Journal Cover
Journal of Pharmaceutical Sciences
Journal Prestige (SJR): 0.984
Citation Impact (citeScore): 3
Number of Followers: 214  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0022-3549 - ISSN (Online) 1520-6017
Published by Elsevier Homepage  [3182 journals]
  • Cis/trans isomerization of unsaturated fatty acids in polysorbate 80
           during light exposure of a monoclonal antibody-containing formulation
    • Abstract: Publication date: Available online 9 November 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Indira Prajapati, Björn-Hendrik Peters, Nicholas R. Larson, Yangjie Wei, Sureshkumar Choudhary, Cavan Kalonia, Suzanne Hudak, Reza Esfandiary, C. Russell Middaugh, Christian Schöneich Light exposure of a monoclonal antibody formulation containing polysorbate 80 (PS80) leads to cis/trans isomerization of mono- and polyunsaturated fatty acids. This cis/trans isomerization was monitored by positive electrospray ionization (ESI) mass spectrometry (MS) of intact PS80 components as well as by negative ion ESI MS analysis of free fatty acids (FFAs) generated via esterase-catalyzed hydrolysis. The light-induced cis/trans isomerization of unsaturated fatty acids in PS80 required the presence of the mAb, or, at a minimum (for mechanistic studies), a combination of N-acetyltryptophan amide (NATA) and glutathione disulfide (GSSG), suggesting the involvement of thiyl radicals generated by photo-induced electron transfer from Trp to the disulfide. Product analysis confirmed the conversion of PS80-bound oleic acid to elaidic acid; furthermore, together with linoleic acid we detected conjugated linoleic acids (CLAs) in PS80, which underwent light-induced cis/trans isomerization.
       
  • Freezing of biologicals revisited: scale, stability, excipients, and
           degradation stresses.
    • Abstract: Publication date: Available online 6 November 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Jean-Rene Authelin, Miguel A. Rodrigues, Serguei Tchessalov, Satish Singh, Timothy McCoy, Stuart Wang, Evgenyi Shalaev .While many biotech products are successfully stored in the frozen state, there are cases of degradation of biologicals during freeze-storage. These examples are discussed in the Perspective to emphasize the fact that stability of frozen biologicals should not be taken for granted. Frozen state degradation (predominantly, aggregation) has been linked to crystallization of a cryoprotector in many cases. Other factors, e.g., protein unfolding (either due to cold denaturation or interaction of protein molecules with ice crystals), could also contribute to the instability. As a hypothesis, additional freezing-related destabilization pathways are introduced in the paper, that is, air bubbles formed on the ice crystallization front, and local pressure and mechanical stresses due to volume expansion during water-to-ice transformation. Furthermore, stability of frozen biologicals can depend on the sample size, via its impact on the freezing kinetics (that is, cooling rates and freezing time) and cryoconcentration effects, as well as on the mechanical stresses associated with freezing. We conclude that, while fundamentals of freezing processes are fairly well described in the current literature, there are important gaps to be addressed in both scientific foundations of the freezing-related manufacturing processes, and implementation of the available knowledge in practice.
       
  • Evaluating heparin products for heparin-induced thrombocytopenia using
           surface plasmon resonance
    • Abstract: Publication date: Available online 6 November 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Fuming Zhang, Payel Datta, Jonathan S. Dordick, Robert J. Linhardt :Heparin-induced thrombocytopenia (HIT) is an adverse immunological disorder caused by antibodies to platelet factor 4 (PF4)-heparin complexes. The analysis of HIT potential for different heparin and heparin-related products is important prior to their clinical application. Here, we report a rapid method for the evaluation of HIT potential of various heparin and heparin-related compounds using surface plasmon resonance (SPR). Solution competition between surface-immobilized heparin and soluble unfractionated heparin, low molecular weight heparin (LMWH), or ultra-LMWH binding to PF4 was performed using SPR to measure the half maximal inhibitory concentration (IC50) of different heparin products. The IC50 values of different unfractionated heparin active pharmaceutical ingredients (APIs) varied from 0.38 to 0.6 μg/ml and the IC50 values of different LMWH APIs ranged from 2.4 to 2.9 μg/ml. The IC50 of Arixtra® (a synthetic pentasaccharide ultra-LMWH) was not measurable even at very high concentrations. These differences in IC50 values for different heparin products suggest a quantitative means for evaluating the HIT potential of various heparins and heparin-related products.
       
  • Role of Surface Characteristics of Mannitol in Crystallization of
           Fenofibrate during Spray Drying
    • Abstract: Publication date: Available online 6 November 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Poonam Singh Thakur, Samarth D. Thakore, Arvind K. Bansal NanoCrySPTM is a novel spray-drying based technology for the generation of nanocrystalline solid dispersions of active pharmaceutical ingredients (APIs) embedded in the matrix of small molecule excipients. API first appears as an amorphous phase, which transforms to crystalline phase during its passage in the drying chamber. Mannitol acts as a crystallization inducer for the intermediate amorphous phase by primary heterogeneous nucleation. Heteronucleation is a surface-assisted phenomenon and surface characteristics of mannitol was hypothesized to play important role. This study investigates the role of surface characteristics of mannitol on crystallization kinetics of amorphous fenofibrate. Crystallization kinetics of amorphous fenofibrate was assessed on two surfaces of mannitol having different porosity, roughness, and polarity. Fenofibrate showed faster crystallization in presence of rougher surface (tind < 1min) compared with smooth surface (tind = 49.28 min). This was attributed to higher porosity (75%) and surface polarity (∼1.25-fold) of rough surface as compared with smooth surface. Polar nature provided primitive sites for faster crystallization of amorphous fenofibrate. These findings can be utilized for generating crystalline solid dispersions using spray drying in the presence of mannitol. The crystalline solid dispersions can used for development of oral solid dosage forms.
       
  • Evaluation of Fraction Unbound Across Seven Tissues of Five Species
    • Abstract: Publication date: Available online 5 November 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Sangwoo Ryu, David Tess, George Chang, Christopher Keefer, Woodrow Burchett, Gregory S. Steeno, Jonathan J. Novak, Roshan Patel, Karen Atkinson, Keith Riccardi, Li Di Binding to various tissues and species is frequently assessed in drug discovery and development to support safety and efficacy studies. To reduce time, cost and labor requirements for binding experiments, we conducted a large comparison study to evaluate the correlation of fraction unbound (fu) across seven tissues of five species, including white adipose, brain, heart, kidney, liver, lung, and skeletal muscle of mouse, rat, dog, monkey and human. The results showed that there were no significant species differences of fu for tissue binding, and a single species (e.g., rat) tissue fu can be used as a surrogate for binding in other species. Cross tissue comparison indicated that brain, heart, liver, and muscle had quite similar fu values, rat liver binding can be used as a surrogate for binding of the other three tissues without any scaling factors. Binding to adipose, kidney, and lung can also be estimated with rat liver fu with scaling factors. This study suggests that a single tissue of a single species (e.g., rat liver) is a good predictor for fu of other tissues of various species with or without scaling factors. Molecular size, lipophilicity, pKa and TPSA are important physiochemical properties influencing tissue fu.
       
  • Exploring Chemical Space for new Substances to stabilize a therapeutic
           Monoclonal Antibody
    • Abstract: Publication date: Available online 5 November 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Andreas Tosstorff, Tim Menzen, Gerhard Winter The physical stability of therapeutic proteins is a major concern in the development of liquid protein formulations. The number of degrees of freedom to control a given protein’s stability is limited to pH, ionic strength and type and concentration of excipient. There are only very few, mostly similar excipients currently in use, restricted to the list of substances generally recognized as safe for human use by the FDA. Opposed to this limited number of available excipients, there is the vastness of chemical space which is hypothesized to consist of 1060 compounds. Its potential to stabilize proteins has never been explored systematically in the context of the formulation of therapeutic proteins. Here we present a screening strategy to discover new excipients to further improve an already stable formulation of a therapeutic antibody. The data is used to build a predictive model that evaluates the stabilizing potential of small molecules. We argue that prior to worrying about the hurdles of toxicity and approval of novel excipient candidates, it is mandatory to assess the actual potential hidden in the chemical space.
       
  • Polymeric nanocarriers with mucus-diffusive and mucus-adhesive properties
           to control pharmacokinetic behavior of orally-dosed cyclosporine A
    • Abstract: Publication date: Available online 4 November 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Hideyuki Sato, Yuuki Kaneko, Kohei Yamada, Kurt D. Ristroph, Hoang D. Lu, Yoshiki Seto, Hak-Kim Chan, Robert K. Prud’homme, Satomi Onoue The present study develops cyclosporine A (CsA)-loaded polymeric nanocarriers with mucus-diffusive and mucus-adhesive potential to control pharmacokinetic behavior after oral administration for the treatment of inflammatory bowel diseases (IBD). CsA-loaded nanocarriers consisting of polystyrene (PS)-block-polyethylene glycol (PEG-CsA) and PS-block-polyacrylic acid (PAA-CsA) were prepared by a flash nanoprecipitation. Both nanocarriers showed redispersibility from lyophilized powder back to uniform nanocarrier with a mean diameter of approximately 150 nm. The nanocarriers exhibited significantly improved release behavior of CsA under pH 6.8 condition compared. A test of muco-diffusion, using artificial mucus, demonstrated the mucus-diffusive and mucus-adhesive potential of PEG-CsA and PAA-CsA, respectively, dependent on the lack of electrostatic interactions between the surface coated polymer and mucin. Oral administrations of PEG-CsA and PAA-CsA (10 mg-CsA/kg) in rats resulted in significant improvements of absorption, as evidenced by 50- and 25-fold higher bioavailability than crude CsA, respectively. PAA-CsA exhibited more sustained and slower absorption process of CsA than PEG-CsA, due to the different diffusion behavior within the mucus layer. In the rat model of IBD, significant suppression of inflammatory symptoms could be achieved by oral treatment with both CsA nanoparticles. These polymeric nanocarriers are promising dosage options to control pharmacokinetic behavior of orally-dosed CsA, contributing to the development of safe and effective treatment for IBD.
       
  • Algorithm-based liquid formulation development including a DoE concept
           predicts long-term viral vector stability
    • Abstract: Publication date: Available online 2 November 2019Source: Journal of Pharmaceutical SciencesAuthor(s): E.B. Reinauer, S.S. Grosso, S.R. Henz, J.A. Rabas, C. Rodenstein, J. Altrichter, M. Scholz, K. Kemter Specifically tailored amino acid-based formulations were previously shown to have a high potential to avoid stress-mediated degradation of complex molecules such as monoclonal antibodies and viral vectors. By using adenovirus 5 (Ad5) as a model, we studied whether such formulations may also efficiently protect viral vectors in thermal stress experiments and during long-term liquid storage. Algorithm-based amino acid pre-selection using an excipient database and subsequent application of Design of Experiment (DoE) in combination with a 37 °C challenging model enabled the prediction of long-term storage stability of Ad5. By statistical analysis of the Ad5 infectivity, amino acids with significant influence on Ad5 stability were detected after two and three weeks of liquid storage at 37 °C. Ad5 formulations comprising positively selected amino acids did not reveal any loss of infectivity after 24 months in liquid storage at 5 °C. By contrast, a two log reduction after three months and complete loss of infectivity after 18 months was observed with a standard viral vector formulation. By an optimization round, we designed a simple and well-balanced formulation avoiding MgCl2, previously considered essential in Ad5 formulations. This work demonstrates the efficacy of an algorithm-based development approach in the formulation development for viral vectors.
       
