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Journal of Pharmaceutical Sciences
Journal Prestige (SJR): 0.984
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  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0022-3549 - ISSN (Online) 1520-6017
Published by Elsevier Homepage  [3184 journals]
  • Adjuvants as Delivery Systems in Antigen-Specific Immunotherapies
    • Abstract: Publication date: Available online 14 September 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Lorena R. Antúnez, Melissa M. Pressnall, Cory J. Berkland Combining autoantigens with immune modulating drugs has emerged as an attractive approach to selectively reinstate tolerance in autoimmune diseases. The disparate properties of autoantigens and small-molecule immunosuppressants commonly used to treat autoimmune diseases can confound efforts to co-deliver these therapies. However, both components may be co-delivered with adjuvants which have been successful in delivering antigens to immune cells. We evaluated several common adjuvants as vehicles to co-deliver a model antigen and immunosuppressant, ovalbumin (OVA) and dexamethasone (DEX), respectively. Formulations were developed, and the release of DEX from adjuvants was investigated. Next, the effect of adjuvant, DEX, and OVA was tested in vitro using a DC line. A MF59-analog (MF59a) formulation was advanced to more sophisticated co-culture studies using OVA-primed bone marrow-derived dendritic cells (BMDCs) and splenocytes or T-cells from OT-II mice. Most of these studies indicated MF59a-based ASITs could diminish the markers of inflammation associated with OVA recognition. We rationalized MF59a co-delivery of antigen and drug could reduce the risk of side effects typically associated with these drugs and reinstate immune tolerance, thus prompting continued investigation of emulsion adjuvants as delivery vehicles for ASIT of autoimmune diseases.
  • In Vitro Simulation of Tissue Back-Pressure for Pen
           Injectors and Auto-Injectors
    • Abstract: Publication date: August 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 8Author(s): Arda Yildiz, Torben Anker Lenau The aim of this project was to show that tissue back-pressure can be measured in vitro using a simple pneumatic model. A thorough literature study revealed 4 relevant papers all describing in vivo studies. One of these studies where the subcutaneous tissue back-pressure was determined in 11 patients was used as a reference for the present work. A pneumatic model capable of simulating the back-pressure and the diffusion of drug during subcutaneous injection was developed. The in vitro model was tested using the same type of pen injector as used in the reference study. Comparison of the results revealed that the measured pressure in the in vitro experiments was similar to the subcutaneous tissue back-pressure measured in vivo. G30 0.3 × 8.0 mm and G32 0.23/0.25 × 4.0 mm needles were used for the in vitro experiments, whereas a G31 0.25 × 6.0 mm needle was used for the in vivo experiments. This is one possible explanation of approximately 30 μL/s higher flow rates for the in vitro experiments compared to the in vivo experiments. The low-complexity model allows repeated measurements and provides a stable data output paving the way for measuring subcutaneous back-pressure in vitro.
  • Sub-visible particulate contamination in cell therapy products – Can
           we distinguish'
    • Abstract: Publication date: Available online 12 September 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Ilona Vollrath, Roman Mathaes, Ahmad S. Sediq, Dhananjay Jere, Susanne Jörg, Jörg Huwyler, Hanns-Christian Mahler Cell therapy products represent an exciting new class of medicinal products, which must be parenterally administered. Thus, compliance with parenteral preparation guidelines is required. One requirement for parenteral products is the characterization of particle contaminations. As cell-based products are turbid suspensions, containing particles –the cells, characterization and control of foreign particle impurities remain a challenge. Within this study, we evaluated a flow imaging microscopy method for the detection and characterization of sub-visible particle contaminations in cell-based products. We found that flow imaging microscopy is a potential method where sub-visible particle contaminations can be differentiated from the cells in cell therapy products.
  • Determining Spectroscopic Quantitation Limits for Misfolded Structures
    • Abstract: Publication date: Available online 12 September 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Brent S. Kendrick, John Gabrielson, Eugene Ma, Libo Wang Protein secondary structures are frequently assessed using infrared and circular dichroism spectroscopies during drug development (e.g. during product comparability and/or biosimilarity studies, reference standard characterization, etc.) However, there is little information on the lower limits of quantitation of structural misfolds and/or impurities for these methods. A model system employing a monoclonal antibody reference material was spiked at various levels with a protein that had a significantly different secondary structure to represent the presence of a stable and discreet structural misfold. The ability of circular dichroism (CD) and two infrared spectroscopic techniques, transmission Fourier transform infrared (FTIR) spectroscopy and microfluidic modulation spectroscopy (MMS), along with various spectral comparison algorithms, were assessed for their ability to detect the presence and quantify the amount of the misfolded structure.
  • Nano- And Microcarriers For Enhancing The Uv Protection Of Sunscreens: An
    • Abstract: Publication date: Available online 12 September 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Elisabetta Damiani, Carmelo Puglia This review addresses a major question of importance to pharmaceutical scientists: how can novel drug delivery systems play a role in maximizing the UV protection of sunscreens' Since more and more people are being diagnosed with skin cancer each year than all other cancers combined, adequate sun protective measures are pivotal. In this context, the present review is to give an up-to-date overview on the different nanocarrier systems that have been explored so far for encapsulating different types of UV filters present on the market. The aim of these carrier systems is to prevent skin penetration and to enhance the photoprotective potential of sunscreen actives. For each supramolecular system, a brief description along with the studies, achievements and pitfalls, on the type of UV actives inside them, ranging from classical UV filters to new generation of UV actives is given. A brief over-view of UV filters encapsulated in microcarriers is also discussed.
  • Quality by Design Driven Process Development of severe fever with
           thrombocytopenia syndrome Vaccine
    • Abstract: Publication date: Available online 12 September 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Xinran Li, Yankun Yang, Rongbin Wang, Guoqiang Liu, Xiuxia Liu, Chunli Liu, Yu Deng, Zhonghu Bai Due to the biological activity of the vaccine, the complicated production process, sterility and uniformity of the product, the producing process of the vaccine is complicated and the product quality hard to control. In recent years, with the development of basic science such as cell biology, molecular biology, and metabolic engineering, bioprocess engineering research has developed rapidly. Therefore, FDA and EMA conduct stringent control over the development of biomedical process engineering and product quality. This case study describes an example of QbD driven process development for manufacturing a human vaccine produced with Vero cells. Cell density in harvest fermentation broth and antigenic titer were chosen as two critical quality attributes (CQAs). The study through three rounds DoE experiment revealed that H2O2 and cell boost 4 (CB4) had a significant effect on antigenic titer. Ethanolamine had significant improvement in the final concentration of cells. Through the Monte Carlo simulation, the design spaces and control space of process parameters were determined. A successful validation in bioreactor was executed to verify the results of spinner flask. Our investigation presents a successful case of QbD principle, which encourages other researchers to combine the methodology into other biopharmaceutical manufacturing process.
  • Mixing of a mAb Formulation in a New Magnetically-Coupled Single-Use
           Mixing System: Key Learnings of Preliminary Experimental and Computational
    • Abstract: Publication date: Available online 12 September 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Kashappa Goud Desai, Liang Li, Mark Palmer, Michell Rosamonte, Paul Schofield, Lisa Pongwa, Jonathan Barnett, Massimo Rastelli, James D. Colandene, Douglas P. Nesta MilliporeSigma recently introduced a new magnetically-coupled single-use mixing system (Mobius® Power MIX) for more efficient mixing of buffers and media in biopharmaceutical applications. Experimental and computational fluid dynamics (CFD) assessments were performed on the Power MIX 100 system to understand product quality impact, shear and mixing efficiency. It was interesting to note slightly higher sub-micron (0.4-1 μm) and sub-visible (1-54 μm) particle formation at the lower mixing speed (50RPM) compared to higher mixing speeds (100/200 RPM). Mixing speed and time showed negligible impact on the other product quality attributes tested, including protein concentration, turbidity, general appearance, purity and soluble aggregates. The computational simulations provided useful information with respect to the impact of batch size (20-100 L), viscosity (2-50 cP) and impeller speed (100-300 RPM) on mixing time (mixing time ranged from 10 to 365 s) and shear (maximum shear was found to be localized around the impeller and it was about 30260 s-1, while the average shear rate ranged from 4-36 s-1). Statistical analysis of the CFD results showed that natural-log transformation and quadratic fitting were found to be suitable statistical models to predict mixing time and shear within the design space of the parameters assessed in the current study.
  • Suppression of cerebral ischemia/reperfusion injury by efficient release
           of encapsulated ifenprodil from liposomes under weakly acidic pH
    • Abstract: Publication date: Available online 11 September 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Takashi Kikuchi, Tatsuya Fukuta, Yurika Agato, Yosuke Yanagida, Takayuki Ishii, Hiroyuki Koide, Kosuke Shimizu, Naoto Oku, Tomohiro Asai Although N-methyl-D-aspartate receptors (NMDAR) antagonists are hopeful therapeutic agents against cerebral ischemia/reperfusion (I/R) injury, effective approaches are needed to allow such agents to pass through the blood-brain barrier (BBB), thus increasing bioavailability of the antagonists to realize secure treatment. We previously demonstrated the usefulness of liposomal delivery of neuroprotectants via spaces between the disrupted BBB induced after cerebral I/R. In the present study, a liposomal formulation of a NMDAR antagonist, ifenprodil, was newly designed; and the potential of liposomal ifenprodil (Ifen-Lip) was evaluated in transient middle cerebral artery occlusion rats. Ifenprodil was encapsulated into liposomes by a remote loading method using pH gradient between internal and external water phases of liposomes, focusing on differences of its solubility in water depending on pH. The encapsulated ifenprodil could be quickly released from the liposomes in vitro under a weakly acidic pH condition, which is a distinctive condition after cerebral I/R. Ifen-Lip treatment significantly alleviated I/R-induced increase in permeability of the BBB by inhibiting superoxide anion production, resulting in ameliorating ischemic brain damage. Taken together, these results suggest that Ifen-Lip could become a hopeful neuroprotectant for cerebral I/R injury via efficient release of the encapsulated ifenprodil under weakly acidic pH conditions.
  • Quantification of ENT1 and ENT2 Proteins at the Placental Barrier and
           Contribution of These Transporters to Ribavirin Uptake
    • Abstract: Publication date: Available online 11 September 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Tomohiro Nishimura, Yuichiro Sano, Yu Takahashi, Saki Noguchi, Yasuo Uchida, Akinori Takagi, Takahiro Tanaka, Satomi Katakura, Emi Nakashima, Masanori Tachikawa, Tetsuo Maruyama, Tetsuya Terasaki, Masatoshi Tomi The aims of this study are to quantify the protein levels of nucleoside transporters in placental microvillous membranes (MVMs) and to clarify the contributions of these transporters to ribavirin uptake at the placental barrier. Placental MVMs of human and rat expressed equilibrative nucleoside transporter (ENT) 1 protein, whereas the expression of ENT2 protein was obscure. Maternal-to-fetal transfer of [3H]ribavirin in rats was much higher than that of [14C]sucrose. The uptake of [3H]ribavirin by rat placental trophoblast TR-TBT 18d-1 cells, which functionally express both ENT1 and ENT2 proteins, was saturable, and was significantly inhibited by 0.1 μM nitrobenzylthioinosine (NBMPR), which selectively abolishes ENT1-mediated uptake. Dipyridamole at 10 μM is capable of inhibiting ENT2 as well as ENT1, but a degree of inhibition by 10 μM dipyridamole on [3H]ribavirin uptake was not much different from that by 0.1 μM NBMPR (ENT1-specific inhibitor). Therefore, ENT2 may contribute little to [3H]ribavirin uptake by these cells. Rat ENT1 cRNA-injected oocytes showed increased [3H]ribavirin uptake compared with water-injected oocytes, while rat ENT2 cRNA-injected oocytes did not. In conclusion, ENT1 protein expressed in placental MVMs appears to play a predominant role in the uptake of ribavirin.
  • Interaction of Aripiprazole with Human α1-Acid
    • Abstract: Publication date: Available online 11 September 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Koji Nishi, Keiki Sakurama, Yoshihiro Kobashigawa, Hiroshi Morioka, Nagiko Udo, Mai Hashimoto, Shuhei Imoto, Keishi Yamasaki, Masaki Otagiri We recently reported that aripiprazole binds strongly to human albumin. In continuing our investigations, we investigated the mechanism responsible for the binding and the related interactions of aripiprazole with α1-acid glycoprotein (AGP). The extrinsic Cotton effects for the binding of aripiprazole and its derivatives to AGP were generated but the magnitudes of the induced CD intensities did not correlate with the those for the binding affinities. It therefore appears that the binding mode of aripiprazole with AGP is somewhat complicated, compared with that of albumin. Isothermal titration calorimetry (ITC) data obtained for the binding of aripiprazole with AGP were different from that for albumin systems in that the three driving reactions, entropy driven, enthalpy-driven and the entropy-enthalpy mixed type were all found for the AGP system, but not albumin. Moreover, the weak binding mode of aripiprazole with the two proteins were supported by a molecular docking model analysis. The concentration of albumin in plasma is about 50 times higher than those of AGP but AGP levels in plasma are increased by about 10 times under inflammatory disease. Therefore, the involvement of these two plasma proteins should be considered in more depth for understanding the pharmacokinetics of aripiprazole.
  • Growth hormone aggregates activation of human dendritic cells is
           controlled by Rac1 and PI3 kinase signaling pathways
    • Abstract: Publication date: Available online 11 September 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Myriam Nabhan, Yann Gallais, Marc Pallardy, Isabelle Turbica The presence of protein aggregates in biological products is suggested to promote immunogenicity, leading to the production of anti-drug antibodies with neutralizing capacities. This suggests a CD4+ T-cell dependent adaptive immune response thus a pivotal role for antigen presenting cells, such as dendritic cells (DC). We previously showed that human growth hormone (hGH) aggregates induced DC maturation, with notably an increase in CXCL10 production. DC phenotypic modifications were sufficient to promote allogeneic CD4+ T-cell proliferation with Th1 polarization. In this work, we identified the main intracellular signaling pathways involved in DC activation by hGH aggregates, showing that aggregates induced p38 MAPK, ERK and JNK phosphorylation, as well as NF-κB subunit p65 nuclear translocation. Next, investigating the implication of Rho GTPases and phosphoinositide 3-kinase (PI3K) in activated DC showed that Rac1 and Cdc42 regulated the phosphorylation of MAP kinases, whereas PI3K was only implicated in JNK phosphorylation. Furthermore, we showed that Rac1 and PI3K pathways, but not Cdc42, regulated the production of CXCL10 via the MAP kinases and NF-κB. Taken together our results bring new insight on how protein aggregates could induce DC activation, leading to a better understanding of aggregates role in therapeutic proteins immunogenicity.
  • Analyzing Nanotheraputics Based Approaches For The Management Of Psychotic
    • Abstract: Publication date: Available online 6 September 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Annu, Saleha Rehman, Shadab Md, Sanjula Baboota, Javed Ali Psychoses are brain disorders clinically manifested by cognitive conditions such as hallucinations, delirium, dementia, schizophrenia, and delusions. Antipsychotic drugs are associated with significant side effects such as dystonia, tardive dyskinesia, involuntary muscle movement, and metabolic disorders. Moreover, those Antipsychotics currently available have poor bioavailability, drug-related adverse effects, poor therapeutic efficacy and poor brain delivery resulting from the blood-brain barrier (BBB). Conventional dosage forms, which release the drugs into the general circulation, fail to deliver the drugs directly to the brain efficiently. Thus, a rational approach based on nanotherapeutics may overcome these limitations; such approaches can be used for the delivery of drug molecules to their targeted site. Nanotherapeutics are colloidal systems comprising nano-size range particles and unique physicochemical properties; these properties include plasticity, biodegradability, bio-acceptability, versatile surface modification properties, and protection of drug molecules from degradation. The present review describes various nanoformulations for delivery of antipsychotic drugs to the brain; these include nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsion, nanosuspensions and carbon nanotubes. The review also considers the ability of these formulations to improve drug bioavailability and targeting affinity, as well as their ability to circumvent the first-pass metabolism.
