comparison with previous studies increased the precipitation and redissolution yields to nearly 100%, without irreversible protein denaturation. The fully reversible IgG–polyE complex formed as a droplet structure, which is similar to a condensate of liquid–liquid phase separation. The droplet structure plays an indispensable role in the salt-induced, redissolved state, which is pertinent to the new application, that takes advantage of the methods to produce highly concentrated protein solutions.
       
  • Redox- and pH-responsive nanoparticles release piperlongumine in a
           stimuli-sensitive manner to inhibit pulmonary metastasis of colorectal
           carcinoma cells
    • Abstract: Publication date: Available online 22 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Hye Lim Lee, Sung Chul Hwang, Jae Woon Nah, Jungsoo Kim, Byungyoul Cha, Dae Hwan Kang, Young-IL. Jeong Redox-responsive nanoparticles having a diselenide linkage were synthesized to target pulmonary metastasis of cancer cells. Methoxy poly(ethylene glycol)-grafted chitosan (ChitoPEG) was crosslinked using selenocystine-acetyl histidine (Ac-histidine) conjugates (ChitoPEGse) for stimuli-responsive delivery of piperlongumine (PL). ChitoPEGse nanoparticles swelled in an acidic environment and became partially disintegrated in the presence of H2O2, resulting in an increase of particle size and in a size distribution having multimodal pattern. PL release increased under acidic conditions and in the presence of H2O2. Uptake of ChitoPEGse nanoparticles by CT26 cells significantly increased in acidic and redox state. PL-incorporated ChitoPEGse nanoparticles (PL NP) showed similar anticancer activity in vitro against A549 and CT26 cells compared to PL itself. PL NP showed superior anticancer and anti-metastatic activity in an in vivo CT26 cell pulmonary metastasis mouse model. Further, an immunofluorescence imaging study demonstrated that PL NP conjugates were specifically delivered to the tumor mass in the lung. Conclusively, ChitoPEGse nanoparticles were able to be delivered to cancer cells with an acidic- or redox state-sensitive manner and then efficiently targeted pulmonary metastasis of cancer cells since ChitoPEGse nanoparticles have dual pH- and redox-responsiveness.
       
  • Model Protein Adsorption on Polymers Explained by Hansen Solubility
           Parameters
    • Abstract: Publication date: Available online 22 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Liang Fang, Ranjana Singh, Lloyd Waxman, Cathy Zhao Hansen Solubility Parameters (HSP) theory has been successful in explaining the wettability of organic solvents on polymer surfaces and miscibility of different polymers.1 Here, we demonstrate that the amount of bovine serum albumin (BSA) protein adsorption on different polymer surfaces can also be explained by HSP. Interestingly, the HSP of the adsorbed BSA proteins calculated from the protein adsorption data is different than the HSP of native BSA protein itself. The HSP of the adsorbed BSA proteins are more hydrophobic than the native BSA protein. This observation suggested adsorbed BSA proteins are partially denatured and exposed their hydrophobic core toward the polymer surfaces. These results highlight a new strategic direction to understand interaction of protein with a surface: a theoretical approach that compliments experimental approach. The model in this study could be used to predict the amount of BSA adsorption on a polymer or any other solid surface, if the HSP of that surface is known. Further, the model can serve as a pre-screen method to identify surfaces that are problematic at the outset and inform subsequent empirical studies to select packaging that will have the least adsorption for the specific biologic application.
       
  • Development and Characterization of Gastroretentive High Density Pellets
           lodged with Zero Valent Iron Nanoparticles
    • Abstract: Publication date: Available online 21 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Ankush Sharma, Amit K. Goyal, Goutam Rath The objective of the present study is to improve iron bioavailability using high density gastroretentive pellets of zero valent iron nanoparticles (ZVINps). ZVINps were prepared by the chemical reduction method and were characterized for surface morphology, surface charge and thermal properties. High density gastro retentive pellets of iron nanoparticles were prepared using spheronization technique. Pellets were characterized for its micromeritic properties, in vitro drug release and ex-vivo permeability. The pharmacokinetics parameters, organ distribution and toxicity of the optimised pellets were investigated in Wistar rats. In-vivo results revealed more than twofold increases in oral bioavailability of iron by pellets compared to plane ferrous sulfate. Toxicological studies of the carriers indicated no evidence of liver damage in acute treatment, however few complications were observed in chronic treatment groups. These results indicated that ZVINPs pellets successfully improve the oral iron bioavailability but need to obtain more information on repeated dose toxicity to initiate the clinical evaluation of investigational products.
       