  • Conjugation of Amine-Functionalized Polyesters with Dimethylcasein Using
           Microbial Transglutaminase
    • Abstract: Publication date: Available online 2 November 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Razan Alaneed, Till Hauenschild, Karsten Mäder, Markus Pietzsch, Jörg Kressler Protein-polymer conjugates have been employed as therapeutics since they exhibit frequently higher stability, prolonged in vivo half-life, and lower immunogenicity compared to native proteins. The first part of this report describes the enzymatic synthesis of poly(glycerol adipate) (PGA(M)) by transesterification between glycerol and dimethyl adipate using lipase B from Candida antarctica (CAL-B). PGA(M) is a hydrophilic, biodegradable but water insoluble polyester. By acylation, PGA(M) is modified with 6-(Fmoc-amino)hexanoic acid and with hydrophilic poly(ethylene glycol) side chains (mPEG12) rendering the polymer highly water soluble. This is followed by the removal of protecting groups, fluorenylmethyloxycarbonyl (Fmoc), to generate polyester with primary amine groups, namely PGA(M)-g-NH2-g-mPEG12. 1H NMR spectroscopy, FTIR spectroscopy, and GPC have been used to determine the chemical structure and polydispersity index of PGA(M) before and after modification. In the second part, we discuss the microbial transglutaminase (mTGase)-mediated conjugation of the model protein dimethylcasein (DMC) with PGA(M)-g-NH2-g-mPEG12 under mild reaction conditions. SDS-PAGE proves the protein-polyester conjugation.
       
  • Taking subvisible particle quantitation to the limit: Uncertainties and
           statistical challenges with ophthalmic products for intravitreal injection
           
    • Abstract: Publication date: Available online 2 November 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Marina Gühlke, Johanna Hecht, Armin Böhrer, Andrea Hawe, Felix Nikels, Patrick Garidel, Tim Menzen Subvisible particles are a critical quality attribute of pharmaceutical products. The reliability of particle quantitation increases with the number of particles in the analyzed sample volume. However, for analyses of low-volume drug products, such as ophthalmic products for intravitreal injection, or biopharmaceuticals in general, sample volumes as small as possible should be used to avoid pooling and consequently, the contamination with foreign particles. The aim of our study was to evaluate the variability of particle concentrations obtained by light obscuration measurements in order to define the minimum required analyzed sample volume to achieve statistically meaningful results by using conditions that are practically feasible. Statistical evaluation suggests that for particle concentrations close to a pre-defined limit, large sample volumes (a multiple of typical intravitreal product volumes) would be required for a high probability to correctly classify samples with respect to the pre-defined limit. Below a minimum analyzed volume, even a measurement result of 0 particles does not allow to conclude compliance with the respective particle concentration limit with sufficient certainty. A small analyzed volume could be justified as long as the measurement uncertainty remains acceptable compared to the pre-defined limit.
       
  • Characterization of Subvisible Particles in Biotherapeutic Pre-Filled
           Syringes: The Role of Polysorbate and Protein on the Formation of Silicone
           Oil and Protein Subvisible Particles After Drop Shock
    • Abstract: Publication date: Available online 2 November 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Nancy Jiao, Gregory V. Barnett, Twinkle R. Christian, Linda O. Narhi, Nathan H. Joh, Marisa K. Joubert, Shawn Cao Subvisible particles (SbVP) are a critical quality attribute for biotherapeutics. Particle content in pre-filled syringes (PFS) of a biotherapeutic can include protein particles and silicone oil particles (SiOP). Here, a real-world protein therapeutic PFS shows that although polysorbate is effective in preventing protein particle formation, it also leads to the formation of SiOP. PFS of protein and buffer formulations in the presence and absence of polysorbate are subjected to a drop shock to generate SbVP and the effect of polysorbate and protein in generating SbVP is investigated. Particle characterization by light obscuration and flow imaging shows that polysorbate prevents protein particle formation as intended, but the presence of polysorbate substantially increases the formation of SiOP. The protein itself also acts as a surfactant and leads to increased SiOP, but to a lesser degree compared to polysorbate. In a separate study, the risk of immunogenicity was assessed using in-vivo and in-vitro models (Joh, N.H. et. al. Silicone Oil Particles in Antibody Drug Product Formulations Did Not Increase Immunogenicity in In Vivo and In Vitro Model Systems, J Pharm Sci). Flow imaging distinguishes between SiOP and protein particles and enables risk assessment of the natures of different SbVP in pre-filled syringes.
       
  • Orthogonal techniques to study the effect of pH, sucrose and arginine
           salts on monoclonal antibody physical stability and aggregation during
           long-term storage
    • Abstract: Publication date: Available online 2 November 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Hristo L. Svilenov, Alina Kulakova, Matja Zalar, Alexander P. Golovanov, Pernille Harris, Gerhard Winter Understanding the effects of additives on therapeutic protein stability is of paramount importance for obtaining stable formulations. In this work, we apply several high- and medium-throughput methods to study the physical stability of a model monoclonal antibody at pH 5.0 and 6.5 in the presence of sucrose, arginine hydrochloride and arginine glutamate. In low ionic strength buffer, the addition of salts reduces the antibody colloidal and thermal stability, attributed to screening of electrostatic interactions. The presence of glutamate ion in the arginine salt partially reduces the damaging effect of ionic strength increase. The addition of 280 mM sucrose shifts the thermal protein unfolding to a higher temperature. Arginine salts in the used concentration reduce the relative monomer yield after refolding from urea, while sucrose has a favorable effect on antibody refolding. In addition, we show 12-month long-term stability data and observe correlations between thermal protein stability, relative monomer yield after refolding and monomer loss during storage. The monomer loss during storage is related to protein aggregation and formation of subvisible particles in some of the formulations. This study shows that the effect of commonly used additives on the long-term antibody physical stability can be predicted using orthogonal biophysical measurements.
       
  • Presentation of HIV-1 Env trimers on the surface of silica nanoparticles
    • Abstract: Publication date: Available online 1 November 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Stefanie Thalhauser, David Peterhoff, Ralf Wagner, Miriam Breunig Inducing immune responses protecting from HIV infection or at least controlling replication poses a huge challenge to modern vaccinology. An increasingly discussed strategy to elicit a potent and broad neutralizing antibody response is the immobilization of HIV’s trimeric envelope (Env) surface receptor on a nanoparticulate carrier. As a conceptual proof, we attached an Env variant (BG505 SOSIP.664) to highly stable and biocompatible silica nanoparticles (SiNPs) via site-specific covalent conjugation or non-specific adsorption to SiNPs. Firstly, we demonstrated the feasibility of SiNPs as platform for Env presentation by a thorough characterization process during which Env density, attachment stability, and antigenicity were evaluated for both formulations. Binding affinities to selected antibodies were in the low nanomolar range for both formulations confirming that the structural integrity of Env is retained after attachment. Secondly, we explored the recognition of SiNP conjugates by antigen presenting cells. Here, the uptake of Env attached to SiNPs via a site-specific covalent conjugation was 4.5-fold enhanced, while adsorbed Env resulted only in a moderate 1.4-fold increase compared to Env in its soluble form. Thus, we propose SiNPs with site-specifically and covalently conjugated Env preferably in a high density as a promising candidate for further investigations as vaccine platform.
       
  • Mechanistic insights of the critical role of hydrogen donor in controlling
           drug release from acrylate adhesive.
    • Abstract: Publication date: Available online 1 November 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Zheng Luo, Chao Liu, Peng Zhang, Peng Quan, Xingzhong Cao, Liang Fang In the present study, a pyrrolidone adhesive and an amide adhesive were synthesized, and their molecular mechanisms of controlled drug release were described. Using zolmitriptan as model drug, in vitro drug release and skin permeation experiments were performed. Adhesive properties were evaluated using modulated differential scanning calorimetry and rheology study. Free volume of polymer was directly obtained by positron annihilation lifetime spectroscopy. Intermolecular interactions between drugs and adhesives were determined by FT-IR spectroscopic analysis and molecular simulation. Release percent (24 h) of zolmitriptan from pyrrolidone adhesive was about 55.8 ± 3.1% (w/w), while from amide adhesive, the release percent (24 h) was about 40.1 ± 1.6% (w/w). The free volume sizes of pyrrolidone adhesive and amide adhesive were about 2309.6 Å3 and 2854.5 Å3, respectively, which were much larger than molecular volume of zolmitriptan (about 285.7 Å3). Thus, the polymer networks might not hinder drug diffusion from the view of free volume. Comparing chemical structures of pyrrolidone group and primary amide group, the main difference was that primary amide group of amide adhesive possessed two hydrogen donors. It was proved that hydrogen bonding between zolmitriptan and hydrogen donor of primary amide group played a critical role in controlling drug release.
       
  • Technical capabilities and limitations of optical spectroscopy and
           calorimetry using water-miscible solvents: The case of dimethyl sulfoxide,
           acetonitrile and 1,4-dioxane
    • Abstract: Publication date: Available online 1 November 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Atsushi Hirano, Satoru Nagatoishi, Momoyo Wada, Kouhei Tsumoto, Karl N. Maluf, Tsutomu Arakawa In drug development, water-miscible solvents are commonly used to dissolve drug substances. Typical routine procedures in drug development include dilution of the stock drug solution into an aqueous solution containing target macromolecules for drug binding assays. However, water-miscible solvents impose some technical limitations on the assays because of their light absorption and heat capacity. Here, we examined the effects of the dilution of three water-miscible solvents, i.e., dimethyl sulfoxide (DMSO), acetonitrile, and 1,4-dioxane, on the baseline stability and signal/noise ratio in circular dichroism (CD) spectroscopy, isothermal titration calorimetry (ITC) and differential scanning calorimetry (DSC). DMSO and 1,4-dioxane affect the signal/noise ratio of CD spectra at typically used concentrations due to their light absorbance. The water-miscible solvents generate interfering signals in the ITC due to their mixing heat. They show negative or positive slope in the DSC. Such interfering effects of the solvents are reduced by appropriate dilution according to the analytical techniques. Because the water-miscible solvents have solubilization capacity for alkyl chain moieties and aromatic moieties of chemicals, drug substances containing these moieties can be dissolved into the solvents and then subjected to the analyses to examine their interactions with target proteins after appropriate dilution of the drug solutions.
       
  • Identification of formaldehyde-induced modifications in diphtheria toxin
    • Abstract: Publication date: Available online 31 October 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Bernard Metz, Thomas Michiels, Joost Uittenbogaard, Maarten Danial, Wichard Tilstra, Hugo D. Meiring, Wim E. Hennink, Daan J.A. Crommelin, Gideon F.A. Kersten, Wim Jiskoot Diphtheria toxoid is produced by detoxification of diphtheria toxin with formaldehyde. This study was performed to elucidate the chemical nature and location of formaldehyde-induced modifications in diphtheria toxoid. Diphtheria toxin was chemically modified using four different reactions with the following reagents: (1) formaldehyde and NaCNBH3, (2) formaldehyde, (3) formaldehyde and NaCNBH3 followed by formaldehyde and glycine, and (4) formaldehyde and glycine. The modifications were studied by SDS-PAGE, primary amino group determination and LC-MS of chymotryptic digests. Reaction 1 resulted in quantitative dimethylation of all lysine residues. Reaction 2 caused intramolecular cross-links, including the NAD+-binding cavity and the receptor-binding site. Moreover, A-fragments and B-fragments were cross-linked by formaldehyde on part of the diphtheria toxoid molecules. Reaction 3 resulted in formaldehyde-glycine attachments, including in shielded areas of the protein. The detoxification reaction typically used for vaccine preparation (reaction 4) resulted in a combination of intramolecular cross-links and formaldehyde-glycine attachments. Both the NAD+-binding cavity and the receptor-binding site of diphtheria toxin were chemically modified. Although CD4+ T-cell epitopes were affected to some extent, one universal CD4+ T-cell epitope remained almost completely unaltered by the treatment with formaldehyde and glycine.
       