  • Near-infrared spectroscopy to determine residual moisture in freeze-dried
           products: model generation by statistical design of experiments
    • Abstract: Publication date: Available online 6 September 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Matthieu Clavaud, Carmen Lema-Martinez, Yves Roggo, Michael Bigalke, Aurélie Guillemain, Philippe Hubert, Eric Ziemons, Andrea Allmendinger Moisture content (MC) is a critical quality attribute of lyophilized biopharmaceuticals and can be determined by near-infrared (NIR) spectroscopy as nondestructive alternative to Karl-Fischer titration. In this study, we create NIR models to determine MC in monoclonal antibody lyophilisates by use of statistical design of experiments (DoE) and multivariate data analysis (MVDA). We varied the composition of the formulation as well as lyophilization parameters covering a large range of representative conditions, which is commonly referred to as ‘robustness testing’ according to quality-by-design concepts. We applied principles of chemometrics with partial least squares and principal component analyses (PCA). The NIR model excluded samples with complete collapse and MC> 6%. The two main components in the PCA were MC (91%) and protein:sugar ratio (6%). The third component amounted to only 3% and remained unspecified but may include variations in process parameters and cake structure. In contrast to traditional approaches for NIR model creation, the DoE-based model can be used to monitor MC during drug product development work including scale-up, and transfer without the need to update the NIR model if protein:sugar ratio and MC stays within the tested limits and cake structure remains macroscopically intact. The use of the DoE approach and MVDA ensures product consistency and improves understanding of the manufacturing process.
  • Overall similarities and a possible factor affecting plasma metabolome
           profiles between venous and capillary blood samples from 20 healthy human
    • Abstract: Publication date: Available online 5 September 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Kosuke Saito, Satoko Ueno, Akira Nakayama, Shin-ichiro Nitta, Koji Arai, Tomoko Hasunuma, Yoshiro Saito Amino acids and lipids are biomarkers used to assess the presence and severity of disease, as well as the toxicological response to drugs. Although upper-extremity venipuncture is a well-used standard technique, fingertip capillary sampling is a more convenient procedure. Delineating the global differences in amino acid and lipid levels in capillary and venous blood samples is paramount for expanding the application of capillary blood tests in biomarker assays. We recruited 20 healthy male subjects and collected plasma obtained from both fingertip capillary and antecubital venous blood. The samples were analyzed to determine the overall profiles of amino acids and lipids and to test for differences in their levels between both vessel types. The results demonstrated that the differences between capillary and venous blood had a lower impact than interindividual variations; however, trends of separation between them were observed for amino acids. The levels of 5 out of 28 amino acids scored fold changes over 30%, while 9 out of 498 lipids had a fold change over 30%. The time required for fingertip blood collection could be a factor for the differences in 3 metabolites. These findings provide useful information for the application of fingertip capillary blood sampling in biomarker assays.
  • Simvastatin Nanoparticles Reduce Inflammation in LPS-Stimulated Alveolar
    • Abstract: Publication date: Available online 5 September 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Alaa S. Tulbah, Elvira Pisano, Emelie Landh, Santo Scalia, Paul M. Young, Daniela Traini, Hui Xin Ong1.0 Simvastatin (SV) is widely used as lipid- lowering medication that has also been found to have beneficial immuno-modulatory effects for treatment of chronic lung diseases. Although its anti-inflammatory activity has been investigated, its underlying mechanisms have not yet been clearly elucidated. In this study, the anti-inflammatory and anti-oxidant effects and mechanism of simvastatin nanoparticles (SV-NPs) on lipopolysaccharide (LPS)-stimulated alveolar macrophages (AM) NR8383 cells were investigated. Quantitative cellular uptake of SV-NPs, the production of inflammatory mediators (interleukin (IL)-6, tumour necrosis factor (TNF) and monocyte chemoattractant protein-1 (MCP-1)), and oxidative stress (nitric oxide, NO) were tested. Furthermore, the involvement of the Nuclear factor KB (NF-KB) signaling pathway in activation of inflammation in AM and the efficacy of SV were visualized using immunofluorescence. Results indicated that SV-NPs exhibit a potent inhibitory effect on NO production and secretion of inflammatory cytokine in inflamed AM, without affecting cell viability. The enhanced anti-inflammatory activity of SV-NPs is likely due to SV improved chemical- physical stability and higher cellular uptake into AM. The study also indicates that SV targets the inflammatory and oxidative response of AM, through inactivation of the NF-ΚB signalling pathway, supporting the pharmacological basis of SV for treatment of chronic inflammatory lung diseases.
  • The Use of a Microfluidic Device to Encapsulate a Poorly Water-Soluble
           Drug CoQ10 in Lipid Nanoparticles and an Attempt to Regulate Intracellular
           Trafficking to Reach Mitochondria
    • Abstract: Publication date: August 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 8Author(s): Mitsue Hibino, Yuma Yamada, Naoki Fujishita, Yusuke Sato, Masatoshi Maeki, Manabu Tokeshi, Hideyoshi Harashima A number of drugs that are currently on the market, as well as new candidates for drugs, are poorly water soluble. Because of this, a need exists to develop drug formulations that will permit the expanded use of such drugs. The use of liposomes and lipid nanoparticles for drug delivery has attracted attention as a technique for solubilizing molecules that are poorly water soluble, but this technique faces serious scale-up risks. In this study, we report on attempts to encapsulate Coenzyme Q10 (CoQ10) as a model of a poorly water-soluble drug in an MITO-Porter, a liposome for mitochondrial delivery using a microfluidic device (a CoQ10-MITO-Porter [μ]). The physical properties of the CoQ10-MITO-Porter [μ] including homogeneity, size, and preparation volume were compared with those for a CoQ10-MITO-Porter prepared by the ethanol dilution method (a CoQ10-MITO-Porter [ED]). In the case where a microfluidic device was used, a small-sized CoQ10-MITO-Porter was formed homogeneously, and it was possible to prepare it on a large scale. Intracellular observations using HeLa cells showed that the CoQ10-MITO-Porter [μ] was efficiently internalized by cells to reach mitochondria. These results indicate that the CoQ10-MITO-Porter [μ] represents a potential candidate for use in mitochondrial nanomedicine.
  • Mucoadhesive hybrid polymer/liposome pastes based on modified
    • Abstract: Publication date: Available online 3 September 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Yarden Shtenberg, Mor Goldfeder, Hodaya Prinz, Janna Shainsky, Yasmine Ghantous, Imad Abu El-Naaj, Avi Schroeder, Havazelet Bianco-Peled Mucoadhesive hybrid polymer/liposome paste is a new drug delivery system presenting controllable and tailorable delivery mechanism. By using mucoadhesive material the delivery can be more specific and local. Here we present a study investigating the effect of polymer type, concentration, functional end group and crosslinking on the release profile of nano liposomes from polymer pastes. Polymer pastes can be expected to combine the mucoadhesion mechanisms of dry and wet dosage forms but have not been studied extensively. In order to better understand the mucoadhesion of pastes, we investigated a series of pastes based on the same polymer and used different chemical modifications that can produce interactions at different levels.Native and thiolated polymers presented enhanced mucoadhesion in a wet environment in comparison to acrylated polymers which dissolved rapidly due to the enhanced solubility of PEG chains in water. Paste crosslinking resulted in a sustained release profile compared to non-crosslinked pastes. Pectin-SH pastes, especially 3% (w/v), showed a linear liposomal release profile which is ascribed to the combination of ionic crosslinking and di-sulfide bridging. By configuring the polymer type or concentration we can control the release mechanisms and achieve distinct inherent properties which can be applied for diverse medical applications.
  • Development of hydrogels for microneedle-assisted transdermal delivery of
           naloxone for opioid induced pruritus
    • Abstract: Publication date: Available online 30 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Xinyi Gao, Nicole K. Brogden Transdermal naloxone delivery could be a potential option for treating opioid-induced pruritus, but naloxone does not permeate skin well due to its hydrophilic nature. Microneedles (MNs) could overcome the skin barrier by painlessly creating microchannels in the skin to permit naloxone absorption to therapeutic levels. This study investigated how ionization correlates with naloxone permeation across MN-treated skin. Hydrogels containing 0.2, 0.5, or 1% naloxone were formulated with 1% crosslinked polyacrylic acid (polymer) and adjusted to pH 5, 6.5, or 7.4. Porcine skin was treated with MNs and naloxone gel, and in vitro permeation studies were performed using an in-line diffusion set-up. Gel structural properties were evaluated using rheology. All gels had viscoelastic properties and good spreadability. Naloxone permeation through intact skin was highest from pH 7.4 gels when naloxone is unionized, in contrast with undetectable concentrations permeated from pH 5 gels with 100% ionization. Combining MN treatment with pH 5 gels significantly enhanced permeation and resulted in steady-state flux that would achieve therapeutic delivery. Absorption lag time was affected by MN length and naloxone gel concentration. Polymer concentration did not influence drug permeability. This study demonstrates that transdermal naloxone delivery with MNs is a viable treatment option for opioid-induced pruritus.
  • Shape Characterization of Subvisible Particles Using Dynamic Imaging
    • Abstract: Publication date: Available online 30 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Roman Mathaes, Mark Cornell Manning, Gerhard Winter, Julia Engert, Glenn A. Wilson Protein aggregates and subvisible particles (SbvP), inherently present in all marketed protein drug products, have received increasing attention by health authorities. Dynamic imaging analysis was introduced to visualize SbvP and facilitate understanding of their origin. The educational USP chapter emphasizes that dynamic imaging analysis could be used for morphology measurements in the size range of 4 – 100 μm [1]. However, adequate morphology characterization, as suggested in the USP proposed size range, remains challenging as non-spherical size standards are not commercially available. In this study, a homogenous and well-defined non-spherical particle standard was fabricated and used to investigate the capabilities of two dynamic imaging analysis systems (micro-flow imaging or MFI and FlowCAM) to characterize SbvP shape in the size range of 2 – 10 μm. The actual aspect ratio of the SbvP was measured by SEM and compared to the results obtained by dynamic imaging analysis.The test proceedure was used to assess the accuracy in determining the shape characteristics of the non-spherical particles. In general, dynamic imaging analysis showed decreasing accuracy in morphology characterization for 5 μm and 2 μm particles. The test procedure was also capable to compare and evaluate differences between the two dynamic imaging methods. The current study should help to define ranges of operation for dynamic imaging analysis systems.
  • Method to Predict Glass Vial Fogging in Lyophilized Drug Products
    • Abstract: Publication date: Available online 29 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Carolin Langer, Hanns-Christian Mahler, Atanas Koulov, Nicolas Marti, Cristina Grigore, Anja Matter, Pascal Chalus, Satish Singh, Thomas Lemazurier, Susanne Joerg, Roman Mathaes Glass fogging is a phenomenon occurring in lyophilized drug products, and can be described as a thin product layer deposited on the inner surface of the glass container, in the area not covered by the lyo cake itself. It is often considered a cosmetic defect, however the loss of container closure integrity is a potential consequence of the fogging’s expansion to the vial neck region, making this a potential critical defect. Thus, a method for predicting the extent of vial fogging before the actual freeze drying is of particular interest for the pharmaceutical industry. For that reason, we evaluated a simple method (“simulated fogging”) applicable to drug product formulations in a specific container closure system. Two different vial types with different surface hydrophilicity were tested using three model protein formulations, comparing the simulated fogging test and the degree of fogging after actual lyophilization.The simulated fogging method could predict fogging and showed a correlation to fogging in lyophilized drug product glass vials. We observed that all formulations showed fogging in the hydrophilic vials. In contrast, hydrophobic vials prevented fogging, however, interestingly with remaining defects of so-called droplet formation. Other than extent of fogging, no additional differences of lyophilized cake properties or other product quality attributes were observed between products using the different glass vial types tested.
  • Stability of polymer coatings on nebulizer membranes during aerosol
    • Abstract: Publication date: Available online 29 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Moritz Beck-Broichsitter The dimensions of orifices found in aperture plates utilized for nebulization can be modified by thin polymer coatings with the aim to control the size distribution of the generated aerosol droplets. However, the stability of such polymer coatings on the surface of nebulizer membranes during aerosol generation has not been elucidated.Nebulizer membranes made of stainless steel were covered with a thin film of poly(chloro-p-xylylene) (∼1 μm) in the presence or absence of a silane-based adhesion promotor. Thereby, the orifice cross-sections of the nebulizer membrane were reduced by ∼50 %, accompanied by a remarkable decline in droplet size. Upon continuous nebulization of aqueous test liquids, the droplet size generated by the non-conditioned (no silane), poly(chloro-p-xylylene)-coated membranes reverted to that of the uncoated nebulizer membrane within ∼5 min. By contrast, no such rapid return of droplet size to “baseline” values was noticed for the silane-conditioned, poly(chloro-p-xylylene)-coated counterparts. Scanning electron microscopy exhibited significant polymer detachment from the orifices of the non-conditioned (no silane) membranes and, thus, confirmed the findings from laser diffraction.Overall, silane-based adhesion promotors can increase the persistence of poly(chloro-p-xylylene) coatings on nebulizer membranes during aerosol generation.
  • The Role of Particle Surface Area and Adhesion Force in the Sticking
           Behavior of Pharmaceutical Powders
    • Abstract: Publication date: Available online 29 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Maxx Capece The effect of particle surface area and adhesion force on sticking behavior for a model pharmaceutical blend was studied. Various lots of an active pharmaceutical ingredient (API) differing in particle size distribution and surface area were blended with commercial grades of microcrystalline cellulose (MCC) ranging in size from 20-110 μm. A dry-coating technique was also used to modify the surface of MCC to reduce its adhesion force. This allowed study of sticking behavior due to effects associated with particle adhesion force independently from effects associated with surface area. Using a removable-tip experiment to quantify the mass of adhered material to a tablet punch, this study concludes that both particle surface area and adhesion force significantly affect sticking behavior. Tablets with higher tensile strength comprised of API with lower surface area relative to the excipient surface area resulted in less sticking. This study found that the difference between the tablet tensile strength of the blend and that of the API normalized by the surface area fraction of API in the blend correlates well with the rate of mass adhered to the punch. This quantity, referred to as the sticking index, can be used to assess sticking propensity for a pharmaceutical blend.
  • Structure-Function Assessment and High Throughput Quantification of Site
           Specific Aspartate Isomerization in Monoclonal Antibody using a Novel
           Analytical Toolkit
    • Abstract: Publication date: Available online 27 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Kaimeng Zhou, Xiang Cao, James Bautista, Zhi Chen, Neil Hershey, Richard Ludwig, Li Tao, Ming Zeng, Tapan K. Das Isomerization of surface exposed aspartic acid in the complimentary determining region (CDR) of therapeutic proteins could potentially impact their target binding affinity due to the sensitive location, and often requires complex analytical tactics to understand its effect on structure-function and stability. Inaccurate quantitation of Asp-isomerized variants, especially the succinimide intermediate, presents major challenge in understanding Asp degradation kinetics, its stability and consequently establishing a robust control strategy. As a practical solution to this problem, a comprehensive analytical tool kit has been developed, which provides a solution to fully characterize and accurately quantify the Asp-related product variants. The toolkit offers a combination of two steps, an ion-exchange chromatography method to separate and enrich the isomerized variants in the folded structure for structure-function evaluation and a novel focused peptide mapping method to quantify the individual CDR isomerization components including the unmodified Asp, succinimide, and iso-aspartate. This novel procedure allowed an accurate quantification of each Asp-related variant and a comprehensive assessment of the functional impact of Asp isomerization, which ultimately helped to establish an appropriate control strategy for this critical quality attribute.
  • Physicochemical stability of monoclonal antibodies: a review
    • Abstract: Publication date: Available online 26 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Y. Le Basle, P. Chennell, N. Tokhadze, A. Astier, V. Sautou Monoclonal antibodies (mAbs) are subject to instability issues linked to their protein nature. In this work, we review the different mechanisms that can be linked to monoclonal antibodies instability, the parameters and conditions affecting their stability (protein structure and concentration, temperature, interfaces, light exposure, excipients and contaminants, and agitation) and the different analytical methods used for appropriate physicochemical stability studies: physical stability assays (aggregation, fragmentation and primary, secondary and tertiary structure analysis), chemical stability assays and quantitative assays . Lastly, data from different published stability studies of mAbs formulations, either in their reconstituted form, or in diluted ready to administer solutions, was compiled. Overall, the physicochemical stability of mAbs is linked to numerous factors such as formulation, environment and manipulations, and must be thoroughly investigated using several complementary analytical techniques, each of which allowing specific characterization information to be harvested. Several stability studies have been published, some of them showing possibilities of extended stability. However, those data should be questioned due to potential lacks in study methodology.