  • Investigation of Metal-Catalyzed Antibody Carbonylation with an Improved
           Protein Carbonylation Assay
    • Abstract: Publication date: Available online 21 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Yi Yang, Anna Mah, Inn H. Yuk, Parbir S. Grewal, Abigail Pynn, Will Cole, Di Gao, Fan Zhang, Jia Chen, Lynn Gennaro, Christian Schöneich Protein carbonylation is a post-translational modification referring to the occurrence of aldehydes and ketones in proteins. The current understanding of how carbonylation, in particular, metal-catalyzed carbonylation, occurs in recombinant monoclonal antibodies (mAbs) during production and storage is very limited. To facilitate investigations into mAb carbonylation, we developed a protein carbonylation assay with improved assay robustness and precision over the conventional assays. We applied this assay to investigate mAb carbonylation under production, storage, and stress conditions, and showed that iron, hydrogen peroxide, and polysorbate 20 at pharmaceutically relevant levels critically influence the extent of mAb carbonylation. In addition, we found that while carbonylation correlates with mAb aggregation in several cases, carbonylation cannot be used as a general indicator for aggregation. Furthermore, we observed that mAb carbonylation level can decrease during storage, which indicates that carbonylation products may not be stable. Finally, we report for the first time a positive correlation between carbonylation and acidic charge heterogeneity of mAbs that underwent metal-catalyzed oxidation. This finding shows that the impact of protein carbonylation on product quality for mAbs is not limited to aggregation, but also extends to charge heterogeneity.
       
  • A simple and inexpensive image analysis technique to study the effect of
           disintegrants concentration and diluents type on disintegration
    • Abstract: Publication date: Available online 20 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Alberto Berardi, Lorina Bisharat, Anaheed Blaibleh, Lucia Pavoni, Marco Cespi Tablets disintegration is often the result of a size expansion of the tablets. In this study, we quantified the extent and direction of size expansion of tablets during disintegration, using readily available techniques, i.e. a digital camera and a public domain image analysis software. After validating the method, the influence of disintegrants concentration and diluents type on kinetics and mechanisms of disintegration were studied. Tablets containing diluent, disintegrant (sodium starch glycolate-SSG, crospovidone-PVPP or croscarmellose sodium-CCS) and lubricant were prepared by direct compression. Projected area and aspect ratio of the tablets were monitored using image analysis techniques. The developed method could describe the kinetics and mechanisms of disintegration qualitatively and quantitatively. SSG and PVPP acted purely by swelling and shape recovery mechanisms. Instead, CCS worked by a combination of both mechanisms, the extent of which changed depending on its concentration and the diluent type. We anticipate that the method described here could provide a framework for the routine screening of tablets disintegration using readily available equipment.
       
  • A tutorial for developing a topical cream formulation based on the Quality
           by Design approach
    • Abstract: Publication date: Available online 20 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Ana Simões, Francisco Veiga, Carla Vitorino, Ana Figueiras The pharmaceutical industry has entered in a new era, as there is a growing interest in increasing the quality standards of dosage forms, through the implementation of more structured development and manufacturing approaches. For many decades, the manufacturing of drug products was controlled by a regulatory framework to guarantee the quality of the final product through a fixed process and exhaustive testing. Limitations related to the Quality by Test (QbT) system have been widely acknowledged.The emergence of Quality by Design (QbD) as a systematic and risk-based approach introduced a new quality concept based on a good understanding of how raw materials and process parameters influence the final quality profile. Although the QbD system has been recognized as a revolutionary approach to product development and manufacturing, its full implementation in the pharmaceutical field is still limited. This is particularly evident in the case of semisolid complex formulation development.The present review aims at establishing a practical QbD framework to describe all stages comprised in the pharmaceutical development of a conventional cream in a comprehensible manner.
       