  • Unique impacts of methionine oxidation, tryptophan oxidation and
           asparagine deamidation on antibody stability and aggregation
    • Abstract: Publication date: Available online 31 October 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Magfur E. Alam, Thomas R. Slaney, Lina Wu, Tapan K. Das, Sambit Kar, Gregory V. Barnett, Anthony Leone, Peter M. Tessier Monoclonal antibodies are attractive therapeutic agents because of their impressive biological activities and favorable biophysical properties. Nevertheless, antibodies are susceptible to various types of chemical modifications, and the impact of such modifications on antibody physical stability and aggregation remains understudied. Here we report a systematic analysis of the impact of methionine oxidation, tryptophan oxidation and asparagine deamidation on antibody conformational and colloidal stability, hydrophobicity, solubility and aggregation. Interestingly, we find little correlation between the impact of these chemical modifications on antibody conformational stability and aggregation. Methionine oxidation leads to significant reductions in antibody conformational stability while having little impact on antibody aggregation except at extreme conditions (low pH and elevated temperature). Conversely, tryptophan oxidation and asparagine deamidation have little impact on antibody conformational stability while promoting aggregation at a wide range of solution conditions, and the aggregation mechanisms appear linked to unique types of reducible and non-reducible covalent crosslinks and, in some cases, to increased levels of attractive colloidal interactions. These findings highlight that even related types of chemical modifications can lead to dissimilar antibody aggregation mechanisms, and evaluating these findings for additional antibodies will be important for improving the systematic generation of antibodies with high chemical and physical stability.
       
  • Development of freeze-drying cycles for pharmaceutical products using a
           micro freeze-dryer
    • Abstract: Publication date: Available online 31 October 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Davide Fissore, Maite Harguindeguy, Daniela Velez Ramirez, Taylor N. Thompson This paper aims to investigate how a small-scale freeze-dryer can be used for process design. The system encompasses a temperature controlled metallic ring that surrounds a small batch of vials, in contact with the external vials through removable thermal conductors. The temperature of the ring can be modified to keep a constant difference with the temperature of one or more vials of the batch. In this paper an extensive validation of the system is given, considering 10% w/w sucrose and 5% w/w mannitol solutions, processed in different types of vials (6 R and 20 R) and in different operating conditions. The micro freeze-dryer was also shown to be able to provide accurate estimates of the overall heat transfer coefficient from the shelf to the product in the vials (Kv) and of the resistance of the dried cake to vapor flux (Rp): both values appeared to be very close to those obtained for the same case studies in a pilot-scale unit. Finally, the use of the micro freeze-dryer to control product temperature and drying time values to simulate a pilot-scale unit was addressed, thus demonstrating the adequacy of this system for process scale-up.
       
  • Mechanical Shock During Shipping of Medications: the Roles of Packaging
           and Transportation Vendors
    • Abstract: Publication date: Available online 31 October 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Dill SL, Brees K, Stahly A, Cheng E, Carpenter J, Caplan L Protein-based medications are expensive and susceptible to damage from mechanical shock, which may occur during shipping to patients from pharmacies. Our objectives were to evaluate the performance of two packaging systems and to describe the mechanical shock that occurs during shipments. The packaging systems evaluated were boxes containing expanded polystyrene (EPS) or soft lint-like foam, prepared with and without polymer cooling packs. In lab-based studies, accelerometers measured g forces in boxes dropped from varying heights. Transportation studies evaluated the EPS cooler when sent to locations via two vendors. The relationship between drop height and maximum force vector was approximately linear for drop heights of 7.5” through 30”, with lower magnitude forces at 45” and 60”. Soft foam reduced force by 9.8g on average compared to EPS (p
       
  • Trehalose or sucrose; which of the two should be used for stabilizing
           proteins in the solid state' A dilemma investigated by in-situ
           micro-Raman and dielectric relaxation spectroscopies during and after
           freeze-drying
    • Abstract: Publication date: Available online 31 October 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Tatiana Starciuc, Benjamin Malfait, Florence Danede, Laurent Paccou, Yannick Guinet, Natalia T. Correia, Alain Hedoux The bioprotective properties of two disaccharides (sucrose and trehalose) were analyzed during the freeze drying (FD) process and at the end of the process, in order to better understand the stabilization mechanisms of proteins in the solid state. In-situ Raman investigations, performed during the FD process have revealed that sucrose was more efficient than trehalose for preserving the secondary structure of lysozyme during FD, especially during the primary drying stage. The lower bioprotective effect of trehalose, was interpreted as a consequence of a stronger affinity of this disaccharide to water, responsible for a severe phase separation phenomenon during the freezing stage. Dielectric spectroscopy investigations on the dried state of protein formulations have shown the capabilities of trehalose assisted by residual water to reduce the molecular mobility of the vitreous matrix, suggesting that trehalose is more efficient to preserve the protein structure during long-term storage.
       
  • Insight from molecular dynamics simulations on the crystallization
           tendency of indomethacin polymorphs in the undercooled liquid state
    • Abstract: Publication date: Available online 31 October 2019Source: Journal of Pharmaceutical SciencesAuthor(s): J. Gerges, F. Affouard The crystallization tendency of two crystalline polymorphs of indomethacin (Iα, Iγ) in the undercooled melt has been investigated using molecular dynamics (MD) simulations. The main thermodynamical and dynamical physical parameters involved in the nucleation and growth processes have been determined. A careful attention has been given to the crystal-liquid interfacial free energy which remains really challenging to determine from experiments. The present work particularly sheds the light on the importance of the interplay between the solid-liquid interfacial free energy and the driving force for crystallization. The nucleation and the growth rates have been also estimated in the framework of the classical nucleation theory (CNT) and some growth modes (normal mode, two-dimensional nucleation, and screw dislocation).
       
  • Accelerated Aggregation Studies of Monoclonal Antibodies: Considerations
           for Storage Stability
    • Abstract: Publication date: Available online 30 October 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Ruben Wälchli, Pieter-Jan Vermeire, Jan Massant, Paolo Arosio Aggregation of monoclonal antibodies is a crucial concern with respect to their safety and efficacy. Among the various properties of protein aggregates, it is emerging that their size can potentially impact their immunogenicity. Therefore, stability studies of antibody formulations should not only evaluate the rate of monomer loss but also determine the size distribution of the protein aggregates, which, in turn, depends on the aggregation mechanisms.Here, we study the aggregation behavior of different formulations of two monoclonal immunoglobulins (IgGs) in the temperature range from 5°C to 50°C over 52 weeks of storage. We show that the aggregation kinetics of both antibodies follow non-Arrhenius behavior and that the aggregation mechanisms change between 40°C and 5°C, leading to different types of aggregates. Specifically, for a given monomer conversion, dimer formation dominates at low temperatures, while larger aggregates are formed at higher temperatures. We further show that the stability ranking of different molecules as well as of different formulations is drastically different at 40°C and 5°C while it correlates better between 30°C and 5°C.Our findings have implications for the level of information provided by accelerated aggregation studies with respect to protein stability under storage conditions.
       
  • The molecular interaction process
    • Abstract: Publication date: Available online 30 October 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Thomas M. Laue, Steven J. Shire Noncovalent molecular interactions, which are central to life, are thermodynamic processes that follow common interaction pathways. This commentary provides a foundation both for considering non-covalent interactions and the interplay between the protein properties and the solvent properties in determining the energetics. In biopharmaceutics non-covalent interactions are a two-edged sword. Foremost, they provide a core function for biopharmaceutical agents, binding to targets, substrates or receptors. At the same time, they are at the root of the solubility and viscosity difficulties encountered in the manufacture, formulation and delivery of protein-based pharmaceuticals. This commentary describes the interaction process and summarizes the energetics of the interaction pathway. The focus will be on protein-protein interactions, while recognizing that the processes and energetics are entirely general and applicable to all solution interactions. The contributions of protein molecular properties and protein colloidal properties to the pathway are described, and the relationship between the two is developed. The processes leading to protein-protein binding are described with respect to the attractive interactions that lead to aggregation and high viscosity. The concept of emergent heterogeneity is introduced, and a model presented for how non-contacting interactions may lead to high viscosities without simultaneously causing low solubility.
       
  • Fcγ Receptor Activation by Human Monoclonal Antibody Aggregates
    • Abstract: Publication date: Available online 30 October 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Minoru Tada, Michihiko Aoyama, Akiko Ishii-Watabe Protein aggregates are a potential risk factor for immunogenicity. The measurement, characterization, and control of protein aggregates in drug products are indispensable for the development of biopharmaceuticals, including therapeutic monoclonal antibodies (mAbs). In this study, Fcγ receptor (FcγR)-expressing reporter cell lines were used to analyze the FcγR-activation properties of mAb aggregates. Comparison of aggregates of mAbs harboring different IgG subclasses revealed that the FcγR-activation profiles of the mAb aggregates were dependent on IgG subclass. In addition, aggregates of Fc-engineered mAb with enhanced FcγR-activation properties exhibited stronger activation of FcγRs than was observed in the wild type aggregates, whereas aggregates of Fc-engineered mAb with decreased FcγR-activation properties showed reduced activation. These results suggest that FcγR activation by mAb aggregates depends greatly on the Fc functions of the native (non-aggregated) mAbs. We also showed that aggregates of mAbs smaller than 1 μm in size have the potential to directly activate FcγRs. Unintended immune cell activation can be induced due to FcγR activation by mAb aggregates and such FcγR activation may contribute to immunogenicity, and therefore analysis of the FcγR-activation properties of mAb aggregates using FcγR-expressing reporter cell lines is a promising approach for the characterization of mAb aggregates.
       
  • Professors John F. Carpenter and Theodore W. Randolph: 2 Giants with a
           
    • Abstract: Publication date: Available online 30 October 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Brent S. Kendrick, Eva Y. Chi
       
  • A Wish List for Drug Development in Pediatrics
    • Abstract: Publication date: Available online 30 October 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Rachel Meyers This commentary illustrates and summarizes some of the many issues with dosage forms and drug delivery that arise in everyday practice for clinicians caring for pediatric patients. While advances in drug development for children and expansion of labeling information in this age group have made great strides in improving care, there is much to be desired in the area of dosage forms. From liquids that are unpalatable to the need for extemporaneous compounding of parenteral doses in syringes that are meant for immediate use but used to store medications for hours to weeks, the list of challenges is long. Many of these problems exist for drugs which have long been generic, but some problems have arisen from new drugs as well. Pediatric clinicians and dosage form developers should work together to create solutions.
       
  • Editorial
    • Abstract: Publication date: Available online 29 October 2019Source: Journal of Pharmaceutical SciencesAuthor(s): Ronald T. Borchardt
       
  • Univariate and Multivariate Models for Determination of Prasugrel Base in
           the Formulation of Prasugrel Hydrochloride Using XRPD Method
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Sathish Dharani, Sogra F. Barakh Ali, Hamideh Afrooz, Mansoor A. Khan, Ziyaur Rahman Prasugrel hydrochloride (PHCl) undergoes salt disproportionation, and the resulting prasugrel free base (PFB) may lead to the poor in vitro and or in vivo performance of the drug product. The aim of the present work was to develop univariate and multivariate models based on X-ray powder diffraction to quantify the salt and base in the powder and tablet formulations. Compositionally identical formulations of PHCl and PFB were prepared and mixed in various proportions to make 0%-30% PFB sample matrices. The formulations consisted of commonly used excipients, which are generally used in commercially available products. X-ray powder diffraction data were collected and subjected to the least square regression and partial least square regression analysis. The model performance parameters such as root mean squared and standard errors were low for univariate models compared to partial least square regression multivariate models. Model predicted values of the independent sample matrices by both methods matched closely with the actual values of PFB and PHCl. However, residual and standard deviation were low in univariate models predicted values. The models developed in this work have been shown to quantitate the PHCl disproportionation to PFB fraction in the drug product and provide a means to control the disproportionation of PHCl.
       