  • AS1411 aptamer/hyaluronic acid-bifunctionalized microemulsion co-loading
           shikonin and docetaxel for enhanced anti-glioma therapy
    • Abstract: Publication date: Available online 26 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Hong Wang, Zhihan Zhu, Guilong Zhang, Feixiang Lin, Yong Liu, Yu Zhang, Jia Feng, Wanghao Chen, Qiang Meng, Lukui Chen In this study, we developed an AS1411 aptamer/hyaluronic acid-bifunctionalized microemulsion co-loading shikonin and docetaxel (AS1411/SKN&DTX-M). Such microemulsion was capable of penetrating the blood-brain barrier (BBB), targeting CD44/nucleolin-overexpressed glioma, and inhibiting the orthotopic glioma growth. AS1411/SKN&DTX-M showed a spherical morphology with a diameter around 30 nm and rapidly released drugs in the presence of hyaluronidase and mild acid. In the U87 cellular studies, AS1411/SKN&DTX-M elevated the cytotoxicity, enhanced the cellular uptake and induced the cell apoptosis. In the artificial BBB model, the transepithelial electrical resistance was decreased after the treatment with AS1411/SKN&DTX-M and thereby of increasing the apparent permeability coefficient. Furthermore, AS1411/SKN&DTX-M showed a strong inhibition against the formation of cancer stem cell-enriched U87 cell spheroids, in which the expression of CD133 was downregulated significantly. In the biodistribution studies, AS1411/SKN&DTX-M could selectively accumulate in the brains of orthotopic Luc-U87 glioma tumor-bearing nude mice. Importantly, AS1411/SKN&DTX-M exhibited the overwhelming inhibition of glioma growth of orthotopic Luc-U87 glioma models and reached the longest survival period among all the treatments. In summary, the codelivery of shikonin and docetaxel using bi-functionalization with hyaluronic acid and AS1411 aptamer offers a promising strategy for dual drug-based combinational anti-glioma treatment.
  • Erratum to “Skin Permeation Enhancement in Aqueous Solution: Correlation
           with Equilibrium Enhancer Concentration and Octanol/Water Partition
    • Abstract: Publication date: Available online 23 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): S. Kevin Li, Doungdaw Chantasart
  • Profiling Insulin Oligomeric States by 1H NMR Spectroscopy for Formulation
           Development of Ultra-Rapid-Acting Insulin
    • Abstract: Publication date: Available online 23 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Bradley T. Falk, Yingkai Liang, Mark A. McCoy Formulations that can increase the dissociation of insulin oligomers into monomers/dimers are important considerations in the development of ultra-rapid-acting insulins with faster onset and shorter duration of actions. Here we present a novel strategy to characterize the oligomeric states of insulin in solution that leverages the ability of nuclear magnetic resonance (NMR) spectroscopy to assess higher-order structure of proteins in solution. The oligomeric structures and solution behaviors of two fast acting insulins, aspart and lispro with varying excipient concentrations were studied using 1D and diffusion profiling methods. These methods can provide insight on the structural differences and distributions of the molecular association states in different insulin formulations, which is consistent with other orthogonal biophysical characterization tools. Additionally, these methods also highlight their sensitivity to subtle changes in solution behaviors in response to excipient that are difficult to monitor with other tools. This work introduces the utility of 1D and diffusion profiling methods to characterize the oligomeric assembly of fast acting insulins, suggesting promising applications in compound screening, excipient selection and formulation development of fast-acting insulins as well as other peptide or protein therapeutics.
  • Implication of Differential Surface Anisotropy on Biopharmaceutical
           Performance of Polymorphic Forms of Ambrisentan
    • Abstract: Publication date: Available online 23 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Jamshed Haneef, Renu Chadha The aim of the present study was to compare the dissolution rate and in-vivo biopharmaceutical performance of two polymorphic forms (form I & II) of ambrisentan (AMT) and correlate with their surface molecular environment. Dominance of various functionalities on the surface of specific crystal facets of both forms was predicted by Bravais–Friedel Donnay–Harker (BFDH) method. Hirshfeld surface analysis maps and 2D fingerprint plots indicate a difference in shape index, curvedness and relative percent contribution of various contacts in both forms. Pre and post intrinsic dissolution compact studied by atomic force microscopy (AFM) showed a significant difference in surface roughness and defects formation in form II as compared to form I which is attributed to the presence of more hydrophilic surfaces. The hydrophilic molecular surface environment of form II is ascribed to its improved intrinsic dissolution rate (IDR) than form I. Further, in-vivo pharmacokinetic study also showed significantly higher AUC0-24 and Cmax in form II compared to form I. Overall, this study demonstrates that form I & II of AMT exhibited the differential surface anisotropy which has significant implications on their biopharmaceutical performance.
  • Binding Characterization of Aptamer-Drug Layered Microformulations and
           In Vitro Release Assessment
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Kei Xian Tan, Michael K. Danquah, Sharadwata Pan, Lau Sie Yon Efficient delivery of adequate active ingredients to targeted malignant cells is critical, attributing to recurrent biophysical and biochemical challenges associated with conventional pharmaceutical delivery systems. These challenges include drug leakage, low targeting capability, high systemic cytotoxicity, and poor pharmacokinetics and pharmacodynamics. Targeted delivery system is a promising development to deliver sufficient amounts of drug molecules to target cells in a controlled release pattern mode. Aptameric ligands possess unique affinity targeting capabilities which can be exploited in the design of high pay-load drug formulations to navigate active molecules to the malignant sites. This study focuses on the development of a copolymeric and multifunctional drug-loaded aptamer-conjugated poly(lactide-co-glycolic acid)–polyethylenimine (PLGA-PEI) (DPAP) delivery system, via a layer-by-layer synthesis method, using a water-in-oil-in-water double emulsion approach. The binding characteristics, targeting capability, biophysical properties, encapsulation efficiency, and drug release profile of the DPAP system were investigated under varying conditions of ionic strength, polymer composition and molecular weight (MW), and degree of PEGylation of the synthetic core. Experimental results showed increased drug release rate with increasing buffer ionic strength. DPAP particulate system obtained the highest drug release of 50% at day 9 at 1 M NaCl ionic strength. DPAP formulation, using PLGA 65:35 and PEI MW of ∼800 Da, demonstrated an encapsulation efficiency of 78.93%, and a loading capacity of 0.1605 mg bovine serum albumin per mg PLGA. DPAP (PLGA 65:35, PEI MW∼25 kDa) formulation showed a high release rate with a biphasic release profile. Experimental data depicted a lower targeting power and reduced drug release rate for the PEGylated DPAP formulations. The outcomes from the present study lay the foundation to optimize the performance of DPAP system as an effective synthetic drug carrier for targeted delivery.
  • Characterization of a Stable 2,2′-Azobis(2-Methylpropanenitrile)
           Degradant and Its Use to Monitor the Oxidative Environment During Forced
           Degradation Studies by Liquid Chromatography/Mass Spectrometry
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Kevin J. Wells-Knecht, Derek Dunn Azo compounds are commonly used to study radical-mediated degradation of pharmaceutical compounds. The favorable chemical and physical properties of 2,2′-azobis(2-methylpropanenitrile) (AIBN) have made it one of the most widely used compound for these type of studies. This article describes the characterization of a stable product, N-(1-cyano-1-methylethyl)-2-methylpropanamide, formed during the decomposition of AIBN. This product is easily detected by liquid chromatography/mass spectrometry and can serve as a marker to confirm the AIBN is working as intended and to monitor the kinetic formation of free radical species.
  • Bile Duct Obstruction Leads to Increased Intestinal Expression of Breast
           Cancer Resistance Protein With Reduced Gastrointestinal Absorption of
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Takumi Kawanishi, Hiroshi Arakawa, Yusuke Masuo, Noritaka Nakamichi, Yukio Kato Liver dysfunction reduces systemic clearance of drugs that are primarily eliminated by the liver. However, liver dysfunction can cause a reduction in the plasma concentration profiles of certain drugs, including several tyrosine kinase inhibitors, after oral administration. The aim of the present study was to clarify the reduction in oral absorption of a tyrosine kinase inhibitor, imatinib, and the mechanisms of action involved under conditions of hepatic dysfunction, focusing on intestinal transporters. The maximum plasma concentration of imatinib after oral administration in mice subjected to bile duct ligation (BDL) was lower than that in sham-operated mice, whereas the plasma concentration profile after intravenous administration was essentially unaffected by BDL. The change in maximum plasma concentration was compatible with a reduction in small intestinal permeability of imatinib observed in the in situ closed loop. Gene expression of abcg2 was increased in BDL mice compared with that in sham-operated mice. Expression of breast cancer resistance protein and P-glycoprotein in the small intestinal brush border membrane fraction from BDL mice was also increased compared with that in sham-operated mice. In summary, the intestinal absorption and permeability of imatinib was decreased in BDL mice, and this may be attributed to the up-regulation of the efflux transporter(s).
  • Development of an In Vivo Retrodialysis Calibration Method Using Stable
           Isotope Labeling to Monitor Metabolic Pathways in the Tumor
           Microenvironment via Microdialysis
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Derek W. Bartlett, Aidong Wu, Xiaorong Li, Manfred Kraus, Hui Wang, Erick Kindt Microdialysis is a technique that utilizes a semipermeable membrane to sample analytes present within tissue interstitial fluid. Analyte-specific calibration is required for quantitative microdialysis, but these calibration methods are tedious, require significant technical skill, and often cannot be performed jointly with the experimental measurements. Here, we describe a method using retrodialysis with stable-isotope-labeled analytes that enables simultaneous calibration and quantification for in vivo tumor microdialysis. Isotope-labeled amino acids relevant to immuno-metabolism in the tumor microenvironment (tryptophan, kynurenine, glutamine, and glutamate) were added to the microdialysis perfusate, and microdialysis probes were inserted in subcutaneous CT26 and MC38 tumors in mice. The levels of both the endogenous and isotope-labeled amino acids in the perfusate outlet were quantified using LC-MS/MS. Plasma and tumor tissue samples were also collected from the same mice and amino acid levels quantified using LC-MS/MS. Amino acids which showed statistically significant differences between the CT26-bearing and MC38-bearing mice in tumor lysate (tryptophan, kynurenine, and glutamine) and plasma (glutamate) were not the same as those identified as significantly different in tumor interstitial fluid (kynurenine and glutamate), underscoring how microdialysis can provide unique and complementary insights into tumor and immune metabolism within the tumor microenvironment.
  • No Inhibition of MATE1/2K-Mediated Renal Creatinine Secretion Predicted
           With Ritonavir or Cobicistat
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Ryota Kikuchi, William J. Chiou, Miriam A. Kasai, Sonia M. de Morais, Daniel A.J. Bow Cobicistat has been reported to increase serum creatinine clinically without affecting glomerular filtration. This was ascribed to transient inhibition of MATE1-mediated renal creatinine secretion. Interestingly, a structurally similar drug, ritonavir, has not been associated with serum creatinine increases at the pharmacoenhancer dose. The present study was aimed to investigate the translation of in vitro MATE1/2K inhibition to clinical creatinine increase (cobicistat) and lack of it (ritonavir) considering their intracellular concentrations in renal proximal tubules. Uptake studies showed ritonavir and cobicistat are unlikely substrates for OCT2. The steady-state unbound concentration in the cytosol of human renal proximal tubule epithelial cells was comparable with the extracellular unbound concentration, suggesting that the entry of these compounds is predominantly mediated by passive diffusion. Ritonavir and cobicistat are MATE1 and MATE2K inhibitors with IC50 values of 3.1 and 90 μM (ritonavir), and 4.4 and 3.2 μM (cobicistat), respectively. However, the unbound cytosolic concentrations (Cu,cytosol) of ritonavir and cobicistat in human renal proximal tubule epithelial cells, 0.065 and 0.10 μM, respectively, after incubation with the clinical maximum total plasma concentrations at pharmacoenhancer doses does not support inhibition in vivo; Cu,cytosol>30 fold lower than IC50s. These results demonstrate that MATE1/2K inhibition is unlikely the mechanism of the clinical creatinine elevations with cobicistat.
  • Population Pharmacokinetics of Baloxavir Marboxil in Japanese Pediatric
           Influenza Patients
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Hiroki Koshimichi, Toru Ishibashi, Toshihiro Wajima Baloxavir marboxil is a prodrug of baloxavir acid, an inhibitor of cap-dependent endonuclease, and suppresses the replication of influenza virus. The aim of this study was to investigate its pharmacokinetic characteristics in Japanese pediatrics. Population pharmacokinetic analysis was conducted for baloxavir acid with 328 plasma concentration data points in a clinical study of 107 Japanese pediatric influenza patients. The plasma baloxavir acid concentration profiles were well captured by a 2-compartment model including first-order absorption and lag time. Body weight was considered to be the most crucial covariate, which affects clearance and volume of distribution. The body weight–based dose regimen (10 mg for 10 kg to less than 20 kg pediatrics, 20 mg for 20 kg to less than 40 kg pediatrics, and 40 mg for at least 40 kg pediatrics) for Japanese pediatrics can provide comparable exposure to baloxavir acid to that for adults. In conclusion, the population pharmacokinetic model would be useful to comprehend the characteristics of baloxavir acid pharmacokinetics in pediatric patients.
  • Rifampin Induces Expression of P-glycoprotein on the THP1 Cell–Derived
           Macrophages, Causing Decrease Intramacrophage Concentration of
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Md. Hasanuzzaman, Myeongjin Yi, Munju Cho, Md Masud Parvez, Su-Jun Lee, Jae-Gook Shin Rifampin (RIF) has been widely used for the treatment of bacterial infections, including tuberculosis (TB). Treatment of drug-resistant TB is a global problem because of reduced drug efficacy. The present study determined the effect of RIF on MDR1 gene (P-glycoprotein, P-gp) expression in THP1 macrophages and analyzed the intracellular concentration of the anti-TB drug prothionamide in the presence of RIF. RIF treatment significantly induced MDR1 protein and mRNA levels in phorbol 12-myristate 13-acetate–stimulated THP1 macrophages (p < 0.001 and 0.01, respectively). The pregnane X receptor inhibitors resveratrol and ketoconazole significantly suppressed RIF-induced P-gp expression in THP1 macrophages (p < 0.05). RIF-treated THP1 macrophages also exhibited strong efflux of P-gp substrate, resulting in a reduced intracellular concentration of rhodamine-123 and prothionamide (p < 0.01 and 0.05, respectively). By contrast, the P-gp inhibitor cyclosporine A significantly increased intracellular concentration of rhodamine-123 and prothionamide (p < 0.001 and 0.05, respectively). The present results suggest that the usage of RIF together with P-gp–substrate drugs to treat TB may lead to deteriorated treatment efficacy because of the lower intracellular drug concentration. Further studies would be necessary to know the influence of RIF-induced P-gp induction on the treatment outcome of patients with TB.