  • Preparation and evaluation of multifunctional auto-fluorescent magnetic
           nanoparticles based drug delivery systems against mammary cancer
    • Abstract: Publication date: Available online 20 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Zhi Li, Junya Zhang, Xiao Li, Xinhong Guo, Zhenzhong Zhang The Fe3O4@C @NaYF4:Yb,Er nano-carriers with multifunctional were synthesized. The mitoxantrone (MTO) were selected as model drug and these nanoparticles have high drug loading (0.63mg/mg). The temperature of Fe3O4@C @NaYF4:Yb,Er in water approached 60°C with 808nm irritation(2.5W/cm2). The cumulative release of these nano drug carriers significantly increased because of temperature increasing, and the 4T1 cells growth inhibition rates were 59.15%, almost 2.25-fold higher than MTO group (p
       
  • Past, present and future of bioequivalence: Improving assessment and
           extrapolation of therapeutic equivalence for oral drug products.
    • Abstract: Publication date: Available online 20 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Rodrigo Cristofoletti, Malcolm Rowland, Lawrence J. Lesko, Henning Blume, Amin Rostami-Hodjegan, Jennifer B. Dressman The growth in the utilization of systems thinking principles has created a paradigm shift in the regulatory sciences and drug product development. Instead of relying extensively on end product testing and one-size-fits-all regulatory criteria, this new paradigm has focused on building quality into the product by design as well as fostering the development of product-specific, clinically relevant specifications. In this context, this commentary describes the evolution of bioequivalence regulations up to the current days and discusses the potential of applying a Bayesian-like approach, considering all relevant prior knowledge, to guide regulatory bioequivalence decisions in a patient-centric environment.
       
  • Pharmacokinetics and Skin Tolerability of Intracutaneous Zolmitriptan
           Delivery in Swine Using Adhesive Dermally Applied Microarray
    • Abstract: Publication date: Available online 19 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Joe Nguyen, Hayley Lewis, Ashley Queja, Anh Ngoc Diep, Guillaume Hochart, Mahmoud Ameri Adhesive Dermally Applied Microarray (ADAM) is a new drug-delivery system that uses microprojections (340-μm long) for intracutaneous drug self-administration. We formulated zolmitriptan, a well-accepted and commonly used migraine medication, for administration using ADAM. In vivo studies were conducted in female prepubescent Yorkshire pigs using ADAM 1.9-mg zolmitriptan applied to the inner thigh and left in place for 1 h. Pharmacokinetic studies showed that the ADAM 1.9-mg zolmitriptan was delivered with high efficiency (85%) and high absolute bioavailability (77%). Furthermore, in vivo evaluation showed a rapid systemic absorption with a median Tmax of 15 min. Skin biopsies of the treatment sites showed a mean depth of microprojection penetration of 105.4 ± 3.6 μm. Mass spectrometry imaging showed that the zolmitriptan after 1 h of patch wear time was predominantly localized to the dermis. ADAM zolmitriptan was well tolerated with a transient mild-to-moderate erythema response. The findings in these studies, particularly the rapid zolmitriptan absorption profile after intracutaneous administration, provided validation to advance ADAM zolmitriptan development.
       
  • Enhanced Precision of Circular Dichroism Spectral Measurements Permits
           Detection of Subtle Higher Order Structural Changes in Therapeutic
           Proteins
    • Abstract: Publication date: Available online 18 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Gregory V. Barnett, Gurusamy Balakrishnan, Naresh Chennamsetty, Brent Meengs, Jeffery Meyer, Jacob Bongers, Richard Ludwig, Li Tao, Tapan K. Das, Anthony Leone, Sambit R. Kar Protein higher order structure (HOS) is an essential quality attribute to ensure protein stability and its proper biological function. Protein HOS characterization is performed during comparability assessments for product consistency as well as during forced degradation studies for structural alteration upon stress. Circular dichroism (CD) spectroscopy is a widely used technique for measuring protein HOS, but it remains difficult to assess HOS with a high degree of accuracy and precision. Moreover, once spectral changes are detected, interpreting the differences in terms of specific structural attributes is challenging. Spectral normalization by the protein concentration remains one of the largest sources of error and reduces the ability to confidently detect differences in CD spectra. This work develops a simple method to enhance the precision of the CD spectral measurements through normalization of the CD spectra by the protein concentration determined directly from the CD measurement. This method is implemented to successfully detect small CD spectral changes in multiple forced degradation studies as well as comparability assessments during biologics drug development. Furthermore, the interpretation of CD spectral changes in terms of HOS differences are provided based on orthogonal data in conjunction with structural insights gained through in-silico homology modeling of the protein structure.
       