  • Erratum to “Skin Permeation Enhancement in Aqueous Solution: Correlation
           With Equilibrium Enhancer Concentration and Octanol/Water Partition
           Coefficient”
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s):
       
  • PKPD Assessment of the Anti-CD20 Antibody Obinutuzumab in Cynomolgus
           Monkey is Feasible Despite Marked Anti-Drug Antibody Response in This
           Species
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Hans Peter Grimm, Eginhard Schick, Dominik Hainzl, Nicole Justies, Li Yu, Christian Klein, Elisabeth Husar, Wolfgang F. Richter The pharmacokinetics (PK) of the anti-CD20 monoclonal antibody obinutuzumab was assessed after single intravenous dosing to cynomolgus monkeys. In addition, the pharmacokinetic-pharmacodynamic (PKPD) relationship for B-cell depletion was characterized. The PKPD model was used to estimate the B-cell repopulation during the recovery phase of chronic toxicology studies, thereby supporting the study design, in particular planning the recovery phase duration. Marked immunogenicity against obinutuzumab was observed approximately 10 days after single dose, leading to an up to ∼30-fold increase in obinutuzumab clearance in the affected monkeys. Despite this accelerated clearance, the PK could be characterized, either by disregarding the clearance in noncompartmental PK analysis or by capturing it explicitly as an additional time-dependent clearance process in compartmental modeling. This latter step was crucial to model the PKPD of B-cells as an indirect response to obinutuzumab exposure, showing that—without immune response—the limiting factor is obinutuzumab elimination with concentrations below 0.02 μg/mL required for initiation of B-cell recovery.Overall, the results demonstrate that despite a marked anti-drug antibody response in the nonclinical animal species, the PK and PKPD of obinutuzumab could be characterized successfully by appropriately addressing the immune-modulated clearance pathway in data analysis and modeling.
       
  • Integration of In Silico Pharmacokinetic Modeling Approaches Into
           In Vitro Dissolution Profiles to Predict Bioavailability of a Poorly
           Soluble Compound
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Takafumi Kato, Tomoyuki Watanabe, Koichi Nakamura, Shuichi Ando The objective of present study is to develop pharmacokinetic (PK) prediction methods using in silico PK model for oral immediate release drug products (i.e. solution, suspension, and amorphous solid dispersion). A poorly water soluble compound with low bioavailability in rat was used (CS-758 as a model compound). A constructed in silico PK model contained an advance compartmental absorption and transit model. For solution, the in silico PK model reproduced an observed rat plasma concentration (Cp)-time profile. In addition, an in vitro dissolution method was developed to predict a rat Cp-time profile for suspension. As a result, the in silico PK model could predict the observed one by using dissolution profiles as the input. Furthermore, a dissolution profile of amorphous solid dispersion was applied to verify the in silico PK model. A result indicated the simulated rat Cp-time profile was significantly comparable to the observed one. This study demonstrated that the integration of an in silico PK model into dissolution profiles can predict rat Cp-time profiles for suspension and amorphous solid dispersion. These results suggest that the integration of in silico PK modeling approaches into dissolution profiles can contribute to the formulation screening for poorly soluble compounds by predicting PK behaviors.
       
  • 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: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(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 monomodal pattern. When H2O2 was added, size distribution was changed to multimodal pattern and morphological 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 photodynamic therapy efficacy in both B16F10 cells and CT26 cells. Especially, CD44-receptor blocking of cancer cells by pretreatment 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 have CD44 receptor–recognition properties.
       
  • αVβ3-Targeted Delivery of Camptothecin-Encapsulated Carbon
           Nanotube-Cyclic RGD in 2D and 3D Cancer Cell Culture
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Byumseok Koh, Sung Bum Park, Eunyoung Yoon, Hee Min Yoo, Dasol Lee, Jung-Nyoung Heo, Sunjoo Ahn Integrin αvβ3 is widely expressed in various types of human cancer lines and plays a key role in angiogenesis for tumor growth and metastasis. Delivery of therapeutics to αvβ3-expressing tumors can thus be a promising approach for treating cancer. For targeted delivery of anticancer therapeutics to αvβ3-expressing tumor cells, cyclic arginylglycylaspartic acid (RGD) peptide was covalently conjugated to the surface of carboxylic acid–functionalized carbon nanotubes (fCNTs), and the topoisomerase I inhibitor camptothecin (CPT) was encapsulated in the fCNTs (CPT@fCNT-RGD). CPT@fCNT-RGD was successfully delivered to αvβ3-expressing A375 cells, and compared with nontargeted CPT@fCNT, it provided 3.78- and 3.02-fold increases in the anticancer effect in 2D and 3D culture. Analysis of apoptosis-related gene expression shows that the expression levels of Bax, cleaved caspase-3, and nuclear factor kappa-light-chain-enhancer of activated B cells were significantly increased in A375 cells incubated with CPT@fCNT-RGD compared with those incubated with CPT@fCNT. These results suggest that cyclic RGD-conjugated CNTs encapsulating an anticancer therapeutic can be a promising platform for treating cancer.
       
  • Development of Hydrogels for Microneedle-Assisted Transdermal Delivery of
           Naloxone for Opioid-Induced Pruritus
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(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 because of 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% cross-linked 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 setup. 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.
       
  • AS1411 Aptamer/Hyaluronic Acid-Bifunctionalized Microemulsion Co-Loading
           Shikonin and Docetaxel for Enhanced Antiglioma Therapy
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(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 blood-brain barrier 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 luciferase-transfected U87 glioma tumor–bearing nude mice. Importantly, AS1411/SKN&DTX-M exhibited the overwhelming inhibition of glioma growth of orthotopic luciferase-transfected U87 glioma models and reached the longest survival period among all the treatments. In summary, the codelivery of shikonin and docetaxel using bifunctionalization with hyaluronic acid and AS1411 aptamer offers a promising strategy for dual drug-based combinational antiglioma treatment.
       
  • Determination of the Structural Relaxation Enthalpy Using a Mathematical
           Approach
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(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 with 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.
       
  • Lysozyme Mucoadhesive Tablets Obtained by Freeze-Drying
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(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 because of saliva swallowing and of 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 hydroxypropyl methylcellulose (HPMC) (i.e., E5, E50, or K100). The tablets were characterized in terms of swelling or erosion behavior, in vitro mucoadhesive properties, lysozyme activity (Micrococcus lysodeikticus), drug release and ability to inactivate Staphylococcus aureus. The formulations prepared with HPMC K100 were discarded because of the fast erosion. All other formulations allowed a sustained release over at least 6 h. Independently of composition, lysozyme activity (78,311 ± 1873 Units/mg) significantly decreased in the case of tablets containing 5% and 10% w/w of protein (55,000 Units/mg and 33,000 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.
       
  • Effect of Spray-Dried Particle Morphology on Mechanical and Flow
           Properties of Felodipine in PVP VA Amorphous Solid Dispersions
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(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. Although 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, spray-drying atomization and drying conditions were tuned to achieve 4 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, whereas mechanical property tests suggested all samples will produce strong tablets at reasonable solid fractions and compression pressures. In addition, Hiestand dynamic tableting indices showed excellent dynamic bonding for 3 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.
       
  • Transdermal Delivery of Sumatriptan Succinate Using Iontophoresis and
           Dissolving Microneedles
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): James Paul Ronnander, Laurent Simon, Andreas Koch This study focuses on the in vitro transdermal transport of sumatriptan succinate using combined iontophoresis and dissolving polymeric microneedle arrays. Permeation experiments were performed to evaluate the effects of formulation parameters on drug release from polyvinylpyrrolidone systems under mild electrical current (≤500 μA/cm2). The preparations consisted of hydrophilic, positively charged molecules encapsulated in a water-soluble and biocompatible polymeric material. Current densities of 100, 300, and 500 μA/cm2 were applied during a 6-h period using silver/silver chloride electrodes. The circular array consisted of 600 needles and occupied a 0.785 cm2 area. Tests, carried out with Franz diffusion cells and skin of Göttingen minipigs, showed that small decreases in the polymer concentration led to negligible lag times and marked increases in the cumulative amount of drug permeated in 6 h (Q6h) and in the flux (Jss). At 500 μA/cm2, Q6h and Jss nearly doubled for a microneedle loaded with 5% (w/w) sumatriptan and 20% (w/w) PVP (lag time = 0 min; Q6h = 2888 μg/cm2; Jss = 490 μg/cm2/h) relative to a system loaded with 5% (w/w) drug and 30% (w/w) PVP (lag time = 36 min; Q6h = 1437 μg/cm2; Jss = 266 μg/cm2/h).
       
  • Anionic Surfactant–Induced Changes in Skin Permeability
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Stephanie A.V. Morris, Kavssery P. Ananthapadmanabhan, Gerald B. Kasting Anionic surfactants compromise skin's barrier function by damaging stratum corneum lipids and proteins. The objective of this study was to examine anionic surfactant–induced changes in the skin's polar and transcellular pathways and the resulting impact on surfactant penetration into the skin. Three anionic surfactant formulations and one control formulation were each applied to split-thickness human cadaver skin in vitro for 24 h. Electrical conductivity of the skin, determined using a four-terminal resistance method, and water permeation across the skin, determined using a radiolabeled water tracer, were simultaneously measured at several points over the experimental period. Surfactant permeation across the skin was similarly measured using a radiolabeled sodium dodecyl sulfate tracer. Anionic surfactants rapidly enhanced skin electrical conductivity and water permeability in the excised human skin, resulting in nonlinear enhancements in surfactant permeation across the skin over time. Surfactant penetration into the skin was found to increase linearly with increasing surfactant monomer concentration. Surfactant zeta potential was found to correlate well with skin conductivity, water permeation across the skin, and surfactant permeation across the skin, particularly with long surfactant exposures. Micelle charge is a significant predictor of anionic surfactant–induced damage to the human skin, with more highly charged surfactants inducing the most damage.
       
  • Constructing an In Silico Three-Class Predictor of Human Intestinal
           Absorption With Caco-2 Permeability and Dried-DMSO Solubility
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Tsuyoshi Esaki, Rikiya Ohashi, Reiko Watanabe, Yayoi Natsume-Kitatani, Hitoshi Kawashima, Chioko Nagao, Hiroshi Komura, Kenji Mizuguchi Absorption of drugs is the first step after dosing, and it largely affects drug bioavailability. Hence, estimating the fraction of absorption (Fa) in humans is important in the early stages of drug discovery. To achieve correct exclusion of low Fa compounds and retention of potential compounds, we developed a freely available model to classify compounds into 3 levels of Fa capacity using only the chemical structure. To improve Fa prediction, we added predicted binary classification results of membrane permeability measured using Caco-2 cell line (Papp) and dried–dimethyl sulfoxide solubility (accuracy, 0.836; kappa, 0.560). The constructed models can be accessed via a web application.
       
  • Effect of Glyceryl Monocaprylate–Modified Chitosan on the Intranasal
           Absorption of Insulin in Rats
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Mingyue Gao, Ying Sun, Yongqiang Kou, Xin Shen, Yingnan Huo, Chang Liu, Zheng Sun, Xin Zhang, Shirui Mao Nasal administration of insulin showed the attractive potential to improve the compliance of diabetic patients and alleviate mild cognitive impairment of Alzheimer's patients. However, the nasal absorption of insulin was not ideal, limiting its therapeutic effect in clinic. This study was to explore the potential of glyceryl monocaprylate–modified chitosan (CS-GMC) on the intranasal absorption of insulin via in vivo pharmacodynamic experiment in conscious rats. It was demonstrated that the absorption-enhancing effect of CS-GMC depended on the existing state of insulin in the formulation, substitution degree of GMC on chitosan and concentration of CS-GMC. Better insulin absorption was achieved when insulin existed in molecular form compared with that in polyelectrolyte complexes. CS-GMC with substitution degree 12% (CS-GMC 12%) was a preferred absorption enhancer, and its absorption enhancing effect increased linearly with the increment of its concentration in the range investigated. Compared with chitosan of the same concentration, CS-GMC12% showed remarkably enhanced and prolonged therapeutic effect up to at least 5 h under the concentration of 0.6% (w/v). CS-GMC12% showed almost no ciliotoxicity to the nasal cilia up to concentration 1.0% (w/v). In conclusion, CS-GMC was a promising absorption enhancer to improve the intranasal absorption of insulin.
       