  • Population Pharmacokinetics of Doripenem in Pediatric Patients and
           Monte-Carlo Pharmacokinetic-Pharmacodynamic Simulations for Dosing Regimen
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Yumiko Matsuo, Toru Ishibashi, Sayaka Matsumoto, Takayuki Katsube, Toshihiro Wajima The aims of this study were to evaluate the pharmacokinetics of doripenem (Finibax®, Doribax®, S-4661), a parenteral carbapenem antibiotic, in pediatric patients based on concentrations of doripenem in plasma after administration of 20 mg/kg 2 or 3 times daily and to evaluate the dosing regimens by using Monte-Carlo pharmacokinetic-pharmacodynamic simulations. Population pharmacokinetic analysis was performed by using 190 plasma concentrations of doripenem from 99 patients (2 months-13 years old). The two-compartment model well described the doripenem plasma concentrations in pediatric patients. Body weight was found to be the most significant influential factor. Gender was also found to be a significant covariate although the effect was relatively small. Monte-Carlo simulations indicated that 20 mg/kg over 1 h infusion would give 90% probability of target attainment for 40% of time above minimum inhibitory concentration against Haemophilus influenzae and Streptococcus pneumoniae, major causative pathogens in pediatric infections, and that 40 mg/kg, the highest approved dose for Japanese pediatric patients, administered over 3 h infusion achieved 98.6% against 8 μg/mL. The developed population pharmacokinetic model of doripenem and Monte-Carlo simulations for pediatric patients should provide useful information for understanding the pharmacokinetic and pharmacokinetic-pharmacodynamic characteristics of doripenem and for optimal treatment of pediatric patients.
  • Enhancing Tumor Drug Distribution With Ultrasound-Triggered Nanobubbles
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Pinunta Nittayacharn, Hai-Xia Yuan, Christopher Hernandez, Peter Bielecki, Haoyan Zhou, Agata A. Exner Issues with limited intratumoral drug penetration and heterogeneous drug distribution continue to impede the therapeutic efficacy of nanomedicine-based delivery systems. Ultrasound (US)-enhanced drug delivery has emerged as one effective means of overcoming these challenges. Acoustic cavitation in the presence of nanoparticles has shown to increase the cellular uptake and distribution of chemotherapeutic agents in vivo. In this study, we investigated the potential of a drug-loaded echogenic nanoscale bubbles in combination with low frequency (3 MHz), high energy (2 W/cm2) US for antitumor therapy. The doxorubicin-loaded nanobubbles (Dox-NBs) stabilized with an interpenetrating polymer mesh were 171.5 ± 20.9 nm in diameter. When used in combination with therapeutic US, Dox-NBs combined with free drug showed significantly higher (*p < 0.05) intracellular uptake and therapeutic efficacy compared with free drug. When injected intravenously in vivo, Dox-NBs + therapeutic US showed significantly higher (*p < 0.05) accumulation and better distribution of Dox in tumors when compared with free drug. This strategy provides an effective and simple method to increase the local dose and distribution of otherwise systemically toxic chemotherapeutic agents for cancer therapies.
  • Optimization of Nanostructured Lipid Carriers of Lurasidone Hydrochloride
           Using Box-Behnken Design for Brain Targeting: In Vitro and In Vivo
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Imrana Jazuli, Annu, Bushra Nabi, Thasleem moolakkadath, Tausif Alam, Sanjula Baboota, Javed Ali Intranasal nanostructured lipid carrier (NLC) of lurasidone hydrochloride (LRD) for brain delivery was prepared by the solvent evaporation method. The effects of independent variables, X1-lipid concentration, X-2 surfactant, and X-3 sonication times on dependent variables, Y1-particle size, Y-2 polydispersity index, and Y-3% entrapment efficiency were determined using Box-Behnken design. Optimized LRD-NLC was selected from the Box-Behnken design and evaluated for their morphological, physiological, nasal diffusion, and in vivo distribution in the brain after intranasal administration. Particle size, polydispersity index, and entrapment efficiency of optimized LRD-NLC were found to be 207.4 ± 1.5 nm, 0.392 ± 0.15, and 92.12 ± 1.0%, respectively. Transmission electron microscopy and scanning electron microscopy was used to determine the particle size and surface morphology of LRD-NLC. The prepared LRD-NLC follows biphasic in vitro drug release. Prepared NLC showed a 2-fold increase in LRD concentration in the brain when compared with the drug solution following intranasal administration. Results showed that intranasal route can be a good and efficient approach for delivering the drug directly to the brain and enhancing the drug efficacy in the brain for the management of schizophrenia and a good alternative to oral drug delivery.
  • Design and Synthesis of Galactose-Biotin Lipid Materials for Liposomes to
           Promote the Hepatoma Cell–Targeting Effect
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Ruihua Ding, Zhenjie Li, Jianyi Wang, Xueyan Zhu, Zhuang Zhao, Mian Wang A series of novel low-toxic hepatoma cell–targeting lipid materials were designed and synthesized, in which monogalactose, digalactose, and galactose-biotin were used as targeting moieties and hydrophilic heads while stearate was used as hydrophobic tail (Mono-Gal-ST, Di-Gal-ST, and Gal-Biotin-ST). The corresponding galactose-biotin-modified liposomes (Mono-Gal-LPs, Di-Gal-LPs, and Gal-Biotin-LPs) and conventional liposomes (LPs) were prepared. These galactose-biotin-modified liposomes can distinguish hepatoma cells from other tissue cells owing to the recognition of asialoglycoprotein receptor by galactose group. Moreover, the ability of liposomes to distinguish hepatoma cells from normal hepatocytes follows a trend of LPs < Mono-Gal-LPs < Di-Gal-LPs < Gal-Biotin-LPs, which is attributed to the cluster glycoside effect and the synergistic effect of galactose and biotin. In addition, the endocytosis of these galactose-biotin-modified liposomes were competitively inhibited by galactose, further confirming these liposomes entered hepatoma cells via asialoglycoprotein receptor–mediated pathway.
  • Effects of Surfactants on Itraconazole-Hydroxypropyl Methylcellulose
           Acetate Succinate Solid Dispersion Prepared by Hot Melt Extrusion. II:
           Rheological Analysis and Extrudability Testing
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Nayan G. Solanki, Suhas G. Gumaste, Ankita V. Shah, Abu T.M. Serajuddin Although hydroxypropyl methylcellulose acetate succinate (HPMCAS) has been widely used as a carrier for amorphous solid dispersion of poorly water-soluble drugs, its application has mostly been limited to spray drying, and the solvent-free method of hot melt extrusion has rarely been used. This is on account of the high temperature (≥170°C) required for extrusion where the polymer and even a drug may degrade. In part 1 of this series of papers, we demonstrated that HPMCAS is miscible with surfactants such as, poloxamer 188, poloxamer 407 and d-alpha tocopheryl polyethylene glycol 1000 succinate, which may also serve as plasticizers (Solanki et al., J Pharm Sci. 2019; 108 (4):1453-1465). The present investigation was undertaken to determine plasticization effects of the surfactants and a model drug, itraconazole, in reducing melt extrusion temperatures of HPMCAS. The determination of complex viscosity as functions of temperature and also as functions of angular frequency at certain fixed temperatures showed that the surfactants and the drug greatly reduce viscosity of HPMCAS by their plasticization effects. Surfactants and drug also had synergistic effects in reducing viscosity. The torque analysis during melt extrusion demonstrated that these additives greatly enhanced extrudability of HPMCAS. Surfactant-drug-polymer mixtures were successfully extruded as stable amorphous solid dispersions at 130°C, which is much lower than the minimum extrusion temperature of 170°C for neat HPMCAS.
  • Possibilities and Limiting Factors for the Use of Dissolution as
           a Quality Control Tool to Detect Presence of Crystallinity for Amorphous
           Solid Dispersions: An Experimental and Modeling Investigation
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Andre Hermans, Filippos Kesisoglou, Wei Xu, Kristel Dewitt, Melanie Marota, Thomas Colace In this article, experiments on tablets containing a model compound, grazoprevir, were conducted to explore how media selection for a quality control dissolution method can influence the sensitivity for the dissolution method toward drug crystallinity detection in an amorphous solid dispersion formulation. The experiment shows that under ideal nonsink conditions with respect to crystalline solubility, dissolution can indeed be predictive of crystallinity in the formulation. However, the limit of detection for crystallinity with quality control dissolution can change based on inherent variabilities in the drug product. In addition, it is demonstrated that the method's sensitivity and accuracy might be reduced if the crystalline particles are sufficiently small with respect to the solid dispersion particles. To further demonstrate the limits of the dissolution method, a dissolution model was also explored to simulate and predict the sensitivity of the dissolution response toward crystallinity based on solubility in the media and particle size of the crystals.
  • Synthesis and Evaluation of Boronated Chitosan as a Mucoadhesive Polymer
           for Intravesical Drug Delivery
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Oluwadamilola M. Kolawole, Wing Man Lau, Vitaliy V. Khutoryanskiy This work reports the synthesis of boronated chitosan by reacting it with 4-carboxyphenylboronic acid to improve its mucoadhesive properties. Three products with differing extent of boronate conjugation were synthesized and characterized using 1H NMR, FT-IR, and UV-Vis spectroscopy, and the potential of these polymers to extend the residence time of loaded model drug in the bladder was investigated. 1H NMR and ninhydrin test were used to evaluate the extent of chitosan modification. Mucoadhesive properties were evaluated using ex vivo flow-through technique on porcine bladder mucosal tissue combined with fluorescent microscopy, where fluorescein sodium was used as a model drug. The mucoadhesive properties of these polymers on porcine bladder mucosa were also studied using tensile test. There was good correlation in the mucoadhesive profiles of the polymers using the flow through and tensile techniques. The degree of chitosan modification had a remarkable influence on their mucoadhesive behavior, and greater mucoadhesion was observed with increased degree of boronation. These chitosan derivatives have the potential as intravesical drug delivery systems to improve bladder therapy.
  • Development of Octreotide-Loaded Chitosan and Heparin Nanoparticles:
           Evaluation of Surface Modification Effect on Physicochemical Properties
           and Macrophage Uptake
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Mahdieh Ghofrani, Leila Rezaie Shirmard, Pouya Dehghankelishadi, Mohsen Amini, Farid A. Dorkoosh Octreotide (OCT) is a therapeutic peptide which is administered for the treatment of acromegaly. The purpose of this study was to design a new polyethylene glycol (PEG)–conjugated nanoparticle (PEG-NP) to overcome the short half-life and poor stability of OCT. The developed PEG-NPs were compared with non-PEGylated NPs with respect to their size, morphological characteristics, loading efficiency, release profile, and macrophage uptake. The OCT-loaded NPs and PEG-NPs were prepared by ionic complexion of chitosan (Cs) with either heparin (Hp) or PEGylated heparin (PEG-Hp). The chemical structure of PEG-Hp was confirmed by IR and proton nuclear magnetic resonance. Morphological analyses by scanning electron microscopy showed that NPs and PEG-NPs have a uniform shape. Dynamic laser scattering measurements indicated that hydrodynamic diameter of NPs and PEG-NPs were 222.5 ± 10.0 nm and 334.9 ± 6.7 nm, respectively. NPs and PEG-NPs had a positive zeta potential of about 32.5 ± 1.1 mv and 20.6 ± 2.4 mv, respectively. Entrapment efficiency was 61.4 ± 1.0% and 55.7 ± 2.4% for NPs and PEG-NPs, respectively. Compared with the NPs, the PEG-NPs exhibited a slower release profile. Subsequently, fluorescein isothiocyanate–labeled chitosanCs was synthesized and used to evaluate the stealth characteristic of PEG-NPs. In vitro macrophage uptake of fluorescently labeled NPs was measured by flow cytometry.
  • Higher-Order Structure Characterization of Pharmaceutical Proteins by 2D
           Nuclear Magnetic Resonance Methyl Fingerprinting
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Gitte W. Haxholm, Bent O. Petersen, Joan Malmstrøm A key challenge in the analytical assessment of therapeutic proteins is the comprehensive characterization of their higher-order structure (HOS). To directly assess HOS, a new type of assay is warranted. The most sensitive and detailed method for characterizing HOS is unquestionably nuclear magnetic resonance (NMR) spectroscopy. NMR spectroscopy provides direct information about the HOS at an atomic level, and with modern NMR spectrometers and improved pulse sequences, this has become feasible even on unlabeled proteins. Hence, NMR spectroscopy could be a very powerful tool for control of HOS following, for example, process changes resulting in structural changes, oxidation, degradation, or chemical modifications. We present a method for characterizing the HOS of therapeutic proteins by monitoring their methyl groups using 2D H, C-correlated NMR. We use a statistical model that compares the NMR spectrum of a given sample to a reference and results in one output value describing how similar the HOS of the samples are. This makes the overall result easy to interpret even for non-NMR experts. We show that the method is applicable to proteins of varying size and complexity (here up to ∼30 kDa) and that it is sufficiently sensitive for the detection of small changes in both primary and HOS.
  • Improving the Solubility, Dissolution, and Bioavailability of Ibrutinib by
           Preparing It in a Coamorphous State With Saccharin
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Xiangjun Shi, Shengjie Song, Zejie Ding, Baibai Fan, Wan Huang, Tiantian Xu At present, coamorphous systems have attracted increasing interest in the pharmaceutical field owing to their enhanced stabilities, increased solubilities, and improved bioavailabilities compared with those of their pure amorphous and crystalline counterparts. In this study, a novel coamorphous solid form of ibrutinib (IBT) and saccharin (SAC) (1:1 molar ratio) was prepared through rotary vacuum evaporation and then characterized. Differential scanning calorimetry and X-ray powder diffraction indicated the formation of the coamorphous IBT-SAC after rotary vacuum evaporation. Compared with amorphous IBT, coamorphous IBT-SAC exhibited enhanced stability owing to the intermolecular interaction between IBT and SAC. Moreover, the solubility and dissolution of the coamorphous IBT-SAC were increased up to 4.0-7.7 times and 4.3 times, respectively, compared with those of its crystalline Form A. In addition to the superior behaviors of coamorphous IBT-SAC in vitro, the in vivo bioavailability study revealed notable increases in the Cmax and area under the curve0-t of the coamorphous form compared with those of its crystalline Form A. The current study demonstrates that the coamorphization of IBT and SAC presents a promising technology to overcome the limitations of solubility and stability that arise from IBT and can therefore contribute to a major improvement in the bioavailability of IBT.
  • Effects of Particle Surface Roughness on In-Die Flow and Tableting
           Behavior of Lactose
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Justin Yong Soon Tay, Berlinda Wen Ting Kok, Celine Valeria Liew, Paul Wan Sia Heng Particle rearrangement takes place during the initial phase of tablet compaction. In this study, rough lactose particles were prepared by roller compaction, and their surface roughness modified by partial surface dissolution using a fluidized bed processor. Flow characteristics of the particles were determined using various flow methods, and their compaction characteristics studied using a compaction simulator with punches of different geometry and compaction pressure. Rougher particles demonstrated poorer compressibility and powder flow due to the higher interparticulate frictional forces required for particle movement. Rearrangement energy during tablet compaction was found to be correlated with compressibility (R2 = 0.92) and increased with surface roughness of the particles. Particle rearrangement was found to be dependent on interparticulate frictional forces, which could be measured using FT4 powder rheometer variable flow rate test and compressibility test. Plastic energy decreased as a result of the increased rearrangement energy requirements. Decrease in tensile strength as a result of decrease in plastic energy was not significantly different. Roller-compacted lactose particles produced tablets of higher tensile strength than crystalline lactose because of prefragmentation of the crystalline structure during roller compaction.
  • Determination of Solute Diffusion Properties in Artificial Sebum
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Senpei Yang, Lingyi Li, Minsheng Lu, Tao Chen, Lujia Han, Guoping Lian Despite a number of studies showed that hair follicular pathway contributed significantly to transdermal delivery, there have been limited studies on the diffusion properties of chemicals in sebum. Here, the diffusion property of 17 chemical compounds across artificial sebum has been measured using diffusion cell. The diffusion flux showed 2 types of distinctive behaviors: that reached steady state and that did not. Mathematical models have been developed to fit the experimental data and derive the sebum diffusion and partition coefficients. The models considered the uneven thickness of the sebum film and the additional resistance of the unstirred aqueous boundary layer and the supporting filter. The derived sebum-water partition coefficients agreed well with the experimental data measured previously using equilibrium depletion method. The obtained diffusion coefficients in artificial sebum only depended on the molecular size. Change in pH for ionic chemicals did not affect the diffusion coefficients but influenced their diffusion flux because of the change of sebum-water partition coefficients. Generally, the measured diffusion coefficients of chemicals in artificial sebum are about one order of magnitude higher than those in the stratum corneum lipids, suggesting the hair follicle might have a non-negligible contribution to the overall permeation.