  • Anti-allodynic and anti-hyperalgesic activities of fentanyl loaded dermal
           clay (FLDC) dressings in rat model of second degree burn injury
    • Abstract: Publication date: Available online 18 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Srinath Rangappa, Krishnaswamy K. Rangan, Tirumalai S. Sudarshan, S. Narasimha Murthy Second degree burn injury is the most common type of burn injury which usually takes 2-3 weeks for complete healing. However, such patients suffer with intense pain associated with development of hyperalgesia and allodynia. Here, we prepare a silver clay patch using Montmorillonite clay, betaine and silver nitrate. Later, the silver clay patches were loaded with fentanyl. Further, the patches were fabricated into burn wound dressings. The dressings were first subjected to ex vivo skin penetration studies and were later evaluated for thermal hyperalgesia and mechanical allodynia using second degree burn injury rodent model. Our results show that application of FLDC dressings for 3hrs showed significant increase of paw withdrawal latency (p
       
  • Tunable SPR-based remote actuation of bimetallic core-shell
           nanoparticles-coated stimuli responsive polymer for switchable
           chemo-photothermal synergistic cancer therapy
    • Abstract: Publication date: Available online 14 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Mitra Amoli-Diva, Rasoul Sadighi-Bonabi, Kamyar Pourghazi New dual light/temperature-responsive nanocarriers were synthesized using bimetallic plasmonic Au-Ag and Ag-Au nanoparticles (NPs) as cores of vehicles which subsequently functionalized with a UCST-based poly acrylamide-co-acrylonitrile using reversible addition-fragmentation chain transfer for spatiotemporally controlled chemo-photothermal synergistic cancer therapy. The bimetallic cores were assigned to sense wavelengths close to the localized SPR of monometallic NP shell to produce heat which not only can increase the surrounding temperature over the UCST of polymer to open the its valves and promote drug diffusion, but also can kill cancerous cells through photothermal effects with increasing in environment temperature nearly 18 °C after about 5 min radiation. The bimetallic NPs were shown good reusability even after five heating/cooling cycles and the efficiency of both photothermal/chemotherapic procedures can be modulated by manipulating carrier’s concentration and radiation time. In addition, the cytotoxicity of drug-free nanocarriers on normal L929 fibroblast and letrozole-loaded nanocarriers on MDAMB 231 breast-cancer cell lines were investigated in the absence/presence of laser radiation. Finally, the prepared nanocomposites were exhibited switchable on/off drug release in two buffered solutions (pH 5.5 and 7.4) with light actuation. The results revealed that the prepared nanocarriers can be served as efficient delivery platforms for remote-control chemo-photothermal synergistic cancer therapy.
       
  • Dipalmitoylphosphatidylcholine (DPPC): Annealing Strategy to Mitigate
           Variability in Thermotropic and Moisture Sorption Behavior
    • Abstract: Publication date: Available online 14 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Saikishore Meruva, Aditya B. Singaraju, Bharath kumar Gowdampally, Bhavani Prasad Vinjamuri, William C. Stagner Dipalmitoylphosphatidylcholine (DPPC) demonstrated complex differential scanning calorimetry (DSC) thermal behavior. Transitions below 100 °C showed variability in their thermotropic reversibility. An experimental design employing a DSC heat-cool-heat-cool-heat cycle and modulated DSC were used to gain insight into the DPPC’s complex thermal nature. An annealing strategy was developed to reduce DPPC’s thermotropic variability, moisture uptake rate, and rate variability. Samples annealed at 110 °C for 5 min provided a reproducible, thermally reversible material. The annealed material also exhibited an 8-fold decrease in moisture sorption rate and a statistically significant (p = 0.0233) 100-fold decrease in water sorption rate variability compared to DPPC “as is”. An optimized validated stability-indicating high performance liquid chromatography with evaporative light scattering detection method was developed and showed no change in DPPC chemical stability under the annealing treatment conditions.
       