  • Identifying, Characterizing, and Understanding Nefiracetam in Its Solid
           State Forms: A Potential Antidementia Drug
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Xavier Buol, Koen Robeyns, Nikolay Tumanov, Johan Wouters, Tom Leyssens In this work, 3 hitherto unidentified solid state forms of the nootropic drug Nefiracetam are identified: a monohydrate and 2 polymorphic phases of the anhydrate. These new forms were investigated from a structural and thermodynamic point of view to evaluate the possibility of using these forms in alternative formulations. Furthermore, their dissolution rate and solubility were compared.
       
  • Mechanism and Impact of Excipient Incompatibility: Cross-Linking of
           Xanthan Gum in Pediatric Powder-for-Suspension Formulations
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Yongjun Li, Dan Zhang, Jason Ash, Xiujuan Jia, Anthony Leone, Allen Templeton Research on pharmaceutical pediatric powder-for-suspension formulations mainly focuses on chemical and physical stability of the active pharmaceutical ingredient. However, the chemical stability of excipients could also play a key role in governing the quality and performance of the product. The suspending agents that are added into formulations to suspend the active pharmaceutical ingredient particles are critical to ensure the suspension dose accuracy. In this article, we investigate the chemical stability of the suspending agent—xanthan gum—in the presence of other excipients, particularly commonly used acid modifiers (i.e., citric acid, malic acid, succinic acid, and fumaric acid) in pediatric powder-for-suspension formulations. We observed that some of the acid modifiers catalyze cross-linking of xanthan gum during accelerated stability studies in powder blends, which significantly decreases the viscosity of the corresponding constituted suspension, resulting in poor suspendability and dose inaccuracy. Furthermore, we found that the cross-linking of xanthan gum is acid-dependent and that a careful selection of acid modifiers can mitigate the degradation issues of xanthan gum. Finally, we characterized the cross-linked xanthan gum using Fourier transform infrared spectroscopy and solid-state nuclear magnetic resonance and discussed the possible degradation mechanisms.
       
  • A Self-Nanoemulsifying Drug Delivery System for Enhancing the Oral
           Bioavailability of Candesartan Cilexetil: Ex Vivo and In Vivo Evaluation
           
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Khaled AboulFotouh, Ayat A. Allam, Mahmoud El-Badry, Ahmed M. El-Sayed The drug delivery of candesartan cilexetil encounters an obstacle of low absolute oral bioavailability which is attributed mainly to its low aqueous solubility and efflux by intestinal P-glycoprotein (P-gp) transporters. However, the extent of P-gp contribution in the reduced oral bioavailability of candesartan cilexetil is not clear. In this study, a previously developed candesartan cilexetil–loaded self-nanoemulsifying drug delivery system (SNEDDS) was evaluated for its ability to increase the drug oral bioavailability via the inhibition of intestinal P-gp transporters. Despite the developed SNEDDS showing P-gp inhibition activity, P-gp–mediated efflux was found to have a minor role in the reduced oral bioavailability of candesartan cilexetil. On the other hand, the high surfactant concentration used in SNEDDS formulation represents a major challenge toward their widespread application especially for chronically administered drugs. The designed acute and subacute toxicity studies revealed that the degree of intestinal mucosal damage decreases as the treatment period increases. The latter observation was attributed to the reversibility of surfactant-induced mucosal damage. Thus, the developed SNEDDS could be considered as a promising delivery system for enhancing the oral bioavailability of chronically administered drugs.
       
  • α1-Acid Glycoprotein Has the Potential to Serve as a Biomimetic Drug
           Delivery Carrier for Anticancer Agents
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Kotaro Matsusaka, Yu Ishima, Hitoshi Maeda, Ryo Kinoshita, Shota Ichimizu, Kazuaki Taguchi, Victor Tuan Giam Chuang, Koji Nishi, Keishi Yamasaki, Masaki Otagiri, Hiroshi Watanabe, Toru Maruyama Nanosize plasma proteins could be used as a biomimetic drug delivery system (DDS) for cancer treatment when loaded with anticancer drugs based on the fact that plasma proteins can serve as a source of nutrients for cancer cells. This prompted us to investigate the potential of α1-acid glycoprotein (AGP) for this role because it is a nanosize plasma protein and binds a variety of anticancer agents. Pharmacokinetic analyses indicated that AGP is distributed more extensively in tumor tissue than human serum albumin, which was already established as a cancer DDS carrier. AGP is possibly being incorporated into tumor cells via endocytosis pathways. Moreover, a synthetic AGP-derived peptide which possesses a high ability to form an α-helix, as deduced from the primary structure of AGP, was also taken up by the tumor cells. AGP loaded with anticancer agents, such as paclitaxel or nitric oxide, efficiently induced tumor cell death. These results suggest that AGP has the potential to be a novel DDS carrier for anticancer agents.
       
  • Data-Driven Development of Predictive Models for Sustained Drug Release
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Stijn H.S. Koshari, Debby P. Chang, Nathan B. Wang, Isidro E. Zarraga, Karthikan Rajagopal, Abraham M. Lenhoff, Norman J. Wagner Mathematical modeling of drug release can aid in the design and development of sustained delivery systems, but the parameter estimation of such models is challenging owing to the nonlinear mathematical structure and complexity and interdependency of the physical processes considered. Highly parameterized models often lead to overfitting, strong parameter correlations, and as a consequence, inaccurate model predictions for systems not explicitly part of the fitting database. Here, we show that an efficient stochastic optimization algorithm can be used not only to find robust estimates of global minima to such complex problems but also to generate metadata that allow quantitative evaluation of parameter sensitivity and correlation, which can be used for further model refinement and development. A practical methodology is described through the analysis of a predictive drug release model on published experimental data sets. The model is then used to design a zeroth-order release profile in an experimental system consisting of an antibody fragment in a poly(lactic-co-glycolic acid) solvent depot, which is validated experimentally. This approach allows rational decision-making when developing new models, selecting models for a specific application, or designing formulations for experimental trials.
       
  • Applying Two Orthogonal Methods to Assess Accuracy of Plasma Protein
           Binding Measurements for Highly Bound Compounds
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(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, 2 orthogonal methods, equilibrium dialysis and ultracentrifugation, are assessed in this study to measure PPB of 10 highly bound drugs (fu < 0.01). The results show that the 2 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.
       
  • Nuances in the Calculation of Amorphous Solubility Enhancement Ratio
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Arushi Manchanda, Mary S. Kleppe, Robin H. Bogner The theoretical amorphous solubility enhancement ratio (Rs) can be calculated based on the free energy difference between amorphous and crystalline forms (ΔGx→a), using several experimentally determined input parameters. This work compares the various approaches for the calculation of Rs and explores the nuances associated with its calculation. The uncertainty of Rs values owing to experimental conditions (differential scanning calorimetry heating rates) used to measure the input parameters was determined for 3 drugs (indomethacin, itraconazole, and spironolactone). The calculated value of Rs was most influenced by the measurement of heat of fusion. The range in values of Rs using the various equations in the literature was within the calculated uncertainty of the theoretical Rs value. Still, all equations appear to overpredict the experimental value of Rs, sometimes by more than a factor of 5, when an experimental value is attainable. Methods for the calculation of ΔGx→a for molecules undergoing additional phase transitions (other than glass transition and melting) were developed, employing itraconazole as a model drug. In addition, the influences of enthalpy relaxation and entropy of mixing for racemic compounds on Rs were also considered. These additional corrections improved agreement between theoretical and experimental Rs.
       
  • Novel Biomimetic Reconstituted Built-in Adjuvanted Hepatitis B Vaccine for
           Transcutaneous Immunization
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Monika Kaurav, Rajendra Kumar, Atul Jain, Ravi Shankar Pandey Transcutaneous immunization is the administration of a vaccine on the skin to generate efficient systemic and mucosal immune responses against an antigen. In the present study, reconstituted hepatitis B surface antigen vesicles (HBsAg-REVs) integrated with monophosphoryl lipid A were prepared by the delipidation-reconstitution method and tested as built-in adjuvanted vaccine, system for transcutaneous immunization using a combined approach of tape strippings, and enhanced antigen skin contact time. Prepared vesicles were extensively characterized for size, shape, zeta potential, and antigen protein loading efficiency. Following topical application, HBsAg-REVs skin permeation on isolated rat skin and cell uptake by bone marrow–derived dendritic cells were determined by confocal laser scanning microscopy and flow cytometry, respectively. The humoral and cellular immune responses elicited by HBsAg-REVs via transcutaneous immunization were comparable to the marketed intramuscular hepatitis B vaccine formulation with predefined immunization protocols. This study supports that delivery of reconstituted HBsAg vesicles via transcutaneous route may open a new vista for designing topical vaccines with possible immune protection against hepatitis B in future.
       
  • An Automated and Qualified Platform Method for Site-Specific Succinimide
           and Deamidation Quantitation Using Low-pH Peptide Mapping
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Mingyan Cao, Weichen Xu, Ben Niu, Ivy Kabundi, Haibin Luo, Meagan Prophet, Weimin Chen, Dengfeng Liu, Sergei V. Saveliev, Marjeta Urh, Jihong Wang mAbs undergo several post-translational modifications, including the formation of succinimide from the deamidation of asparagine or the isomerization of aspartic acid. Because of the potential impact of succinimide formation on the biological activity of mAbs, detection and quantification of this species is a key area of interest for the pharmaceutical industry. However, studies assessing succinimide stability have been limited, and methods developed to monitor succinimide are either product specific or not robust. Here, we report the development of a platform low-pH peptide-mapping method using a combination of low-pH-resistant Lys-C and modified trypsin to maintain succinimide stability, eliminate deamidation assay artifact, and achieve efficient mAb digestion equivalent to conventional tryptic peptide-mapping method under alkaline condition. Using this method, succinimide stability in serum was accurately assessed in vitro study and the half-life was determined to be 1.5 days. With potential patient exposure to succinimide intermediate, a reliable method was developed to measure site-specific deamidation and succinimide intermediate. Coupled with a single quadrupole mass detector, our method was automated from digestion to data processing and applicable in a good manufacturing practice environment. The method was fully qualified to demonstrate accuracy, precision, linearity, and robustness.
       
  • On-Chip Preparation of Amphiphilic Nanomicelles–in–Sodium Alginate
           Spheroids as a Novel Platform Against Triple-Negative Human Breast Cancer
           Cells: Fabrication, Study of Microfluidics Flow Hydrodynamics and Proof of
           Concept for Anticancer and Drug Delivery Applications
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Doaa Ragab, Sally Sabra, Ying Xia, David Goodale, Alison L. Allan, Sohrab Rohani Spheroidal microparticles versatility as a drug carrier makes it a real workhorse in drug delivery applications. Despite of their long history, few research publications emphasize on how to improve their potential targeting ability, production rate, and dissolution characteristics. The current research presents an example of the combined state of the art of nano- and microparticles development technologies. Here in a novel on-chip, microfluidics approach is developed for encapsulating amphiphilic nanomicelles–in–sodium alginate spheroid. The designed nano-in-micro drug delivery system revealed a superior cytotoxicity against triple-negative human breast cancer cell line (MDA-MB-231), besides, a more sustained release of the drug. Hydrodynamics of the designed microchip was also investigated as a function of different flow rates with an insight on the dimensionless numbers; capillary number and Weber number throughout the microchannels. Our study confirmed the efficient encapsulation of nanomicelles within the alginate shell. The current microfluidics approach can be efficiently applied for uniform production of nano-in-microparticles with potential anticancer capability.
       