  • Gastrointestinal Responsive Polymeric Nanoparticles for Oral Delivery of
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Yan Fang, Qi Wang, Xiaojie Lin, Xuechao Jin, Dongjuan Yang, Shan Gao, Xiyan Wang, Mingshi Yang, Kai Shi Gastrointestinal responsive polymeric nanospheres (NPs) based on hydroxypropyl methylcellulose phthalate were prepared using spontaneous emulsification solvent diffusion method for improved oral administration of insulin. The NPs prepared under optimized conditions have an encapsulation efficiency of 90% and a particle size of about 200 nm. In vitro drug release experiments demonstrated that the NPs exhibited a gradient release profile of loaded drug when the pH value gradually increased from 3.0 to 7.4. Enzyme resistance experiments showed that under simulated gastrointestinal conditions, the NPs protected more than 60% of the drug from being degraded by trypsin. The oral hypoglycemic experiments revealed that insulin-loaded NPs could significantly reduce blood glucose levels in diabetic rats with a relative bioavailability of 8.6%. Ex vivo imaging investigation of rat tissues showed that the drug-loaded NPs could promote the absorption of insulin in the ileum and colon. The work described here suggests that the gastrointestinal responsive polymeric NPs may be promising candidates for improving gastrointestinal tract delivery of hydrophilic biomacromolecules. Accordingly, the results indicated that hydroxypropyl methylcellulose phthalate NPs with gastrointestinal stimuli responsiveness could be a promising candidate for oral insulin delivery.
  • Simultaneously Improving the Physicochemical Properties, Dissolution
           Performance, and Bioavailability of Apigenin and Daidzein by
           Co-Crystallization With Theophylline
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Shan Huang, Qian Xue, Jia Xu, Sida Ruan, Ting Cai Co-crystals have received increasing attention during the past decades for their ability to modify the solubility and other physicochemical properties of active pharmaceutical ingredients. Apigenin (Agn) and Daidzein (Dai) are flavonoid compounds with a variety of biological effects. However, the bioavailability and clinical applications of flavonoid compounds are usually limited by their poor aqueous solubilities. In this study, theophylline (Thp) is used as a coformer to co-crystallize with Agn and Dai. The solid-state properties of the co-crystals of Thp with Agn and Dai are characterized by powder X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, Raman spectroscopy, and nuclear magnetic resonance experiments. In addition, both co-crystals show a greater resistance to hydration than Thp alone. The solubilities, intrinsic dissolution rates, and permeabilities of Agn-Thp co-crystal and Dai-Thp co-crystal are improved compared with those of parent flavonoids. The pharmacokinetic study shows that the bioavailabilities of both co-crystals are enhanced in comparison with the corresponding physical mixtures and parent flavonoids. This study demonstrates that the co-crystallization by using theophylline is a promising strategy to improve physicochemical properties and bioavailability of flavonoid compounds.
  • Freeze-Dryer Equipment Capability Limit: Comparison of Computational
           Modeling With Experiments at Laboratory Scale
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Gayathri Shivkumar, Vaibhav Kshirsagar, Tong Zhu, Israel B. Sebastiao, Steven L. Nail, Gregory A. Sacha, Alina A. Alexeenko The equipment capability curve is one of the bounding elements of the freeze-drying design space, and understanding it is critical to process design, transfer, and scale-up. The second bounding element of the design space is the product temperature limit beyond which the product collapses. The high cost associated with freeze-drying any product renders it crucial to operate using the most efficient cycle within the limits of the equipment and the product. In this work, we present a computational model to generate the equipment capability curve for 2 laboratory scale freeze-dryers and compare the results to experimentally generated equipment capability curves. The average deviations of the modeling results from the experiments for the 2 lyophilizers modeled are −4.8% and −7.2%. In addition, we investigate the effect of various numerical and geometric parameters on the simulated equipment capability. Among the numerical parameters, the chamber wall thermal boundary conditions exert the largest influence with a maximum value of 12.3%. Among the geometric parameters, the inclusion of the isolation valve reduces the equipment capability by 23.7%. Larger isolation valves, required for controlled nucleation technology, choke the flow in the duct at lower sublimation rates, thereby lowering the equipment capability limit.
  • Co-Spray-Dried Urea Cross-Linked Hyaluronic Acid and Sodium Ascorbyl
           Phosphate as Novel Inhalable Dry Powder Formulation
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Arianna Fallacara, Laura Busato, Michele Pozzoli, Maliheh Ghadiri, Hui Xin Ong, Paul M. Young, Stefano Manfredini, Daniela Traini The pathogenesis and progression of several lung disorders is propagated by inflammatory and oxidative processes, which can be controlled by adjunctive inhaled therapies. The present study aimed to develop an inhalable dry powder formulation consisting of co-spray-dried urea-crosslinked hyaluronic acid and sodium ascorbyl phosphate (SD HA-CL–SAP), a novel combination which was recently shown to possess anti-inflammatory, antioxidant, and wound healing properties. Native HA and SAP were co-spray dried (SD HA–SAP) and evaluated as control formulation. Yield (Y%) and encapsulation efficiency (EE%) were 67.0 ± 4.8% and 75.5 ± 7.2% for SD HA–SAP, 70.0 ± 1.5% and 66.5 ± 5.7% for SD HA-CL–SAP, respectively. Both formulations were shown to be suitable for lung delivery in terms of morphology, particle size (median volumetric diameter ∼ 3.4 μm), physical and thermal stability, in vitro aerosol performance - respirable fraction: 30.5 ± 0.7% for SD HA–SAP and 35.3 ± 0.3% for SD HA-CL–SAP. SAP release was investigated using Franz cells and air-interface Calu-3 cell model (>90% of SAP transported within 4 h). The innovative SD HA-CL–SAP formulation holds potential as inhalable dry powder for the treatment of inflammatory lung disorders.
  • Investigation of Electrostatic Behavior of Dry Powder-Inhaled Model
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Martin W. Jetzer, Bradley D. Morrical The accumulation of electrostatic charge on drug particles and excipient powders arising from interparticulate collisions or contacts with other surfaces can lead to agglomeration and adhesion problems during the manufacturing process, filling, and delivery of dry powder inhaler (DPI) formulations. The objective of the study was to investigate the role of triboelectrification to better understand the influence of electrostatic charge on the performance of DPIs with 2 capsule-based dimensionally similar devices constructed with different materials. In addition, strategies to reduce electrostatic charge build up during the manufacturing process, and the processes involved in this phenomenon were investigated. Electrostatic charge measurements showed that there was a significant difference in electrostatic charge generated between tested formulations and devices. This affects particle detachment from carrier and thus significantly impacts aerosol performance. Conditioning fluticasone DPI capsules at defined temperature and humidity conditions reduced electrostatic charges acquired during manufacturing. Conditioning salmeterol DPI capsules at same conditions seemed disadvantageous for their aerosol performance because of increasing capillary forces and solid bridge formation caused by water absorption. Knowledge and understanding of the role of electrostatic forces in influencing DPI formulation performance was increased by these studies.
  • Pharmacokinetics and Tissue Distribution of Pilocarpine After Application
           to Eyelid Skin of Rats
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Gerard Lee See, Ayano Sagesaka, Hiroaki Todo, Konstanty Wierzba, Kenji Sugibayashi Extending the delivery of drugs into the eyes while reducing systemic bioavailability is of utmost importance in the management of chronic ocular diseases. Topical application onto the lower eyelid skin, as an alternative to eye drops, is seen to be a valuable strategy in the treatment of chronic eye diseases. To elucidate the critical value of delivering drugs in solution onto the eyeball through the eyelid skin, pharmacokinetic studies of pilocarpine were conducted, and the results were verified using a direct pharmacodynamic study in rats. The mean residence time of pilocarpine after topical eyelid application to the eyelid skin, conjunctiva, eyeball, and plasma were 14.9, 8.50, 6.29, and 8.11 h, respectively. Conjunctiva and eyeball concentrations of pilocarpine at 8 h were 80-fold and 8-fold higher after topical eyelid application, respectively, than those for eye drops. Pupillary constriction was sustained over 8 h after topical eyelid application. Topical eyelid skin application exhibited a localized drug absorption and specific drug accumulation in the ocular tissues. Hence, it is rational to prepare topical formulations directed onto the eyelid skin, which is suitable for drugs required for long-term treatment.
  • Quantifying the Value of Orally Delivered Biologic Therapies:
           A Cost-Effectiveness Analysis of Oral Semaglutide
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Alex Abramson, Florencia Halperin, Jane Kim, Giovanni Traverso Oral semaglutide, which has undergone multiple phase 3 clinical trials, represents the first oral biologic medication for type 2 diabetes in the form of a daily capsule. It provides similar efficacy compared with its weekly injection counterpart, but it demands a dose on the order of 100 times as high and requires more frequent administration. We perform a cost effectiveness analysis using a first and second order Monte Carlo simulation to estimate quality-adjusted life expectancies associated with an oral daily capsule, oral weekly capsule, daily injection, and weekly injection of semaglutide. We conclude that the additional costs incurred to produce extra semaglutide for the oral formulation are cost effective, given the greater quality of life experienced when taking a capsule over a weekly injection. We also demonstrate that the potency of semaglutide allows the formulation to be cost effective, and less potent drugs will require increased oral bioavailability to make a cost effective oral formulation.
  • Coating With Chitooligosaccharides Enhances the Cytokine Induction of
           Listeria ivanovii–Based Vaccine Strain
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Xiang Zhang, Lin Su, Huan Huang, Mingjuan Jiang, Sijing Liu, Yongyu Li, Ting Liu, Yuzhen Zhou, Tian Tang, Safy Eidin Mahdy, Chuan Wang Listeria ivanovi (LI) is an available live bacterial vaccine vector. This work attempted to coat LI-based vaccine candidates (LI-Rv0129c) with chitooligosaccharides (COSs) as an adjuvant to enhance the cellular immune responses induced. COS-bacteria composite was achieved by mixing the bacteria suspension with equal volume of COS solution, and this process accompanied with the increase of bacteria superficial zeta potential and formation of special superficial configurations. COS coating improved the ratio swallowed by the macrophage-like RAW264.7 cells from 0.54% to 2.88% (p < 0.001). In vivo, the COS-coated LI-Rv0129c strain did elicit significantly higher specific CD4+ IFN-γ, CD4+ TNF-α or CD8+ IFN-γ secretion (0.91%, 1.00%, 0.30%, respectively) than naked LI-Rv0129c (0.32%, 0.38%, 0.07%, respectively) (p < 0.01). These results demonstrated that COS is a promising adjuvant to enhance the protective cellular immune responses induced by LI-based vaccine strains. Our work provided a notion for developing adjuvant for Listeria and other bacterial vector-based vaccines.
  • Effect of Amorphous Nanoparticle Size on Bioavailability of Anacetrapib in
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Filippos Kesisoglou, Michael Wang, Kendra Galipeau, Paul Harmon, Grace Okoh, Wei Xu Amorphous solid dispersions (ASDs) are used as bioavailability-enhancing formulations on the premise of the increased solubility of the amorphous form over its crystalline counterpart. Recent studies have shown that ASDs can, during dissolution, generate amorphous nanoparticles that were initially postulated to serve as a source of rapidly dissolving compound during absorption. Researchers have proposed that nanoparticles, including crystalline nanoparticles, may provide additional benefits to absorption such as drifting in the mucous layer. However, there are limited published data on the impact of nanoparticle size on bioavailability in vivo and, to our knowledge, there have been no published examples looking at the impact of differential size of in situ–generated nanoparticles from an ASD. Anacetrapib, a highly lipophilic, Biopharmaceutics Classification System IV compound, formulated as an ASD that generates nanoparticles on dissolution, was used in the studies described in this article. A differential response in bioavailability was observed with ∼100 nm or smaller particles, resulting in higher average exposure compared to ∼200 nm or larger particles. This increase in bioavailability could not be fully accounted for by the improvement in dissolution rate and was not as pronounced as that achieved by improving solubilization by coadministration with a high-fat meal.
  • An Ex Vivo Evaluation of Moxifloxacin Nanostructured Lipid Carrier
           Enriched In Situ Gel for Transcorneal Permeation on Goat Cornea
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Shilpkala Gade, Krishna Kumar Patel, Chandan Gupta, Md. Meraj Anjum, Deepika Deepika, Ashish Kumar Agrawal, Sanjay Singh The study was designed to fabricate the moxifloxacin nanostructured lipid carriers (MOX-NLCs) loaded in situ gel for opthalmic application to improve the corneal permeation and retention and also subside the toxic effect associated with intracameral injection of moxifloxacin in endophthalmitis treatment. Initially, Box-Behnken design was used to optimize the various factors significantly affecting the final formulation attributes. MOX-NLCs with particle size 232.1 ± 9.2 nm, polydispersity index 0.247 ± 0.031, zeta potential −16.3 ± 1.6 mV, entrapment efficiency 63.1 ± 2.4%, and spherical shape was achieved. The optimized MOX-NLCs demonstrated the Higuchi release kinetics with highest regression coefficient. Besides this, FTIR, differential scanning calorimetry, and X-ray diffraction results suggested that MOX had excellent compatibility with excipients. Furthermore, the results of ex-vivo permeation study demonstrated 2-fold higher permeation (208.7 ± 17.6 μg), retention (37.26 ± 2.83 μg), and flux (9.57 ± 0.73 μg/cm2 h) compared with free MOX in situ gel. In addition, MOX-NLCs exhibited normal corneal hydration and did not show any sign of structural damage to the corneal tissue as confirmed by histology. Therefore, the findings strongly suggest that MOX-NLCs in situ gel with higher permeation and retention can be a better alternative strategy to prevent and treat the endophthalmitis infection.
  • Effects of Processing on a Sustained Release Formulation Prepared by
           Twin-Screw Dry Granulation
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Xingyou Ye, Venkataraman Kallakunta, Dong Wuk Kim, Hemlata Patil, Roshan V. Tiwari, Sampada B. Upadhye, Ron S. Vladyka, Michael A. Repka Dry granulation is an indispensable process used to improve the flow property of moisture-sensitive materials. Considering the limitations of currently available dry granulation techniques, it is necessary to develop a novel technique. In this study, a twin-screw dry granulation (TSDG) technology was successfully applied to produce a sustained-release dry granule formulation, which was subsequently compressed into sustained-release tablets. Based on a preliminary study, theophylline was selected as model drug, Klucel™ EF, Ethocel™, and magnesium stearate were selected as excipients. A Resolution V Irregular Fraction Design was applied to determine the effect of different processing parameters (screw speed, feeding rate, barrel temperature, and screw configuration) on product properties (flow properties, particle size distribution, and dissolution time). A reliable model was achieved by combining the data obtained, and processing parameters were automatically optimized to attain the setting goal. In general, TSDG was demonstrated to be an alternative method for the preparation of dry granules. The continuous processing nature, simplicity of operation, and ease of optimization made TSDG competitive compared with other conventional dry granulation techniques.
  • Entirely S-Protected Thiolated Silicone: A Novel Hydrophobic Mucoadhesive
           and Skin Adhesive
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Andrea Fürst, Randi Angela Baus, Noemi Lupo, Andreas Bernkop-Schnürch The aim of this study was the synthesis and evaluation of an entirely S-protected thiolated silicone as novel hydrophobic mucoadhesive and skin adhesive. 2-[(2-Amino-2-carboxyethyl)disulfanyl]nicotinic acid was covalently attached to a poly(dimethylsiloxane)-graft-polyacrylate via amide bond formation. Adhesive properties were determined via the rotating cylinder method and tensile studies on porcine small intestinal mucosa besides on porcine abdominal skin. Rheological characteristics were evaluated on a cone-plate rheometer. The S-protected thiolated silicone exhibited 128 ± 18 μmol immobilized 2-mercaptonicotinic acid per gram of polymer and showed a 5.9-fold extended time of mucosal adhesion compared with the unmodified silicone on the rotating cylinder. With a 2.3-fold higher maximum detachment force and a 1.7-fold higher total work of adhesion tested on porcine small intestinal mucosa, the S-protected thiolated silicone is superior to the unmodified silicone. Furthermore, using porcine abdominal skin, a 2.4-fold higher maximum detachment force and a 4.4-fold higher total work of adhesion obtained for the S-protected thiolated silicone outlines the preferentially adhesion to skin. Triggered by N-acetyl-L-cysteine liberated thiol groups form interchain and intrachain disulfide bonds within the polymer (6.7% m/v) causing a 23.0-fold increase in dynamic viscosity (ƞ). In parallel, the elastic modulus (G’) and the viscous modulus (G”) increased 39.2-fold and 8.1-fold, respectively.