  • Investigation of Drug Delivery in Rats via Subcutaneous Injection: Case
           Study of Pharmacokinetic Modeling of Suspension Formulations
    • Abstract: Publication date: Available online 14 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Po-Chang Chiang, Karthik Nagapudi, Peter W. Fan, Jia Liu With the rising cost of drug research, “do more with less” has become a new emphasis in the pharmaceutical industry. Consequently, the early analysis of PK/PD, efficacy, and safety parameters for a new drug target is critical for ensuring informed decision-making as soon as possible during the drug discovery process. When ADME properties of compounds are suboptimalwhich is especially true during the early stages of drug discovery, obtaining the desired exposure can be challenging via the most common routes (oral, IV). Therefore, subcutaneous (SC) injection is often explored as an alternate route of delivery. Although SC injection is used widely in the industry, information about how to model and predict the absorption of drugs administered via SC injection is not readily available. In the current research, we analyzed the absorption behavior of 12 model compounds covering a wide range of physicochemical properties following SC injection. We introduced a compound-specific parameter, the absorption factor (Af) from single SC injections of suspension doses of each compound, to aid in modeling and predicting of drug absorption profiles. The PK models derived in this study are capable of describing and predicting the absorption properties of SC injection for individual compounds.
       
  • The Value of U.S. Pharmacopeial Standards: A Review of the Literature
    • Abstract: Publication date: Available online 13 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): James Heyward, William Padula, Jonothan C. Tierce, G. Caleb Alexander While there are many standard-setting health care organizations, the United States Pharmacopeia’s (USP) role includes the creation of documentary and physical standards for therapeutics, including chemical drugs, excipients and biologics. Despite the ubiquity of these standards, little work has been done to characterize and quantify their value. We reviewed the peer-reviewed and grey literature relevant to such evaluations. The review yielded 36 articles, focused variously on accreditation and other standards in healthcare, the broad impact of pharmacopeial standards, and evaluations of specific USP standards. We did not find any study quantifying the impact of USP or other pharmacopeial standards, but many reports have been published that suggest the utility of USP standards to drug development, quality assurance and public health. Frequently cited areas of impact include equitably advancing the analytical capabilities of manufacturers; enabling the creation of legally enforceable naming conventions; detecting mislabeled and substandard drugs in the marketplace, especially in the context of increased globalization of drug markets; and facilitating the harmonization of diverse international drug quality standards. Our insights provide opportunities for empiric assessments of the effects of USP standards on important outcomes including their promotion of efficient drug development, market competition, drug quality, and patient safety.
       
  • Food Effect Projections via Physiologically Based Pharmacokinetic
           Modeling: Predictive Case Studies
    • Abstract: Publication date: Available online 12 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Christophe Tistaert, Tycho Heimbach, Binfeng Xia, Neil Parrott, Tanay Samant, Filippos Kesisoglou Food can alter the absorption of orally administered drugs. Biopharmaceutics physiologically based pharmacokinetic (PBPK) modeling offers the possibility to simulate a compound’s pharmacokinetics under fasted or fed states. To advance the utility of PBPK modeling, with a view to regulatory impact, we have pooled our experience across four pharmaceutical companies to propose a general multi-step PBPK workflow leveraging pre-existing clinical data for immediate release formulations of BCS I and BCS II compounds. With this strategy, we wish to promote pragmatic PBPK approaches for compounds where absorption is well understood, i.e. compounds with moderate to high permeability that are not substrates for uptake transporters. Five case studies demonstrate how food effect can be well predicted using appropriately established and validated models. The case studies integrate solubility and/or dissolution data for initial model development and apply a “middle-out” validation with clinical data in one prandial state. Then, whenever possible, a validation against both fasted and fed state data is recommended prior to application of the models prospectively for to-be-marketed formulations. Thus, when combined with limited clinical data, PBPK models could be used to simulate outcomes for new doses, formulations, or API forms, in lieu of a clinical food effect study.
       