  • Utility of Three-Dimensional Skin From Human-Induced Pluripotent Stem
           Cells as a Tool to Evaluate Transdermal Drug Permeation
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Chihiro Naito, Tomoko Yamaguchi, Hidemasa Katsumi, Suyo Kimura, Sachi Kamei, Masaki Morishita, Toshiyasu Sakane, Kenji Kawabata, Akira Yamamoto Transdermal drug delivery is an attractive route for administration of drugs, and it offers several advantages such as painless administration. To accurately predict the rate of human skin permeation for new transdermal drug formulations, we developed a novel assessment system using induced pluripotent stem cells (iPSCs). Skin was generated from iPSC-derived keratinocytes and fibroblasts. In the histological and immunohistochemical examination, cellular markers (keratin 14 and keratin 10) for the epidermal basal and suprabasal layers were clearly detected within the multilayer structures produced in the human iPSC-based three-dimensional skin model. The results from our permeation study indicate that an initial lag time exists during permeation of 5(6)-carboxyfluorescein and fluorescein isothiocyanate dextran 4000. Furthermore, the permeation for these model drugs in human iPSC-based skin was inversely proportional to the molecular weight of the drugs. These results of the present iPSC-based skin are useful basic information as a first step for developing a new assessment system to predict the efficacy of drug permeation in human skin by using iPSC-based skin.
       
  • Why We Need Continuous Pharmaceutical Manufacturing and How to Make It
           Happen
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Clive Badman, Charles L. Cooney, Alastair Florence, Konstantin Konstantinov, Markus Krumme, Salvatore Mascia, Moheb Nasr, Bernhardt L. Trout We make the case for why continuous pharmaceutical manufacturing is essential, what the barriers are, and how to overcome them. To overcome them, government action is needed in terms of tax incentives or regulatory incentives that affect time.
       
  • A Proposal for an Alternative Approach to Particle Size Method Development
           During Early-Stage Small Molecule Pharmaceutical Development
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(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 because of 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 definable characteristic. Accordingly, precision is then a measure of the ability to reproducibly achieve a measurement of unknown relevance.This article 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 CQA; that is, correlation should be demonstrated, without which the measured particle size cannot be defined as a critical material attribute.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.
       
  • Continuous Twin Screw Wet Granulation and Drying—Control Strategy for
           Drug Product Manufacturing
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Gabriella Dahlgren, Pirjo Tajarobi, Eric Simone, Brendon Ricart, Jason Melnick, Vibha Puri, Courtney Stanton, Gurjit Bajwa The use of continuous manufacturing has been increasing within the pharmaceutical industry over the last few years. Continuous direct compression has been the focus of publications on the topic to date. The use of wet granulation can improve segregation resistance, uniformity, enhance density, and flow properties for improved tabletability, or improve stability of products that cannot be manufactured by using a direction compression process. This article focuses on development of appropriate control strategies for continuous wet granulation (especially twin screw wet granulation) through equipment design, material properties and manufacturing process along with areas where additional understanding is required. The article also discusses the use of process analytical technologies as part of the control and automation approach to ensure a higher assurance of product quality. Increased understanding of continuous wet granulation should result in increased utilization of the technique, thereby allowing for an increase in diversity of products manufactured by continuous manufacturing and the benefits that comes with a more complex process such as wet granulation compared with direct compression process.
       
  • Development of Dexlansoprazole Delayed-Release Capsules, a Dual
           Delayed-Release Proton Pump Inhibitor
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Haiyan Grady, Yusuke Murakawa, Darcy Mulford, Michael Kukulka Proton pump inhibitors (PPIs) 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 use 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.
       
  • Refractive Index Measurement of Pharmaceutical Solids: A Review of
           Measurement Methods and Pharmaceutical Applications
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Shikhar Mohan, Eiji Kato, James K. Drennen, Carl A. Anderson Refractive index is an important optical parameter that can be used to characterize the physicochemical properties of pharmaceutical solids. The complexity of most drugs and solid oral dosage systems introduces challenges for refractive index measurement methods. These challenges are highlighted, and different types of measurement methods are discussed in this review article. These measurements provide pharmaceutical scientists the opportunity to improve the drug-development process and enhance product quality. Pharmaceutical applications range from identification and quantification of drug crystallinity and polymorphism to mechanical strength assessment of tablets. This review article surveys the literature and evaluates the current and potential future characterization of pharmaceutical solids using refractive index measurements.
       
  • Impact of Acid-Reducing Agents on Gastrointestinal Physiology and Design
           of Biorelevant Dissolution Tests to Reflect These Changes
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Domagoj Segregur, Talia Flanagan, James Mann, Andrea Moir, Eva M. Karlsson, Matthias Hoch, David Carlile, Sakina Sayah-Jeanne, Jennifer Dressman BackgroundOf the various drug therapies that influence gastrointestinal (GI) physiology, one of the most important are the acid-reducing agents (ARAs). Because changes in GI physiology often influence the pharmacokinetics of drugs given orally, there is a need to identify in vitro methods with which such effects can be elucidated.ObjectiveLiterature concerning the effects of ARAs (antacids, H2-receptor antagonists, and proton pump inhibitors [PPIs]) on GI physiology are reviewed with the aim of identifying conditions under which drugs are released after oral administration in the fasted state. In vitro dissolution tests to mimic the effects in the stomach were designed for H2-receptor antagonists and PPIs.ConclusionsThe impact of ARAs on GI physiology depends on the type, duration, and amount of ARA administered as well as the location in the GI tract, with greatest impact on gastric physiology. While ARAs have a high impact on the gastric fluid pH and composition, changes in volume, viscosity, surface tension, and gastric emptying appear to be less profound. The proposed dissolution tests enable a ready comparison between dosage form performance in healthy adults and those receiving PPIs or H2-receptor antagonists.
       
  • Editorial Advisory Board
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s):
       
  • Stability of Polymer Coatings on Nebulizer Membranes During Aerosol
           Generation
    • Abstract: Publication date: November 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 11Author(s): Moritz Beck-Broichsitter The dimensions of orifices found in aperture plates used 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 promoter. 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 nonconditioned (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 nonconditioned (no silane) membranes and thus confirmed the findings from laser diffraction. Overall, silane-based adhesion promoters can increase the persistence of poly(chloro-p-xylylene) coatings on nebulizer membranes during aerosol generation.
       
  • Forced Degradation of Monoclonal Antibodies After Compounding: Impact on
           Routine Hospital Quality Control
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Emmanuel Jaccoulet, Thomas Daniel, Patrice Prognon, Eric Caudron Compounded therapeutic mAbs used in a hospital require quality control (QC). In our hospital, analytical QC process intended to mAbs identification and quantification is based on flow injection analysis associated with second-derivative UV spectroscopy and matching method algorithm. We studied the influence of degraded mAbs after compounding on this validated QC. Three forced stress conditions including mechanical, thermal, and freeze-thawing stresses were studied to yield degraded mAbs from 2 model compounds, that is, bevacizumab (IgG1) and nivolumab (IgG4). Different degraded mAbs were generated and were analyzed in terms of turbidity, the percentage of aggregation, size distribution, and changes in tertiary structure. Stresses showed to be mAb-dependent in terms of aggregation. Tertiary structural changes were observed in most of the stressed samples by principal component analysis of the UV second-derivative data. The structural and physicochemical modifications conducted to mismatch depending on the nature of the stress. The mismatch ranged from 17% to 72% for the mAbs, except for freeze-thawed bevacizumab for which a perfect match (100%) was reached. The quantification with an unfulfilled relative error of the concentration (i.e.,> ±15%) was detected only for mechanically stressed mAbs. In conclusion, the study revealed that the influence of the mAbs and the type of stress impact on the QC of compounded mAbs.
       
  • A Relative Permittivity Approach for Fast Drug Solubility Screening of
           Solvents and Excipients in Lipid-Based Delivery
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Andreas Niederquell, Gabriela Dujovny, Susana Ecenarro Probst, Martin Kuentz Drug solubility screening in solvents and lipids is central for the development of lipid-based formulations (LBFs), and any guidance to reduce the experimental workload would be highly desirable. Solubility parameters are interesting as they can be predicted in silico for a drug but they are hardly predictable for complex lipids. This paper uses a new approach to convert an in silico drug solubility parameter to an estimated relative permittivity, εr. Diverse solvents and lipid-based excipients were then experimentally tested for εr and solubility using fenofibrate as model. The typical excipients and solvents used in LBFs showed an εr range of about 2-24, and good solubility of fenofibrate was indeed evidenced in vicinity of its estimated relative permittivity 13.2 ± 2.7. Mixtures of promising excipients were studied subsequently, and the obtained εr was predictable based on the known values of the individual components. The novel permittivity approach has demonstrated its usefulness, it has much potential in early development for ranking of suitable excipients, and it gives an initial orientation to design formulations. Future research may clarify further opportunities and limits of the novel approach for LBFs.
       
  • Understanding the Influence of Nanocarrier-Mediated Brain Delivery on
           Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Yang Hu, Margareta Hammarlund-Udenaes, Markus Fridén This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation.
       
  • Substrate Transport Properties of the Human Peptide/Histidine Transporter
           PHT2 in Transfected MDCK Cells
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Yuqing Wang, Ping Li, Feifeng Song, Xi Yang, Yayun Weng, Zhiyuan Ma, Lu Wang, Huidi Jiang PHT2, a member of the proton-coupled oligopeptide transporter family, participates in the transportation of small peptides and histidine from lysosomes to the cytosol. It facilitates maintenance of intracellular peptide homeostasis. However, it remains a challenge to elucidate the functional properties of PHT2 due to its localization in the lysosomal membrane. The aim of this study was to explore the transport function and substrate properties of human PHT2 (hPHT2) by transfecting Madin-Darby canine kidney cells with hPHT2 mutants to obtain stably expressed protein in the cell membrane. Using this cell model, we found that the transport activity of hPHT2 reached a maximum capacity when the extracellular pH was 5.5. hPHT2 showed relatively low affinity for Gly-Sar and relatively high affinity for d3-L-histidine, with Km values of 428 ± 88 μM and 66.9 ± 5.7 μM, respectively. Several typical substrates or inhibitors of PEPT1 and PEPT2, including valacyclovir, Gly-Gly-Gly, and cefadroxil but not 5-aminolevulinic acid or captopril, were proven to be substrates of hPHT2. However, hPHT2 showed low affinity for valacyclovir with a Km value of 5350 ± 1234 μM. In conclusion, this study established a suitable and efficient cell model to explore the function of hPHT2 in vitro and provided important information on the transport activity and substrate properties of hPHT2.
       
  • Design of Virus-Mimicking Polyelectrolyte Complexes for Enhanced Oral
           Insulin Delivery
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Chang Liu, Huan Xu, Ying Sun, Xin Zhang, Hongbo Cheng, Shirui Mao The viscous and elastic mucus layer is still an undesirable barrier for oral insulin delivery. To solve the problem, virus-mimicking nanosized polyelectrolyte complex (PEC) was designed and their capacity in enhancing peroral insulin absorption in combination with bifunctional material sodium dodecyl sulfate (SDS) coating was investigated. Inspired by nature, virus-mimicking chitosan (CS)-modified L-Phe derivatives were synthesized to simulate the components of viral envelopes and then PECs between CS-g-N-Phe copolymers and insulin were prepared to achieve both structure and composition simulation of virus envelope. Based on the results from both in vitro and in vivo studies, it was concluded that in vitro mucodiffusion and in vivo hypoglycemic effect were dependent on L-Phe graft ratio, with CS-g-N-Phe20.2%/insulin PECs presenting 2.0- to 2.2-fold higher relative pharmacological bioavailability than nonmodified CS/insulin PECs. Thereafter, SDS solution was applied as outer layer coating on the surface of virus-mimicking PECs. The coated PECs showed improved enzymatic stability, enhanced transport across mucus layer as well as intestinal epithelium in an SDS concentration–dependent manner, with 0.6% SDS coating presenting the best effect, with further enhanced relative pharmacological bioavailability in healthy rats and prolonged therapeutic effect up to 9 h.
       