  • A Rapid High-Sensitivity Reversed–Phase Ultra High Performance Liquid
           Chromatography Mass Spectrometry Method for Assessing Polysorbate 20
           Degradation in Protein Therapeutics
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Ying Cheng, Mark Hu, Camellia Zamiri, Toshiro Carcelen, Barthélemy Demeule, Anthony Tomlinson, Jie Gu, Yinges Yigzaw, Matt Kalo, X. Christopher Yu Polysorbate 20 (PS20), a widely used surfactant in protein therapeutics, has been reported to undergo hydrolytic degradation during product storage, causing the release of free fatty acids. The accumulation of free fatty acids in protein therapeutics was found to result in the formation of particles due to their limited aqueous solubility at 2°C-8°C. Quantitation of free fatty acids originating from PS20 degradation is thus important during bioprocess optimization and stability testing in formulation development to ensure optimum PS20 stability as well as product and process consistency in final drug products. This work reports the development of a simple and robust, high-throughput, reversed-phase ultra high performance liquid chromatography mass spectrometry method for high-sensitivity quantitation of lauric acid and myristic acid by using isotope-labeled fatty acid internal standards. The high sensitivity (
  • Spectroscopic Evidence of Tertiary Structural Differences Between Insulin
           Molecules in Fibrils
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Malthe Møhl Schack, Kevin Dahl, Thomas Rades, Minna Groenning, John F. Carpenter Protein fibrils are of great interest due to their involvement in several pathologies and their roles in the degradation of many therapeutic protein products. Fibrils share highly similar secondary structural motifs across different proteins and applied stress conditions. However, fibril morphology differs according to the surrounding conditions, with aromatic and hydrophobic amino acids playing important roles in mature fibril formation. In this study, we use Raman microscopy, by means of the aromatic amino acids in insulin molecules as markers, to probe for tertiary structure differences within fibrils. We compared 2 different fibril types, linear fibril bundles and spherulites. Generation of linear fibril bundles was undertaken in an acetic acid–containing formulation, whereas spherulites were generated in a hydrochloric acid–containing formulation. The Raman intensities of tyrosine and phenylalanine side chains suggest that there are significant differences between the fibril bundles. The findings suggest that the insulin components of the fibril strands are not arranged identically in the 2 fibril types and that this gives rise to differences in their tertiary structures. Overall, the work indicates that the physicochemical properties of fibril structures can be altered by changing the formulation and that these alterations can be monitored by Raman spectroscopy.
  • Polymorphism in Sulfanilamide: 14N Nuclear Quadrupole Resonance
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Zvonko Trontelj, Janko Lužnik, Janez Pirnat, Vojko Jazbinšek, Zoran Lavrič, Stanko Srčič To demonstrate the selectivity of 14N nuclear quadrupole resonance (14N NQR) spectroscopy in chemistry and pharmacy, a study of sulfanilamide polymorphism was undertaken. We studied 3 known polymorphs of sulfanilamide by 14N NQR. We found at room temperature 2 sets of 3 14N NQR transition frequencies, corresponding to 2 different nitrogen sites in the crystal structure for each of 3 polymorphs. We measured the temperature dependence of all quadrupole frequencies ν+, ν−. In each set, only 1 of the 3 14N NQR frequencies is enough to characterize the polymorph. Spin-lattice relaxation time (T1) measurement is supplemental information. We also measured the transition temperature between polymorphs and estimated the ratio of polymorphs after thermal treatment of sample.
  • The Degradation Chemistry of GSK2879552: Salt Selection and
           Microenvironmental pH Modulation to Stabilize a Cyclopropyl Amine
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): John M. Campbell, Mei Lee, Jacalyn Clawson, Sonya Kennedy-Gabb, Sarah Bethune, Ashley Janiga, Leanda Kindon, Kevin P. Leach The cyclopropyl amine moiety in GSK2879552 (1) degrades hydrolytically in high pH conditions. This degradation pathway was observed during long-term stability studies and impacted the shelf life of the drug product. This article describes the work to identify the degradation impurities, elucidate the degradation mechanism, and design a stable drug product. It was found that salt selection and control of the microenvironmental pH of the drug product formulation blend significantly improved the chemical stability of the molecule in the solid state.
  • The Degradation Chemistry of Prasugrel Hydrochloride:
           Part 1—Drug Substance
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Steven W. Baertschi, Lindsay Maxwell-Backer, Matthew Clemens, Tim A. Smitka, Jerry R. Draper, K. Wayne Taylor, Andreas Kaerner, Patrick J. Jansen Prasugrel hydrochloride is the active ingredient in Effient™, a thienopyridine platelet inhibitor. An extensive study of the degradation chemistry of prasugrel hydrochloride (LY640315 hydrochloride) has been carried out on the drug substance (part I) and on the drug product (part II, future article) using a multidimensional approach including hydrolytic, oxidative, and photolytic stressing, computational chemistry, HPLC analysis, and structure elucidation by various spectroscopic techniques. The major degradation products formed from the drug substance under the various stress conditions have been isolated and structures unambiguously determined, and the pathways leading to these products have been proposed. Fourteen new (not previously disclosed) products were discovered and characterized, in addition to 4 degradation products that had been previously identified in the literature. The pathways indicate that prasugrel is susceptible to hydrolysis, autoxidation (both radical-initiated and single-electron mediated), and peroxide-mediated oxidation; in solution, prasugrel is susceptible to photodegradation.
  • Cryptopharmaceuticals: Increasing the Safety of Medication by a Blockchain
           of Pharmaceutical Products
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Lasse Nørfeldt, Johan Bøtker, Magnus Edinger, Natalja Genina, Jukka Rantanen The future health-care system will contain an ever expanding number of digital elements. The data stored both at a centralized health-care level and at a local, patient level (e.g., on a smartphone) will be core elements when deciding treatment strategies in a health-care scenario with Internet of things–based elements. The current way of manufacturing pharmaceutical products and related existing logistic solutions is not ready for such a revolution. One of the key challenges is cybersecurity and related robust public key infrastructure solution. This work introduces one element of a potential solution at a prototype level: the concept of cryptopharmaceuticals where pharmaceutical products are connected in a patient-specific blockchain of individual dosage units. This technology is based on the concept where each produced dosage unit has a unique information-rich pattern. A proof-of-concept smartphone application was applied to demonstrate the visualization of this blockchain at different levels. This includes the manufacturing of the individualized dosage unit, the patient view for his/her personal blockchain, and integration of these products into a health Internet of things system. This unbreakable blockchain of personal medication history will provide means to avoid counterfeit products and to enable innovative logistic solutions.
  • The Discriminatory Power of the BCS-Based Biowaiver: A Retrospective With
           Focus on Essential Medicines
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Martin A. Hofsäss, Jennifer B. Dressman This article summarizes historic developments, recent expert opinions, and (currently) unresolved challenges concerning the Biopharmaceutics Classification System (BCS)-based Biowaiver. An overview of approval statistics and application potential, case examples addressing the discriminatory power of the procedure, as well as an outlook on possible refinements in the future are provided and critically discussed. Over the last decade, regulatory guidance documents have been harmonized, for example, following scientific consent on allowing biowaivers for BCS class III drugs, making over 50% of orally administered drugs on the World Health Organization Essential Medicines List eligible for an abbreviated approval. Biowaiver monographs that present a complete risk-benefit evaluation for individual drugs have been issued by the International Pharmaceutical Federation for more than 25% of those drugs with the long-range aim of covering all essential drugs. Unresolved issues that have emerged from reported examples of false-negative and false-positive outcomes in the literature demand further adjustments to the regulatory requirements. Possible solutions for resolving these issues are the use of modeling and simulation and refined biorelevant in vitro tests that are better able to discriminate between dosage forms with unequal performance in vivo, potentially allowing biowaivers for selected BCS II drugs.
  • Editorial
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Ronald T. Borchardt
  • Editorial Advisory Board
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s):
  • Simultaneous Particle Size Reduction and Homogeneous Mixing to Produce
           Combinational Powder Formulations for Inhalation by the Single-Step Co-Jet
    • Abstract: Publication date: September 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 9Author(s): Junhong Ling, Sharad Mangal, Heejun Park, Shaoning Wang, Alex Cavallaro, Qi Tony Zhou Homogeneous mixing of 2 cohesive jet-milled drug powders is a challenge for pharmaceutical manufacturing on account of their cohesive nature resulting in the formation of strong and random agglomerates. In this study, colistin and ciprofloxacin were co-jet milled to develop combinational antibiotic dry powder formulations for inhalation. The properties of particle size, morphology, content uniformity, and in vitro aerosolization were evaluated. The distribution of 2 drugs in the co-jet milled powders was assessed using time-of-flight–secondary ion mass spectrometry. The co-jet milled powders demonstrated an acceptable content uniformity indicating homogeneity. In general, time-of-flight–secondary ion mass spectrometry images showed relatively homogeneous distributions of ciprofloxacin and colistin in the co-milled formulations. Importantly, the 2 drugs generally had the similar fine particle fraction and deposition behavior in each combinational formulation supporting that the particle mixtures were relatively homogenous and could maximize the antimicrobial synergy. In conclusion, co-jet milling could be a viable technique to produce the combination powders for inhalation.
  • Activation of human monocytes by colloidal aluminium salts
    • Abstract: Publication date: Available online 23 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Hilde Vrieling, Sietske Kooijman, Justin de Ridder, Dominique Thies-Weesie, Peter Soema, Wim Jiskoot, Elly van Riet, Albert Heck, Albert Philipse, Gideon Kersten, Hugo Meiring, Jeroen Pennings, Bernard Metz Subunit vaccines often contain colloidal aluminium salt-based adjuvants to activate the innate immune system. These aluminium salts consist of micrometre-sized aggregates. It is well known that particle size affects the adjuvant effect of particulate adjuvants. In this study, the activation of human monocytes by hexagonal-shaped gibbsite (ø=210±40 nm) and rod-shaped boehmite (ø= 83±27 nm) was compared with classical aluminium oxyhydroxide adjuvant (alum). To this end, human primary monocytes were cultured in the presence of alum, gibbsite or boehmite. The transcriptome and proteome of the monocytes were investigated by using quantitative polymerase chain reaction and mass spectrometry. Human monocytic THP-1 cells were used to investigate the effect of the particles on cellular maturation, differentiation, activation and cytokine secretion, as measured by flow cytometry and enzyme-linked immuno sorbent assay. Each particle type resulted in a specific gene expression profile. IL-1ß and IL-6 secretion was significantly upregulated by boehmite and alum. Of the seven surface markers investigated, only CD80 was significantly upregulated by alum and none by gibbsite or boehmite. Gibbsite hardly activated the monocytes. Boehmite activated human primary monocytes equally to alum, but induced a much milder stress-related response. Therefore, boehmite was identified as a promising adjuvant candidate.
  • Determination of the Structural Relaxation Enthalpy Using a Mathematical
    • Abstract: Publication date: Available online 23 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Karsten Flügel, Robert Hennig, Markus Thommes Structural relaxation is a well-known phenomenon in amorphous materials such as amorphous solid dispersions. It is generally understood as a measure for molecular mobility and has been shown to impact certain material properties such as the dissolution rate. Several quantification methods to evaluate structural relaxation using differential scanning calorimetry have been proposed in the past, but all approaches exhibit disadvantages. In this work, a mathematical model was developed and fitted to calorimetric data enabling the analysis of the structural relaxation enthalpy by separating the structural relaxation peak from the underlying glass transition. The proposed method was validated using a parameter sensitivity analysis. Differently stressed amorphous samples were analyzed applying the new model and the results were compared to commonly applied quantification methods in literature. The proposed method showed high robustness and accuracy and overcame the observed disadvantages of the established methods. The heating rate dependence of the calculated structural relaxation enthalpy was in accordance to theoretical considerations of previous studies, supporting the validity of the results. Thus, the proposed model is suitable to accurately quantify the degree of structural relaxation and should be a valuable tool for further investigations regarding the impact of structural relaxation on material properties.
  • Shifting paradigms revisited: biotechnology and the pharmaceutical
    • Abstract: Publication date: Available online 23 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Daan J.A. Crommelin, Enrico Mastrobattista, Andrea Hawe, Karin H. Hoogendoorn, Wim Jiskoot In 2003 Crommelin et al. published an article titled: ‘Shifting paradigms: biopharmaceuticals versus low molecular weight drugs’ ( In the current commentary, 16 years later, we discuss pharmaceutically relevant aspects of the evolution of biologics since then. First, we discuss the increasing repertoire of biologics, in particular the rapidly growing monoclonal antibody family and the advent of advanced therapy medicinal products (ATMPs). Next, we discuss trends in formulation and characterization as well as summarize our current insights into immunogenicity of biologics. We spend a separate section on new product(ion) paradigms for biologics, such as cell-free production systems, production of ATMPs and down-scaled production approaches. Furthermore, we share our views on issues related to reaching the patient, including routes and techniques of administration, alternative development models for affordable biologics, biosimilars and handling of biologics. In the concluding section we outline outstanding issues and make some suggestions for resolving those.
  • Lysozyme Mucoadhesive Tablets Obtained By Freeze-Drying
    • Abstract: Publication date: Available online 22 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Chiara G.M. Gennari, Paola Sperandeo, Alessandra Polissi, Paola Minghetti, Francesco Cilurzo Lysozyme is particularly attractive for the local treatment of oral pathologies related to microbiological infections. However, the requirement of a prolonged release is difficult to achieve due to saliva swallowing and to the protein denaturation which can occur during production and storage of a dosage form. This work demonstrates the feasibility to prepare lysozyme mucoadhesive tablets by freeze-drying. Tablets were prepared by using alginate (ALG) physically "cross-linked" with calcium ion and different grades of HPMC (i.e. E5, E50 or K100). The tablets were characterized in terms of swelling/erosion behavior, in vitro mucoadhesive properties, lysozyme activity (M. lysodeikticus), drug release and ability to inactivate S. aureus. The formulations prepared with HPMC K100 were discarded due to the fast erosion. All other formulations allowed a sustained release over at least six hours. Independently of composition, lysozyme activity (78311±1873 Unit/mg) significantly decreased in the case of tablets containing 5 and 10% w/w of protein (55000 Units/mg and 33000 Units/mg, respectively). Conversely, no modifications occurred in the case of tablets containing 1% w/w lysozyme. The formulation prepared by ALG/ HPMC E5 7/3 ratio was efficacious against S. aureus. After 3 months of storage at 5±3 °C, no significant decrease in lysozyme activity was observed.
  • Proposal of a Parameter for OATP1B1 Inhibition Screening at the early Drug
           Discovery Stage
    • Abstract: Publication date: Available online 22 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Hiroyuki Murata, Soichiro Ito, Hiroyuki Kusuhara, Yukihiro Nomura, Toshio Taniguchi It is known that potent inhibition of organic anion transporting polypeptide (OATP)1B1 increases exposure to statins, leading to severe adverse effects. The aim of this study is to propose a parameter and its criteria in OATP1B1 inhibition assay at the early drug discovery stage in order to avoid compounds with the risk of statin-related adverse effects. According to drug label information, most of compounds classified as “contraindicated” or “should be avoided” when administered concomitantly with statins increased their AUCs more than 4-fold. Generally, R values where R=1+plasma unbound fraction (fu)×maximum inhibitor concentration at the inlet to the liver/IC50 are used to evaluate the extent of clinical drug interaction. However, clinical doses and Cmax cannot be determined at the screening stage. Therefore, we estimated the correlations between change in AUC of statins concomitantly administered with OATP1B1 inhibitors and various parameters including fu/IC50. Cyclosporin A, rifampicin, and telaprevir increased the AUC of statins more than 4-fold and fu/IC50 of these compounds were> 0.1 L/μmol. On the other hand, fu/IC50 of other compounds were ≤ 0.03 L/μmol. This study indicates that fu/IC50 is a useful parameter to avoid compounds that seriously affect statin potency through interaction with OATP1B1 at the screening stage.