  • Development of a Vaginal Fast-Dissolving Insert Combining Griffithsin and
           Carrageenan for Potential Use Against Sexually Transmitted Infections
    • Abstract: Publication date: Available online 11 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Manjari Lal, Manshun Lai, Shweta Ugaonkar, Asa Wesenberg, Larisa Kizima, Aixa Rodriguez, Keith Levendosky, Olga Mizenina, José Fernández-Romero, Thomas Zydowsky Precoital, on-demand topical microbicides to reduce a woman’s risk of sexually transmitted infections have been in development for nearly three decades, but no product has been approved due to acceptability issues and poor adherence in clinical trials. We set out to develop a self-administered vaginal fast-dissolving insert (FDI) produced by freeze-drying that would deliver safe and effective amounts of the antiviral agents griffithsin (GRFT) and carrageenan (CG) and would have properties women and their partners find acceptable. We evaluated FDI physical criteria, attributes of the gel produced upon dissolving, and GRFT stability. The lead formulation, FDI-024, was selected from 13 candidates and contains 4 mg of GRFT, 15 mg of CG, and excipients (the cryoprotectant sucrose and bulking agents dextran 40 and mannitol). The FDI exhibits good friability and hardness and is stable for at least 6 months at up to 40°C/75% relative humidity. It disintegrates in less than 60 seconds in a physiologically relevant volume (∼1 mL) of simulated vaginal fluid, forming a viscous semi-solid gel with favorable mucoadhesive and spreading properties. The formulation retains the antiviral activity of GRFT and CG against human immunodeficiency virus type 1 and human papillomavirus, respectively, in cell-based assays.
       
  • Significant Drying Time Reduction using Microwave-Assisted Freeze-Drying
           for a Monoclonal Antibody
    • Abstract: Publication date: Available online 8 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Julian H. Gitter, Raimund Geidobler, Ingo Presser, Gerhard Winter Microwave-assisted freeze-drying is a rapid drying process well-known in food technology. However, little is known about its application to biologicals. In this study, we investigated the applicability and feasibility of this technology to different monoclonal antibody formulations and the influence on the resulting product properties. Moreover, one of our main objectives was to study if significant reductions in drying times could be achieved. Additionally, the effect of the drying process on the accelerated stability of a sucrose-based antibody formulation at 40 °C and 25 °C over 12 weeks was investigated. Microwave-assisted freeze-drying resulted in drying time reduction> 75 %. For all model formulations, cake appearance and solid state properties were found to be comparable to standard lyophilized products. These formulations covered a wider range of lyophilization excipients comprising sucrose and trehalose, semi-crystalline forming solids like mannitol:sucrose-mixtures and others like arginine phosphate and a mixture of HP-β-CD with sucrose. Moreover, comparable low changes in relative monomer content, the relative amount of soluble aggregates and cumulative particles ≥ 1μm per mL were observed over 12 weeks of storage, regardless of the drying technology. This makes MFD a promising innovative alternative for the rapid production of freeze-dried biologicals while maintaining product quality.
       
  • Optimization of Primary Drying in Lyophilization during Early Phase Drug
           Development using a Definitive Screening Design with Formulation and
           Process Factors
    • Abstract: Publication date: Available online 8 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Johnathan M. Goldman, Haresh T. More, Olga Yee, Elizabeth Borgeson, Brenda Remy, Jasmine Rowe, Vikram Sadineni Development of optimal drug product lyophilization cycles is typically accomplished via multiple engineering runs to determine appropriate process parameters. These runs require significant time and product investments, which are especially costly during early phase development when the drug product formulation and lyophilization process are often defined simultaneously. Even small changes in the formulation may require a new set of engineering runs to define lyophilization process parameters. In order to overcome these development difficulties, an eight factor definitive screening design (DSD), including both formulation and process parameters, was executed on a fully human monoclonal antibody (mAb) drug product. The DSD enables evaluation of several interdependent factors to define critical parameters that affect primary drying time and product temperature. From these parameters, a lyophilization development model is defined where near optimal process parameters can be derived for many different drug product formulations. This concept is demonstrated on a mAb drug product where statistically predicted cycle responses agree well with those measured experimentally. This design of experiments (DoE) approach for early phase lyophilization cycle development offers a workflow that significantly decreases the development time of clinically and potentially commercially viable lyophilization cycles for a platform formulation that still has variable range of compositions.
       