  • Hybrid Nanostructured Films for Topical Administration of Simvastatin as
           Coadjuvant Treatment of Melanoma
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Antonella Barone, Maria Mendes, Célia Cabral, Rosario Mare, Donatella Paolino, Carla Vitorino This work aims at (1) assessing the potential of repurposing simvastatin (SV) to support the most common therapies against melanoma and (2) developing an innovative topical adhesive film, composed by chitosan-coated nanostructured lipid carriers (Ch-NLC) used as drug vehicle. A factorial design approach was employed as the basis for the formulation development. Optimized Ch-NLC displayed a particle size of 108 ± 1 nm, a polydispersity index of 0.226, a zeta potential of 17.0 ± 0.6 mV, as well as an entrapment efficiency of 99.86 ± 0.08%, and SV loading of 14.99 ± 0.01%. The performance of SV-Ch-NLC films was assessed in terms of release, permeation, and adhesion, as critical quality attributes. Cutaneous tolerability and in vitro cytotoxicity studies were performed to warrant film safety and drug effectiveness, respectively. The topical films provided a sustained release kinetic profile of SV and were classified as nonirritant systems. The encapsulation of SV increased cytotoxicity in melanoma cells. The key role of squalene as nanostructuring agent of the lipid nanoparticle matrix and as permeation enhancer was highlighted, suggesting its key action for potentiating skin permeation and uptake into melanoma cells. Topical SV-Ch-NLC films are thus able to provide an in situ extended drug delivery and useful as coadjuvant treatment of melanoma skin lesions.
       
  • Nanostructured Lipid Carriers for Oral Bioavailability Enhancement of
           
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Archu Singh, Yub Raj Neupane, Bharti Mangla, Kanchan Kohli Exemestane (EXE) is a novel oral steroidal aromatase inhibitor approved for the treatment of breast cancer. However, its oral clinical application is limited because of low aqueous solubility and low oral bioavailability. Here, we aim to design and fabricate nanostructured lipid carriers (NLCs) using Precirol® ATO 5 and flaxseed oil as the solid lipid and liquid lipid, respectively. EXE-loaded NLCs were spherical in shape and with a hydrodynamic diameter of 131.3 ± 2.43 nm, polydispersity index 0.205 ± 0.06, and percentage entrapment efficiency 85.6 ± 1.20%. In vitro release study demonstrated a sustained release pattern for 24 h, with relative burst release at the initial time point. Differential scanning calorimetry and powder X-ray diffraction studies showed reduced crystallinity and complete encapsulation of drug within the lipid matrix. Ex vivo gut permeation study and confocal laser scanning microscopy revealed that NLCs comprising a lipid blend and surfactant enhanced intestinal permeability of EXE. Moreover, in vivo pharmacokinetic study on female Wistar rats found to augment 3.9-fold in oral bioavailability of EXE through NLCs compared with EXE suspension. Herein, we depict that loading of EXE into NLCs hold promising approach for the oral delivery of EXE in cancer therapy.
       
  • Effect of Iron Oxide Nanoparticles on the Oxidation and Secondary
           Structure of Growth Hormone
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Ninad Varkhede, Björn-Hendrik Peters, Yangjie Wei, C. Russell Middaugh, Christian Schöneich, M. Laird Forrest Oxidation of therapeutic proteins (TPs) can lead to changes in their pharmacokinetics, biological activity and immunogenicity. Metal impurities such as iron are known to increase oxidation of TPs, but nanoparticulate metals have unique physical and chemical properties compared to the bulk material or free metal ions. Iron oxide nanoparticles (IONPs) may originate from equipment used in the manufacturing of TPs or from needles during injection. In this study, the impact of IONPs on oxidation of a model protein, rat growth hormone (rGH), was investigated under chemical stress. Hydrogen peroxide (H2O2)- and 2,2′-azobis (2-methylpropionamidine) dihydrochloride oxidized methionine residues of rGH, but unexpectedly, oxidation was suppressed in the presence of IONPs compared to a phosphate buffer control. Fourier transform infrared spectroscopy indicated splitting of the α-helical absorbance band in the presence of IONPs, whereas circular dichroism spectra showed a reduced α-helical contribution with increasing temperature for both rGH and rGH-IONP mixtures. The results collectively indicate that IONPs can increase the chemical stability of rGH by altering the kinetics and preference of amino acid residues that are oxidized, although the changes in protein secondary structure by IONPs may lead to alterations of physical stability.
       
  • ATR-FTIR Characterization of Janus Nanoparticles—Part II:
           Follow-Up Skin Application
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Kamilia Kemel, Arlette Baillet-Guffroy, Vincent Faivre, Cécile Laugel Attenuated total reflection by Fourier transform infrared (ATR-FTIR) was used to implement reliable infrared descriptors over time of Janus nanoparticles (JNP), to follow their behavior before and after cutaneous application. In the last study, ATR-FTIR spectroscopic analysis allowed us to identify the evolution of intensity ratio of ν(C=O) at 1739 cm−1 and δ(H-O-H) at 1639 cm−1 as a spectroscopic descriptor, for JNP before cutaneous application (on the CaF2 window). This descriptor can be used to follow the physical stability (presence) of nanoparticles over time. The purpose of this study was to understand the behavior of JNP on the surface of the human skin. Therefore, a comparative study with the untreated skin and the skin after cutaneous application of lipophilic phase (Labrafil) of JNP was conducted using Franz cells. The suitability of the ATR-FTIR descriptor of JNP was evaluated, and a research of other descriptors was performed to understand the interaction that may exist between nanoparticles and the skin.
       
  • Influence of the Punch Speed on the Die Wall/Powder Kinematic Friction
           During Tableting
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Léo Desbois, Pierre Tchoreloff, Vincent Mazel Influence of the compaction speed on the final tablet properties is an important challenge during the scale-up of a solid dosage form. This strain rate sensitivity is generally attributed to the time dependent deformation behavior of the powder. In this work, we studied the influence of the speed on another important factor during compaction: friction between the tablet/powder and the die. An original experimental methodology was developed to study the evolution of the kinematic friction coefficient between the tablet and the die as a function of the sliding speed of the tablet on the die wall. This methodology made it possible to separate the speed used to make the tablet from the speed used to measure the friction coefficient. Results indicate that the kinematic coefficient of friction increases with the sliding speed following a logarithmic trend. This trend was observed for 4 different pharmaceutical excipients. Moreover, it was proved that the speed dependency is an intrinsic property of the friction between a tablet and a die lubricated using magnesium stearate.
       
  • Formulation and Characterization of Spray-Dried Powders Containing
           Vincristine-Liposomes for Pulmonary Delivery and Its Pharmacokinetic
           Evaluation From In Vitro and In Vivo
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Jiaqiu Xu, Xiaoyu Lu, Xiaojie Zhu, Yue Yang, Qi Liu, Di Zhao, Yang Lu, Jiayu Wen, Xijing Chen, Ning Li Vincristine (VCR) has been used in the treatment of lung cancer. To improve its efficacy, the designs of elevating lung exposure to drug and decreasing the clearance with extended time were brought out. Pulmonary delivery is regarded as a good choice in pulmonary diseases treatment. Spray-drying is a technology for the preparation of drugs that can be delivered to lung via a dry powder inhaler. The results showed an appropriate particle size and shape for the pulmonary delivery. The aerosol behaved a sustained-release profile while VCR solution released rapidly within 10 h. The antitumor activity was characterized by 3-(4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide assay, and half maximal inhibitory concentration values of VCR-liposomes spray-dried powder were 24.42 ± 1.88 nM and 55.28 ± 4.76 nM in MCF-7 and A549 cells, respectively. Compared with the free VCR, the aerosol performed better pharmacokinetic behavior: increased maximum concentration (630.8%) and systemic exposure (429.6%) and decreased elimination half-life (81.1%). The clearance was decreased by 83.2%. Comprehensively, the pulmonary delivery seemed to be a recommendable way to effectively treat the pulmonary disease.
       
  • X-Ray Diffraction and Theoretical Calculation–Supported Formation of
           Polymorphic Cocrystals Discovered Through Thermal Methods: A Case Study
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Zhengzheng Zhou, Mónica Calatayud, Julia Contreras-García, Liang Li, Henry H.Y. Tong, Ying Zheng Polymorphism commonly exists in the preparation of cocrystals and has attracted widespread attention from both the pharmaceutical industry and academia. However, few studies have examined how to discover polymorphic cocrystals and their potential formation mechanism. In this study, we report the novel discovery of salicylic acid: 3-nitrobenzamide (SA-3NBZ) polymorphic cocrystals by thermal methods. The formation mechanism is elucidated based on theoretical calculations. SA-3NBZ polymorphic cocrystals with molar ratio of 1:1 and 2:2 were discovered using the combination of differential scanning calorimetry and hot stage microscopy. Single-crystal X-ray diffraction analysis confirmed this discovery. Density functional theory calculations corrected with dispersion were conducted to illustrate the energetic stabilization of SA polymorphic cocrystals. Compared with the starting materials, formation of the cocrystals at 1:1 and 2:2 present a weak stabilization with overall energy reduction of −0.01 and −0.05 eV/molecule, respectively. The calculated noncovalent interactions index further suggests that intralayer hydrogen bonds and van der Waals forces contribute to these weak interactions. The density functional theory calculations are in good agreement with the X-ray diffraction data. Hence, thermal analysis is a simple and reliable method to discover polymorphic cocrystals.
       
  • Improved Intestinal Mucus Permeation of Vancomycin via Incorporation Into
           Nanocarrier Containing Papain-Palmitate
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Nuri Ari Efiana, Aida Dizdarević, Christian W. Huck, Andreas Bernkop-Schnürch The aim of this study was to improve intestinal mucus permeation of a peptide antibiotic via incorporation into papain-palmitate–modified self-emulsifying drug delivery systems (SEDDS) as nanocarrier. Vancomycin as a peptide antibiotic was lipidized by hydrophobic ion pair formation using sodium bis-2-ethylhexyl-sulphosuccinate before incorporation in SEDDS comprising Capmul MCM, propylenglycol, and Kolliphor EL (2:1:2). As mucolytic agent, 0.5% papain-palmitate was introduced in SEDDS formulation containing the vancomycin-sodium bis-2-ethylhexyl-sulphosuccinate ion pair. The formulation was evaluated regarding droplet size, zeta potential, and cytotoxicity using Caco-2 cells previous to intestinal mucus permeation studies using Transwell diffusion and rotating tube method. The hydrophobic ion pair product yielded from surfactant to drug ratio of 3:1 provided a 25-fold increase in lipophilicity, drug payload in SEDDS of 5%, and log DSEDDS/release medium of 2.2. The formulation exhibited a droplet size and zeta potential of 221.5 ± 14.8 nm and −4.2 ± 0.8 mV, respectively. Cytotoxicity study showed that SEDDS formulations were not toxic. Introducing 0.5% papain-palmitate increased the mucus permeability of SEDDS 2.8-fold and 3.3-fold in Transwell diffusion and rotating tube studies, respectively. According to these results, papain decorated SEDDS might be a potential strategy to improve the mucus permeating properties of peptide antibiotics.
       