  • Effect of spray-dried particle morphology on mechanical and flow
           properties of felodipine in PVP VA amorphous solid dispersions
    • Abstract: Publication date: Available online 22 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Alyssa Ekdahl, Deanna Mudie, David Malewski, Greg Amidon, Aaron Goodwin Amorphous solid dispersions (ASDs) are commonly used to enhance the oral absorption of drugs with solubility or dissolution rate limitations. While the ASD formulation is typically constrained by physical stability and in vivo performance considerations, ASD particles can be engineered using the spray drying process to influence mechanical and flow properties critical to tableting. Using the ASD formulation of 20% w/w felodipine dispersed in polyvinyl pyrrolidone vinyl acetate (PVP VA), spray drying atomization and drying conditions were tuned to achieve four different powders with varying particle properties. The resulting particles ranged in volume moment mean diameter from 4 to 115 μm, bulk density from 0.05 to 0.38 g cm-3, and morphologies of intact, collapsed, and fractured hollow spheres. Powder flowability by shear cell ranged from poor to easy flowing, while mechanical property tests suggested all samples will produce strong tablets at reasonable solid fractions and compression pressures. Additionally, Hiestand dynamic tableting indices showed excellent dynamic bonding for three powders, and low viscoelasticity with high brittleness for all powders. This work demonstrates the extent spray-dried ASD particle morphologies can be engineered to achieve desired powder flow and mechanical properties to mitigate downstream processing risks and increase process throughput.
  • A proposal for an alternative approach to particle size method development
           during early stage small molecule pharmaceutical development
    • Abstract: Publication date: Available online 21 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): John F. Gamble, Neil Dawson, Dean Murphy, Andrew Theophilus, Paul Kippax Particle size analysis in the pharmaceutical industry has long been a source of debate regarding how best to define measurement accuracy; the degree to which the result of a measurement or calculation conforms to the true value. Defining a ‘true’ value for the size of a particle can be challenging as the output of its measurement will differ due to variations in measurement approaches, instrumental differences and calculation methods. Consequently, for ‘real’ particles, a universal ‘true’ value does not exist and accuracy is therefore not a useful characteristic. Accordingly, precision is then a measure of the ability to reproducibly measure of value of unknown value.This paper proposes, in place of accuracy, a means to define the ‘appropriateness’ of a measurement in line with the Critical Quality Attributes (CQA) of the material being characterized. The decision as to whether the measurement is correct should involve a link to the CQAs; that is, correlation should be demonstrated, without which the measured particle size cannot be defined as a Critical Material Attribute (CMA).Correspondingly, methods should also be able to provide sufficient precision to demonstrate discrimination relating to variation in the CQA. The benefits and challenges of this approach are discussed.
  • Applying Two Orthogonal Methods to Assess Accuracy of Plasma Protein
           Binding Measurements for Highly Bound Compounds
    • Abstract: Publication date: Available online 13 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Sangwoo Ryu, Keith Riccardi, Roshan Patel, Larisa Zueva, Woodrow Burchett, Li Di Significant advances have been made over the years to accurately measure plasma protein binding (PPB) of highly bound compounds. However, because of perceived uncertainty based on historical suboptimal methods and limitation of radiochemical purity of radiolabeled materials, current regulatory guidelines recommend using an arbitrary cutoff fraction unbound (fu) of 0.01 as the lower limit for drug-drug interaction (DDI) prediction. This can result in significant overprediction of DDI for highly bound compounds, unnecessary DDI clinical trials and more restrictive drug product labels. To build confidence in the accuracy of PPB measurement for highly bound compounds, two orthogonal methods, equilibrium dialysis and ultracentrifugation, are assessed in this study to measure PPB of ten highly bound drugs (fu < 0.01). The results show that the two very different methods yield comparable fu values, generally within 2-fold of each other. The data suggest that PPB of highly bound compounds can be measured accurately using current state-of-art methods, and the experimental fu should be used for DDI prediction to provide a more realistic evaluation of DDI risk in the clinic.
  • Alteration of Physicochemical Properties for Antibody Drug Conjugates and
           Their Impact on Stability
    • Abstract: Publication date: Available online 10 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Jakob W. Buecheler, Matthias Winze, Christian Webe, Henning Giesele Antibody conjugates, in particular antibody drug conjugates (ADC), are a fast-growing area in research and in the pharmaceutical industry. The covalent attachment of an antibody to a chemical moiety can be an effective measure for drug targeting or can also positively impact pharmacokinetics of small molecular compounds by serum half-life extension. Stability, physicochemical properties and degradation pathways of biotherapeutics or small molecule therapeutics are often not totally known and understood. However, ADCs represent a hybrid of small- and macromolecular components and their properties are still not fully understood and described. This review discusses the alteration of the physicochemical properties of antibodies upon conjugation of chemical moieties to its surface and the resulting impact on ADC stability.
  • Proteolysis and oxidation of therapeutic proteins after intradermal or
           subcutaneous administration
    • Abstract: Publication date: Available online 10 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Ninad Varkhede, Rupesh Bommana, Christian Schöneich, M. Laird Forrest The intradermal (ID) and subcutaneous (SC) routes are commonly used for therapeutic proteins (TPs) and vaccines; however, the bioavailability of TPs is typically less than small molecule drugs given via the same routes. Proteolytic enzymes in the dermal, SC and lymphatic tissues may be responsible for the loss of TPs. In addition, the TPs may be exposed to reactive oxygen species (ROS) generated in the SC tissue and the lymphatic system in response to injection-related trauma and impurities within the formulation. The ROS can oxidize TPs to alter their efficacy and immunogenicity potential. Mechanistic understandings of the dominant proteolysis and oxidative routes are useful in the drug discovery process, formulation development, and to assess the potential for immunogenicity and altered pharmacokinetics (PK). Furthermore, in vitro tools representing the ID or SC and lymphatic system can be used to evaluate the extent of proteolysis of the TPs after the injection and prior to systemic entry. The in vitro clearance data may be included in physiologically based pharmacokinetic (PBPK) models for improved PK predictions. In this review, we have summarized various physiological factors responsible for proteolysis and oxidation of TPs after ID and SC administration.
  • Feasibility Study for the Rectal Route of Administration for Gentamicin
           Evaluated in the Neonatal Minipig Model
    • Abstract: Publication date: Available online 9 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): David H. McAdams, Manjari Lal, Manshun Lai, Manjari Quintanar-Solares Neonatal infections are a major cause of newborn mortality in low- and middle-income countries, particularly in areas without access to inpatient care. To address this, the World Health Organization developed guidelines for delivering simplified antibiotic regimens (oral amoxicillin and intramuscular gentamicin) in outpatient settings to young infants with suspected serious bacterial infection when referral is not feasible. However, there are still limitations to access, as the regimen requires a health care provider trained in giving intramuscular injections to infants. To provide a needle-free, simplified alternate to intramuscular delivery, PATH investigated the feasibility of the rectal administration of gentamicin. Potential formulations were screened by in vitro testing, and two liquid enema formulations and a cocoa butter suppository were developed and evaluated in a preclinical study of the rectal uptake of gentamicin in a neonatal minipig model. Sera samples from the control group, dosed by intramuscular injection, resulted in expected sera concentrations of gentamicin, but no gentamicin was detected in the sera of groups rectally dosed with the test formulations. The results of this study did not provide evidence to support the therapeutic feasibility of rectally absorbed gentamicin.
  • Recombinant subunit rotavirus trivalent vaccine candidate: physicochemical
           comparisons and stability evaluations of three protein antigens
    • Abstract: Publication date: Available online 7 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Sanjeev Agarwal, John M. Hickey, Neha Sahni, Ronald T. Toth, George A. Robertson, Robert Sitrin, Stanley Cryz, Sangeeta B. Joshi, David B. Volkin Although live attenuated rotavirus (RV) vaccines are available globally to provide protection against enteric RV disease, efficacy is substantially lower in low to middle income settings leading to interest in alternative vaccines. One promising candidate is a trivalent non-replicating rotavirus (NRRV) vaccine, comprised of three truncated rotavirus VP8 subunit proteins fused to the P2 CD4+ epitope from tetanus toxin (P2-VP8-P[4/6/8]). A wide variety of analytical techniques were employed to compare the physicochemical properties of these three recombinant fusion proteins. Various environmental stresses were used to evaluate antigen stability and elucidate degradation pathways. P2-VP8-P[4] and P2-VP8-P[6] displayed similar physical stability profiles as function of pH and temperature while P2-VP8-P[8] was relatively more stable. Forced degradation studies revealed similar chemical stability profiles with Met1 most susceptible to oxidation, the single Cys residue (at position 173/172) forming inter-molecular disulfide bonds (P2-VP8-P[6] was most susceptible), and Asn7 undergoing the highest levels of deamidation. These results are visualized in a structural model of the NRRV antigens. The establishment of key structural attributes of each antigen, along with corresponding stability-indicating methods, have been applied to vaccine formulation development efforts (see companion paper), and will be utilized in future analytical comparability assessments.
  • Characterizing and minimizing aggregation and particle formation of three
           recombinant fusion-protein bulk antigens for use in a candidate trivalent
           rotavirus vaccine
    • Abstract: Publication date: Available online 7 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Sanjeev Agarwal, Neha Sahni, John M. Hickey, George A. Robertson, Robert Sitrin, Stanley Cryz, Sangeeta B. Joshi, David B. Volkin In a companion paper, the structural integrity, conformational stability and degradation mechanisms of three recombinant fusion-protein antigens comprising a non-replicating rotavirus (NRRV) vaccine candidate (currently being evaluated in early-stage clinical trials) are described. In this work, we focus on the aggregation propensity of the three NRRV antigens coupled to formulation development studies to identify common frozen bulk candidate formulations. The P2-VP8-P[8] antigen was most susceptible to shaking and freeze-thaw-induced aggregation and particle formation. Each NRRV antigen formed aggregates with structurally altered protein (with exposed apolar regions and inter-molecular β-sheet) and dimers containing a non-native disulfide bond. From excipient screening studies with P2-VP8-P[8], sugars/polyols (e.g., sucrose, trehalose, mannitol, sorbitol) and various detergents (e.g., Pluronic F-68, polysorbate 20 and 80, PEG-3350) were identified as stabilizers against aggregation. By combining promising additives, candidate bulk formulations were optimized to not only minimize agitation-induced aggregation, but also particle formation due to freeze-thaw stress of P2-VP8-P[8] antigen. Due to limited material availability, stabilization of the P2-VP8-P[4] and P2-VP8-P[6] was confirmed with the lead candidate P2-VP8-P[8] formulations. The optimization of these bulk NRRV candidate formulations is discussed in the context of subsequent drug product formulations in the presence of aluminum adjuvants.
  • CD44 receptor specific- and redox-sensitive nanophotosensitizers of
           hyaluronic acid-chlorin e6 tetramer having diselenide linkages for
           photodynamic treatment of cancer cells
    • Abstract: Publication date: Available online 5 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Doo-Man Kim, Yong Ho Shim, Hanjin Kwon, Jong-Pil Kim, Ji-In Park, Do Hoon Kim, Douk-Hoon Kim, Jin Hyeok Kim, Young-IL. Jeong For reactive oxygen species (ROS) sensitive and CD44-receptor mediated delivery of photosensitizers, chlorin e6 (ce6) tetramer was synthesized using tetra acid (TA) via selenocystamine linkages and then conjugated with hyaluronic acid (HA) (Abbreviated as HAseseCe6TA). HAseseCe6TA nanophotosensitizers were fabricated by dialysis procedure. HAseseCe6TA nanophotosensitizers showed spherical morphology with small particle sizes less than 100 nm and mono-modal pattern. When H2O2 was added, size distribution was changed to multi-modal pattern and morphogical observation showed disintegration of nanophotosensitizers, indicating that HAseseCe6TA nanophotosensitizers have ROS-sensitivity. Furthermore, H2O2 addition resulted in acceleration of Ce6 release from HAseseCe6TA nanophotosensitizers. In vitro cell culture study, HAseseCe6TA nanophotosensitizers increase Ce6 uptake ratio, ROS production efficiency, and PDT efficacy in both B16F10 cells and CT26 cells. Especially, CD44-receptor blocking of cancer cells by pre-treatment of HA showed that fluorescence intensity in B16F10 cells was significantly decreased while fluorescence intensity in CT26 cells was not significantly changed, indicating that HAseseCe6TA nanophotosensitizers can be delivered by CD44-receptor mediated pathway. In vivo animal tumor xenograft study, HAseseCe6TA nanophotosensitizers was selectively delivered to B16F10 tumor rather than CT26 tumor. These results indicated that HAseseCe6TA nanophotosensitizers have ROS-sensitivity and are CD44 receptor-recognition properties.
  • Development of Dexlansoprazole Delayed-Release Capsules, a Dual
           Delayed-Release Proton Pump Inhibitor
    • Abstract: Publication date: Available online 3 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Haiyan Grady, Yusuke Murakawa, Darcy Mulford, Michael Kukulka Proton pump inhibitors (PPI) are widely used for treating acid-related disorders. For an “ideal PPI,” achieving maximal absorption and sustaining pharmacodynamic effects through the 24-h dosing cycle are critical features. Dexlansoprazole offers a relevant case study on how an improved PPI was developed capitalizing on the rational optimization of a precursor molecule—in this case, using lansoprazole as a starting point, leveraging its chemical properties on pharmacokinetics, and exploring optimized formulations.Dexlansoprazole is the R(+)-enantiomer of lansoprazole and shows stereoselective differences in absorption and metabolism compared with the racemic mixture of lansoprazole. The formulation was further refined to utilize pulsate-type granules with enteric coating to withstand acidic gastric conditions, while allowing prolonged absorption in the proximal and distal small intestine. As a result, the dual delayed-release formulation of dexlansoprazole has a plasma concentration-time profile characterized by 2 distinct peaks, leading to an extended duration of therapeutic plasma drug concentrations compared with the conventional delayed-release lansoprazole formulation. The dual delayed-release formulation maintains plasma drug concentrations longer than the lansoprazole delayed-release formulation at all doses.
  • Expedited investigation of powder caking aided by rapid 3D prototyping of
           testing devices
    • Abstract: Publication date: Available online 3 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Cosima Hirschberg, Johan Boetker, Jens Risbo, Changquan Calvin Sun, Jukka Rantanen Powder caking can dramatically affect powder handling and downstream production processes. Understanding the key factors that contribute to bulk powder caking are crucial. This paper introduces the Hirschberg caking device (HCD), which is a 3D printed device allowing for parallel testing of powder caking in a cylindrical geometry. In the HCD set-up, the powder sample is stored in controlled conditions in the sample holder. Upon removal of the sample holder, the caked powder will remain in the shape determined by the sample geometry while the remaining powder will fall down. Caking indices can be calculated based on image analysis and weight measurement. The results obtained for the caking of lactose monohydrate with the HCD were in good agreement with the results obtained by a ring shear tester. Additionally a strain tester was used to measure the strength of the formed cakes. Using this approach, critical storage conditions and the required concentration of a given anti-caking agent (talc) for lactose monohydrate could be identified. This work demonstrates the potential of rapid prototyping in powder characterization by introducing a fast and affordable approach for exploring and trouble-shooting powder caking.