  • PEGylation of Carbonate Apatite Nanoparticles Prevents Opsonin Binding and
           Enhances Tumor Accumulation of Gemcitabine
    • Abstract: Publication date: Available online 6 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Fitya Syarifa Mozar, Ezharul Hoque Chowdhury pH sensitives carbonate apatite (CA) has emerged as a targeted delivery vehicle for chemotherapeutics agent with tremendous potential to increase the effectivity of breast cancer treatment. The major challenge for intravenous delivery of drug-incorporated nanoparticles is their rapid opsonization, resulting in accumulation within the organs of reticuloendothelial system, such as liver and spleen. Therefore, surface modification by polyethylene glycol was implemented to improve the half-life of drug-particle complexes and enhance their uptake by target tissues. A simple, rapid, and sensitive triple quadrupole liquid chromatography–mass spectrometry method was developed and validated for quantification of gemcitabine in plasma, various organs and tumor tissues of mice with breast carcinoma, whereas sodium dodecyl sulfate-polyacrylamide gel electrophoresis, quadrupole-time of flight liquid chromatography–mass spectrometry and analysis by SwissProt.Mus_musculus database were performed for protein separation, identification, and homology search by comparing the de novo sequence tag. PEGylated CA exhibited almost 6-fold increase in gemcitabine accumulation in tumor with significant reduction in other organs within 1 h of intravenous administration, compared to free drug. In addition, plasma drug amount was found to be higher in PEGylated particles, implying their role in prolonging blood circulation time of particle-bound gemcitabine. Investigation of protein corona composition demonstrated notable reduction in opsonin interactions after PEGylation of CA particles. Overall, the results indicate that the composition and dynamics of protein corona subjected to alteration by PEGylation play crucial roles in affecting successful nanoparticle-based targeted delivery of a cytotoxic drug.
       
  • Preparation and Quality Evaluation of Salvianolic Acids and Tanshinones
           Dry Powder Inhalation
    • Abstract: Publication date: Available online 6 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Jianhong Wang, Wenwen Zhai, Jiaqi Yu, Jie Wang, Jundong Dai Salvianolic acids and tanshinones both exhibit efficacy in treating idiopathic pulmonary fibrosis (IPF), but their formulation limits their clinical use. This study aimed to prepare the salvianolic acids and tanshinones dry powder for inhalation (SPI) to achieve pulmonary delivery for the treatment of IPF. The variable quantities of salvianolic acids and tanshinones composite powder were optimized using the central composite design-response surface method. Different carriers with various drug-carrier ratios were optimized to prepare SPI. The final optimized formulation of SPI was as follows: InhaLac 230® was selected as the carrier with drug:carrier = 1:6, and the milled lactose InhaLac 400® was added at 5%. The developed SPI characterized with an angle of repose 52.46 ± 1.04°, Carr's index of 34.00 ± 0.50% and showed high lung deposition in vitro, indicating the potential of pulmonary delivery for the treatment of IPF.
       
  • Effect of 2 Emulsion-Based Adjuvants on the Structure and Thermal
           Stability of Staphylococcus aureus Alpha-Toxin
    • Abstract: Publication date: Available online 6 June 2018Source: Journal of Pharmaceutical SciencesAuthor(s): Yangjie Wei, Jian Xiong, Nicholas R. Larson, Vidyashankara Iyer, Gautam Sanyal, Sangeeta B. Joshi, David B. Volkin, C. Russell Middaugh The effects of 2 squalene-based emulsion adjuvant systems (MedImmune emulsion 0 [ME.0] and Stable Emulsion [SE]) on the structure and stability of the recombinant protein antigen alpha-toxin (AT), a potential vaccine candidate for Staphylococcus aureus infection, were investigated using Fourier-transform infrared spectroscopy and both steady-state and time-resolved intrinsic fluorescence spectroscopy as well as differential scanning calorimetry (DSC). A component study, performed to identify the effects of the individual emulsion's components, showed negligible interactions between AT and ME.0. DSC analysis showed the ME.0 emulsion thermally destabilized AT, probably because of changes in the buffer composition of AT upon mixing. The SE emulsion caused increased alpha-helix and decreased beta-sheet content in AT, and a significant blue shift in the fluorescence spectra relative to that of AT in solution. DSC analysis showed SE exerted a dramatic thermal stabilization effect on AT, probably attributable to an interaction between AT and SE. Size exclusion chromatography showed a complete loss in the recovery of AT when mixed with SE, but not ME.0, indicating a high degree of interaction with SE. This work successfully characterized the biophysical properties of AT in the presence of 2 emulsion adjuvants including a component study to rationalize how emulsion components affect protein antigen stability.
       
 
 
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