  • Why We Need Continuous Pharmaceutical Manufacturing and How to Make it
           Happen: A Summary of Thoughts from the International Symposium on
           Continuous Manufacturing
    • Abstract: Publication date: Available online 2 August 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Clive Badman, Charles L. Cooney, Robert T. Haslam, Alastair Florence, Konstantin Konstantinov, Markus Krumme, Salvatore Mascia, Moheb Nasr, Bernhardt L. Trout, Raymond F. Baddour
  • Preparation and Characterization of Cellulose Ether Liposomes for the
           Inhibition of Prion Formation in Prion-Infected Cells
    • Abstract: Publication date: August 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 8Author(s): Keiko Nishizawa, Kenta Teruya, Ayumi Oguma, Yuji Sakasegawa, Hermann Schätzl, Sabine Gilch, Katsumi Doh-ura Prion accumulation in the brain and lymphoreticular system causes fatal neurodegenerative diseases. Our previous study revealed that cellulose ethers (CE) have anti-prion activities in vivo and in prion-infected cells when administered at high doses. This study aims to improve the bioavailability of a representative CE using a liposomal formulation and characterized CE-loaded liposomes in cultured cells. The liposomal formulation reduced the EC50 dose of CE by
  • Development of Rectodispersible Tablets and Granulate Capsules for the
           Treatment of Serious Neonatal Sepsis in Developing Countries
    • Abstract: Publication date: August 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 8Author(s): Tina Kauss, Marie-Hélène Langlois, Alice Guyonnet-Dupérat, Thida Phoeung, Xiao Yu Xie, Anthony Cartwright, Nicholas White, Melba Gomes, Karen Gaudin Current pediatric antibiotic therapies often use oral and parenteral routes of administration. Neither are suitable for treating very sick neonates who cannot take oral medication and may be several hours away from hospital in developing countries. Here, we report on the development of rectal forms of ceftriaxone, a third-generation cephalosporin. Rectodispersible tablets and capsules were developed and successfully passed 6-month accelerated stability tests. Rabbit bioavailability showed plasma concentrations above the minimal inhibitory concentrations for 3 formulations of rectodispersible tablets and 2 formulations of hard capsules. Clinical batches are currently being prepared for human evaluation with the prospect of offering therapeutic alternatives for treating critically ill neonates. This proof of concept for efficient rectal delivery of antibiotics could help the development of other rectal antibiotic treatments and increase options for noninvasive drug development for pediatric patients.
  • Identification of Major Esterase Involved in Hydrolysis of Soft
           Anticholinergic (2R3’R-SGM) Designed From Glycopyrrolate in Human and
           Rat Tissues
    • Abstract: Publication date: August 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 8Author(s): Ahmed Samir, Kayoko Ohura, Nicholas Bodor, Teruko Imai The glycopyrrolate soft analog, SGM, designed to be easily hydrolyzed into the significantly less active zwitterionic metabolite, SGa, typifies soft drug that reduces systemic side effects (a problem often seen with traditional anticholinergics) following local administration. In this study, hydrolysis of 2R3’R-SGM, the highest pharmacologically active stereoisomer of SGM, was investigated in human and rat tissues. In both species, 2R3’R-SGM was metabolized to 2R3’R-SGa in plasma but was stable in liver and intestine. The half-life of 2R3’R-SGM was found to be 16.9 min and 9.8 min in human and rat plasma, respectively. The enzyme inhibition and stimulation experiments showed that plasma paraoxonase 1 (PON1) is responsible for the hydrolysis of 2R3’R-SGM in humans and rats. The PON1-mediated hydrolysis of 2R3’R-SGM was confirmed in the lipoprotein-rich fractions of human plasma. As PON1 is naturally attached to high-density lipoprotein, it might be absent in topical tissues where 2R3’R-SGM is applied, supporting its local stability and efficacy. The metabolic behavior of 2R3’R-SGM indicates that it is an ideal soft drug to be detoxified as soon as it moves into systemic circulation. Furthermore, the similarity of 2R3’R-SGM metabolism in humans and rats showed that the rat is a suitable animal for preclinical study.
  • Prediction of Ticagrelor and its Active Metabolite in Liver Cirrhosis
           Populations Using a Physiologically Based Pharmacokinetic Model Involving
    • Abstract: Publication date: August 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 8Author(s): Min Zhang, Xiang You, Meng Ke, Zheng Jiao, Hongwei Wu, Pinfang Huang, Cuihong Lin Ticagrelor, a P2Y12 receptor antagonist, has been highly recommended for use in acute coronary syndrome. The major active metabolite (AM) is similar to the parent drug, which exhibits antiplatelet activity. The inhibition of platelet aggregation (IPA) is used as an assay to demonstrate the anticoagulant efficacy of ticagrelor. In this study, we developed a physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of ticagrelor and its AM and combined this model with a pharmacodynamics model to reflect potential pharmacodynamic alterations in liver cirrhosis populations. The simulated results obtained using the PBPK model were validated by fold error values, which were all smaller than 2. Comparisons of exposure in different classifications of liver cirrhosis indicated that exposure to ticagrelor increased significantly with an increase in the degree of cirrhosis severity, whereas exposure to AM was decreased. The total concentration of ticagrelor and AM was related to the IPA included in the Sigmoid Emax model. The PBPK model of ticagrelor and AM could predict the pharmacokinetics of all populations, and a combination of PD models was used to extrapolate for predicting unknown scenarios. Liver cirrhosis may result in prolonged IPA, depending on the severity degree of this disease. The combined PBPK model including IPA can reveal changes in pharmacokinetics and pharmacodynamics in populations affected by liver cirrhosis and indicate the risk potential.
  • Analysis of the Complicated Nonlinear Pharmacokinetics of Orally
           Administered Telmisartan in Rats Using a Stable Isotope-IV Method
    • Abstract: Publication date: August 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 8Author(s): Keiko Minami, Haruki Higashino, Makoto Kataoka, Kazutaka Togashi, Kuninori Mutaguchi, Shinji Yamashita This study aimed to kinetically analyze the nonlinear absorption and systemic exposure of telmisartan (TEL) after oral administration to rats by using a stable isotope-IV method. Rats were orally administered different dose of TEL, followed by the intravenous injection of 0.005 mg/kg of deuterium-labeled TEL (TEL-d3). Assuming that TEL-d3 shows same pharmacokinetic properties with TEL, systemic clearance (CLtot), oral bioavailability (Foral), and intestinal and hepatic availability (Fa*Fg, Fh) of TEL were calculated in each individual rat. AUCpo of TEL increased disproportionately with dose and showed a sigmoid-type relation, indicating the involvement of multi-nonlinear processes in oral absorption of TEL. Fa*Fg of TEL increased with dose at the low-dose range while decreased at the high-dose range. In contrast, Fh increased and CLtot decreased significantly in the middle range (2 to 6 mg/kg). As main factors of nonlinearity, saturations of solubility, efflux transport in the intestine, and the hepatic uptake of TEL were indicated. In conclusion, this study demonstrated a high possibility of a stable isotope-IV method to characterize complicated pharmacokinetic properties of oral drugs in animals, which can help to consider the future risks in their clinical use.
  • Optimal Dosing Regimen of Phenytoin for Korean Epilepsy Patients: From
           Premature Babies to the Elderly
    • Abstract: Publication date: August 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 8Author(s): Jinju Guk, Sang-Guk Lee, Dongwoo Chae, Jeong-Ho Kim, Kyungsoo Park Phenytoin has been decreasingly used because of the high interindividual variability in drug concentration and the narrow therapeutic window. Despite such drawbacks, phenytoin is still essential as a second-line therapy for status epilepticus when patients are resistant to benzodiazepines. This study aimed to develop a population pharmacokinetic model of phenytoin and to propose the optimal dose regimen of phenytoin in Korean epilepsy patients. Concentrations collected from electronic medical records for 117 patients, with 1 or 2 measurements per patient, were analyzed using NONMEM 7.3.0. One-compartment model with first-order elimination where allometry scaling was considered best described the data, yielding the estimates of V and CL of 68.19 (L) and 0.63 (L/h), respectively, for patients with a body weight of 60 kg. Covariate analyses showed that, after birth, clearance increases with age, reaching adult level at 4 years, and after 20 years, it decreases with age. Simulation results showed that the dosing interval should be reduced to achieve optimal dosing in neonates and infants, and the optimal dose required increases with weight. This work demonstrates that a model-based approach can serve as a useful tool to individualize phenytoin therapy.
  • Effect of Rifampicin on the Plasma Concentrations of Bile Acid-O-Sulfates
           in Monkeys and Human Liver-Transplanted Chimeric Mice With or Without Bile
           Flow Diversion
    • Abstract: Publication date: August 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 8Author(s): Issey Takehara, Nobuaki Watanabe, Daiki Mori, Osamu Ando, Hiroyuki Kusuhara The present study examined the significance of enterohepatic circulation and the effect of rifampicin [an inhibitor of organic anion–transporting polypeptide 1B (OATP1B)] on the plasma concentrations of bile acid-O-sulfates (glycochenodeoxycholate-O-sulfate, lithocholate-O-sulfate, glycolithocholate-O-sulfate, and taurolithocholate-O-sulfate) in monkeys and human liver-transplanted chimeric mice (PXB mouse). Rifampicin significantly increased the area under the curve of bile acid-O-sulfates in monkeys (13-69 times) and PXB mice (13-25 times) without bile flow diversion. Bile flow diversion reduced the concentration of plasma bile acid-O-sulfates under control conditions in monkeys and the concentration of plasma glycochenodeoxycholate-O-sulfate in PXB mice. It also diminished diurnal variation of plasma lithocholate-O-sulfate, glycolithocholate-O-sulfate, and taurolithocholate-O-sulfate in PXB mice under control conditions. Bile flow diversion did not affect the plasma concentration of bile acid-O-sulfates in monkeys and PXB mice treated with rifampicin. Plasma coproporphyrin I and III levels were constant in monkeys throughout the study, even with bile flow diversion. This study demonstrated that bile acid-O-sulfates are endogenous OATP1B biomarkers in monkeys and PXB mice. Enterohepatic circulation can affect the baseline levels of plasma bile acid-O-sulfates and modify the effect of OATP1B inhibition.
  • Establishment of an Evaluation Method for Gene Silencing by Serial
           Pulmonary Administration of siRNA and pDNA Powders: Naked siRNA Inhalation
           Powder Suppresses Luciferase Gene Expression in the Lung
    • Abstract: Publication date: August 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 8Author(s): Takaaki Ito, Tomoyuki Okuda, Ryo Takayama, Hirokazu Okamoto In order to evaluate the in vivo effect of inhaled formulations, it is a gold standard to create a lung metastasis model by intravenously injecting cancer cells into an animal. Because the cancer grows from the blood vessel side, there is a possibility of underestimating the effect of an inhaled formulation administered to the lung epithelium side. In addition, the metastasis model has disadvantages in terms of preparation time and expense. The present study aimed to establish a new method to evaluate the effect of an inhaled small interfering RNA (siRNA) formulation that is more correct, more rapid, and less expensive. We investigated whether siRNA can suppress gene expression of plasmid DNA (pDNA) by serial pulmonary administration of siRNA and pDNA powders prepared by spray-freeze-drying. We revealed that formulations of dry siRNA powder significantly suppressed gene expression of pDNA powder compared with a control group with no siRNA. Naked siRNA inhalation powder with no vector showed the suppression of gene expression equivalent to that of an siRNA-polyethyleneimine complex without damaging tissues. These results show that the present method is suitable for evaluating the gene-silencing effect of inhaled siRNA powders.
  • New Insight Into Thermodynamical Stability of Carbamazepine
    • Abstract: Publication date: August 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 8Author(s): Agnieszka Dołęga, Piotr M. Zieliński, Natalia Osiecka-Drewniak Carbamazepine (CBZ)—an antiepileptic drug—belongs to Biopharmaceutics Classification System II Class. It has low solubility and consequently limited bioavailability. One of the ways to improve drugs solubility is amorphization of their structure. Herein, cooling CBZ—at different cooling rates—was investigated as a way to obtain glassy, better soluble form. During preliminary differential scanning calorimetry experiments, some peculiar behavior of the examined material, different from those stated in the literature, was observed. Further investigations using differential scanning calorimetry, thermogravimetric analysis, and polarizing optical microscope revealed that decomposition temperature of CBZ is about 30°C lower than previously assumed. Moreover, high-resolution thermogravimetric measurements indicate that some decomposition processes could start even below the temperature reported as the melting point of the form I of CBZ.
  • Application of Box-Behnken Design in the Preparation, Optimization, and
           In Vitro Evaluation of Self-Assembly–Based Tamoxifen- and
           Doxorubicin-Loaded and Dual Drug–Loaded Niosomes for Combinatorial
           Breast Cancer Treatment
    • Abstract: Publication date: August 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 8Author(s): Pratik Kulkarni, Deepak Rawtani This study was developed with the objective to prepare self-assembled niosomes to support sufficient entrapment and sustained drug release of the drugs having different solubility and mechanisms. In the current work, Tamoxifen- and Doxorubicin-loaded niosomes were prepared for combinatorial breast cancer treatment with statistical optimization by Box-Behnken experimental design. Atomic force microscopy revealed a spherical shape morphology of the niosomes. The entrapment efficiencies for the drugs were found to be 74.3% and 72.7% for Tamoxifen and Doxorubicin, respectively. The drug release experiments at different pH values displayed a sustained release up to 3 days. Fourier transform infrared spectroscopy and differential scanning calorimetry showed a robust drug-excipient compatibility. The niosomes were stable over a period of 6 months with no significant changes. In vitro cytotoxicity studies on MCF-7 cell line showed a 15-fold improvement (0.01 μg per mL) and a better synergistic effect of the niosomes in comparison to the free drug combination (0.15 μg per mL). Moreover, the nanocarrier uptake studies by fluorescence microscopy and flow cytometry showed a good distribution and greater uptake of the niosomes throughout the cells. These results suggest a profound therapeutic application of the niosomes for a combinatorial breast cancer treatment.
  • Using Milling to Explore Physical States: The Amorphous and Polymorphic
           Forms of Sulindac
    • Abstract: Publication date: August 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 8Author(s): Mansour Latreche, Jean-François Willart, Mathieu Guerain, Alain Hédoux, Florence Danède This article shows how milling can be used to explore the phase diagram of pharmaceuticals. This process has been applied to sulindac. A short milling has been found to trigger a polymorphic transformation between form II and form I upon heating which is not seen in the nonmilled material. This possibility was clearly demonstrated to result from crystalline microstrains induced by the mechanical shocks. A long milling has been found to induce a total amorphization of the material. Moreover, the amorphous fraction produced during milling appears to have a complex recrystallization upon heating which depends on the milling time. The investigations have been mainly performed by differential scanning calorimetry and powder X-ray diffraction.
  • Rat Kidney Slices for Evaluation of Apical Membrane Transporters in
           Proximal Tubular Cells
    • Abstract: Publication date: August 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 8Author(s): Hiroshi Arakawa, Hikaru Kubo, Ikumi Washio, Angelina Yukiko Staub, Shiho Nedachi, Naoki Ishiguro, Takeo Nakanishi, Ikumi Tamai Kidney slice has been often used as a tool reflecting basolateral transport in renal tubular epithelial cells. Recently, we reported that several important apical reabsorptive transporters such as Octn1/2, Sglt1/2, and Pept1/2 were functional in mouse kidney slices as well as transporter activities in basolateral side, which have been well accepted. Because rats are often used for preclinical pharmacodynamic and pharmacokinetic studies as well as mice, it is important to confirm applicability of rat kidney slices for evaluation of apically expressed transporters. The present study investigates usefulness of kidney slices from rats for evaluation of apical membrane transporters for efflux (multidrug resistance 1a, mdr1a) as well as influx (Octn1/2, Sglt1/2, Pept1/2). Na+-dependent uptake of ergothioneine (Octn1), carnitine (Octn2), and methyl-α-D-glucopyranoside (Sglt1/2) by rat kidney slices was observed, and the uptake was decreased by selective inhibitors. In addition, uptake of glycyl-sarcosine (Pept1/2) showed H+-dependence and was decreased by selective inhibitor. Furthermore, accumulation of mdr1a substrate azasetron was increased in the presence of zosuquidar, an mdr1a inhibitor, while strain differences existed. In conclusion, rat kidney slices should be useful for evaluation of renal drug disposition regulated by transporters in apical as well as basolateral membranes of rat renal proximal tubule cells.
  • Editorial
    • Abstract: Publication date: Available online 3 July 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Mary Warner, Kenneth Audus
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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Fax: +00 44 (0)131 4513327
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