  • Development of Coprocessed Chitin-Calcium Carbonate as Multifunctional
           Tablet Excipient for Direct Compression, Part 2: Tableting Properties
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Mohammad Chaheen, Bernard Bataille, Ahmad Yassine, Emmanuel Belamie, Tahmer Sharkawi The use of multifunctional excipients is gaining interest as it simplifies formulations by replacing the need of multiple monofunctional excipients. In previous work, coprocessed chitin-calcium carbonate (CC) showed to have good potential as a multifunctional excipient for fast disintegrating tablets produced by direct compression. It allowed for good tablet strength, enhanced powder flowability, and higher true and bulk densities with fast disintegrating properties. The objective of this work is to gain insight on CC tableting properties under different tablet manufacturing conditions (different lubrication levels, compression speeds, and dwell times) and in formulations with drug models: ibuprofen and paracetamol. Results showed that CC exhibited good tabletability, compressibility, and compactibility profiles. CC does not require the addition of lubricant and can be used at high compression speeds and different dwell times. When included in formulations with ibuprofen and paracetamol at different percentages, CC enhanced tablets strength and promoted fast disintegration and drug dissolution. In conclusion, this study shows that CC can be used as a multifunctional excipient (filler-disintegrant-binder) for fast disintegrating tablets produced by direct compression.
       
  • Forced Oxidative Degradation Pathways of the Imidazole Moiety of
           Daclatasvir
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Yande Huang, Bao-Ning Su, Jonathan Marshall, Scott A. Miller Daclatasvir hydrochloride (DCV) is the active pharmaceutical ingredient of Daklinza, a marketed product for the treatment of hepatitis C viral infection. The intrinsic stability of daclatasvir was evaluated via a forced degradation study. DCV was found to be stable in the solid state. In solution, its carbamate moiety is susceptible to basic hydrolysis, whereas its imidazole is liable to base-mediated autoxidation to form degradants 1 and 3, 7-8, respectively. The imidazole moiety can also be oxidized to form degradants 6-7 in the presence of hydrogen peroxide or azobisisobutyronitrile. The chloro-adduct degradant 9 was also observed in hydrogen peroxide solution. Furthermore, the imidazole moiety is sensitive to photodegradation in solution. Degradants 2-8 were observed in a solution of DCV exposed to high intensity light/UV light; the formation of degradants 2 and 5-8 was postulated through 4 degradation pathways. The degradants 3 and 4 were deemed to be secondary degradants of 7 and 5, respectively.
       
  • A Spray-Dried Combination of Capreomycin and CPZEN-45 for Inhaled
           Tuberculosis Therapy
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Ragan A. Pitner, Phillip G. Durham, Ian E. Stewart, Steven G. Reed, Gail H. Cassell, Anthony J. Hickey, Darrick Carter Tuberculosis (TB) remains the single most serious infectious disease attributable to a single-causative organism. A variety of drugs have been evaluated for pulmonary delivery as dry powders: capreomycin sulfate has shown efficacy and was safely delivered by inhalation at high doses to human volunteers, whereas CPZEN-45 is a new drug that has also been shown to kill resistant TB. The studies here combine these drugs—acting by different mechanisms—as components of single particles by spray-drying, yielding a new combination drug therapy. The spray-dried combination powder was prepared in an aerodynamic particle size range suitable for pulmonary delivery. Physicochemical storage stability was demonstrated for a period of 6 months. The spray-dried combination powders of capreomycin and CPZEN-45 have only moderate affinity for mucin, indicating that delivered drug will not be bound by these mucins in the lung and available for microbicidal effects. The pharmacokinetics of disposition in guinea pigs demonstrated high local concentrations of drug following direct administration to the lungs and subsequent systemic bioavailability. Further studies are required to demonstrate the in vivo efficacy of the combination to confirm the therapeutic potential of this novel combination.
       
  • Optimization and Application of In Vitro and Ex Vivo Models for Vaginal
           Semisolids Safety Evaluation
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Rita Monteiro Machado, Ana Palmeira-de-Oliveira, Luiza Breitenfeld, José Martinez-de-Oliveira, Rita Palmeira-de-Oliveira Preclinical safety assessment of vaginal products includes cytotoxicity assays upon cell lines. Furthermore, tissue explants have been considered for application on ex vivo models. In this study, traditional and renewed methods were studied for toxicity assessment of vaginal semisolids upon products currently used in clinical practice as antimicrobials (Gino-Canesten®, Sertopic®, Dermofix®, Gyno-Pevaryl®, Lomexin®, Gino Travogen®, Dalacin V®), containing estrogens (Ovestin®, Blissel®, Colpotrophine®), and reference formulations (Replens®, Universal Placebo). Two in vitro cytotoxicity tests were performed: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and neutral red uptake upon uterine (HEC-1A), cervical (HeLa) and vaginal (VK2 E6/E7) cells, according to ISO/EN 10993-5 (in vitro evaluation of medical devices). Similarly, a strategy to determine tissue viability on ex vivo porcine vaginal model (through MTT reduction assay and histological analysis) was developed and optimized. The vaginal cell line VK2 E6/E7 conducted to the most accurate calculation of half-maximal toxic concentration among all cells on the MTT assay. However, it was shown not be sensitive to the neutral red uptake assay. Tissues from the porcine model were collected with approx. 15% variability in thickness and variation coefficients lower than 25% when testing negative and positive controls were achieved. These models can improve cost-efficiency in early steps of product development.
       
  • Some Preformulation Studies of Pyruvic Acid and Other α-Keto Carboxylic
           Acids in Aqueous Solution: Pharmaceutical Formulation Implications for
           These Peroxide Scavengers
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Antonio Lopalco, Rodney Deeken, Justin Douglas, Nunzio Denora, Valentino J. Stella The purpose of this study is to assess some of the variables determining the aldol-like condensation of pyruvic acid (1), a peroxide scavenger, in aqueous solution to parapyruvic acid and higher oligomers. Its stability is compared to 3 other α-keto carboxylic acids, 2 with sterically hindered methylene groups alpha to the keto functionality (2-3) and phenylglyoxylic acid (4) with no methylene group. High-performance liquid chromatography, nuclear magnetic resonance, and liquid chromatography mass spectroscopy techniques are used in the kinetics and product analyses. 1 condensation is concentration dependent and base catalyzed above pH 7, consistent with the reaction mechanism proceeding through the attack of the fraction of the methylene group, alpha to the keto group, in its anionic form, at the keto group of a second molecule of 1. The major product is confirmed to be parapyruvic acid, but higher-order oligomers are also observed. All 3 of the other α-keto carboxylic acids 2-4 are considerably less reactive, with 4 being completely stable. Stable solutions of 1 can be prepared by the use of relatively dilute solutions maintained at slightly acidic pH values. 1 prevents the oxidation of methionine on addition of hydrogen peroxide.
       
  • Solid-State Reactivity of Mechano-Activated Simvastatin: Atypical Relation
           to Powder Crystallinity
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Dattatray Modhave, Peter Laggner, Michael Brunsteiner, Amrit Paudel The present study investigated the impact of solid-state disorders generated during milling on the chemical reactivity of simvastatin. An amorphous and a partially crystalline simvastatin powders were generated via cryomilling simvastatin crystals for either 90 or 10 min, respectively. The thoroughly characterized milled powders were stored at 40°C/75% RH, in open and closed containers. The effect of milling and storage conditions on physical stability was investigated using simultaneous small and wide-angle X-ray scattering and differential scanning calorimetry. The chemical degradation was evaluated using liquid chromatography–mass spectrometry. Compared with the fully amorphous state, the partially crystalline simvastatin crystallized to a lower extent in the expense of higher chemical degradation on open storage. The closely stored samples degraded to a lower extent and crystallized to a higher extent than the openly stored ones. However, the trends of the total crystallinity and degradation between amorphous and partially crystalline powders were similar. Small-angle X-ray scattering revealed that the partially crystalline simvastatin comprised a higher extent of nanoscale density heterogeneity than the fully amorphous powder. The overall results pointed toward the role of the remaining amorphous content and the nanoscale and mesoscale density heterogeneity on the chemical reactivity in the disordered simvastatin.
       
  • Impact of Surfactant and Surfactant-Polymer Interaction on
           Desupersaturation of Clotrimazole
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Wei Zhang, Siddhi S. Hate, David J. Russell, Hao Helen Hou, Karthik Nagapudi The impact of surfactants on supersaturation of clotrimazole solutions was systematically evaluated. Four clinically relevant surfactants, sodium dodecyl sulfate, vitamin E TPGS, Tween 80, and docusate sodium were studied. The induction time for nucleation and rate of desupersaturation were determined at a supersaturation ratio of 90% amorphous solubility. Measurement was also performed in the presence of predissolved hydroxypropyl methylcellulose acetate succinate to study the effect of surfactant-polymer interaction on desupersaturation. The 4 surfactants showed varied effects on desupersaturation. From supersaturation maintenance perspective, in the presence of hydroxypropyl methylcellulose acetate succinate, the rank order for the 4 surfactants was found to be: docusate sodium> vitamin E TPGS> sodium dodecyl sulfate> Tween 80. Given the importance of maintaining supersaturation and varied effect of surfactants on nucleation kinetics and desupersaturation rate, a careful examination of active pharmaceutical ingredient, polymer and surfactant interaction on an individual basis is recommended for selecting an appropriate surfactant for use in amorphous solid dispersion formulation.
       
  • Nilotinib Alters the Efflux Transporter-Mediated Pharmacokinetics of
           Afatinib in Mice
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Ronilda R. D’Cunha, Daryl J. Murry, Guohua An Small-molecule tyrosine kinase inhibitors (TKIs) are novel anticancer agents with enhanced selectivity and superior safety profiles than conventional chemotherapeutics. A major shortcoming in TKI therapy is the development of acquired resistance. An important resistance mechanism is reduced intracellular drug accumulation due to an overexpression of efflux transporters such as P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) in cancer cells. TKIs have dual roles as substrates and inhibitors of Pgp and BCRP; thus, combination TKI therapy could potentially reverse efflux transporter-mediated TKI resistance. In the present study, the effect of 14 TKIs on Pgp-, Bcrp1-, and BCRP-mediated afatinib efflux was investigated in vitro. Nilotinib was a potent inhibitor of Pgp, Bcrp1, and BCRP, with EC50 values of 2.22, 2.47, and 0.692 μM, respectively. Consequently, the pharmacokinetics of afatinib with and without the coadministration of nilotinib was determined in mice plasma and various tissues. Nilotinib increased afatinib AUC by 188% in plasma, and this altered tissue AUC by −38.8% to +221%. Nilotinib also decreased the clearance of afatinib by 65.3%, from 609 to 211 mL/h. Further studies are warranted to assess nilotinib’s chemosensitizing effect in tumor xenograft models.
       
  • Developing Cream Formulations: Renewed Interest in an Old Problem
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Ana Simões, Francisco Veiga, Carla Vitorino This work aimed at establishing a framework to screen and understand the product variability deeming from factors that affect the quality features of cream formulations.As per Quality by Design – based approach, cream quality target profile and critical quality attributes were identified, and a risk assessment analysis was conducted to qualitatively detect the most critical variables for cream design and development. A Plackett-Burman design was used to screen out unimportant factors, avoiding collecting large amounts of data. Accordingly, 2 designs of experiments (DoE-1 and DoE-2) were performed, and the effects of independent variables on the cream formulations responses were estimated. At different factor combinations, significant variability was observed in droplet size, consistency, hardness, compressibility, and adhesiveness with values ranging from 2.6 ± 0.9 to 10 ± 6 μm, 7.93 ± 0.05 to 13.53 ± 0.14 mm, 27.6 ± 0.3 to 58.4 ± 1.1 g, 38 ± 6 to 447 ± 37 g.s, and 25.7 ± 2.1 to 286 ± 33 g.s, respectively. The statistical analysis allowed determining the most influent factors. This study revealed the potential of Quality by Design methodology in understanding product variability, recognizing the most critical independent variables for the final product quality. This systematic approach in the pharmaceutical field will yield more robust products and processes, provisioning time and cost effective developments.
       
  • Solubilization of Cyclosporine in Topical Ophthalmic Formulations:
           Preformulation Risk Assessment on a New Solid Form
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Ke Wu, Anu Gore, Richard Graham, Richard Meller Owing to the discovery of a less soluble crystalline form (form 2) of cyclosporine (CsA), risks in solubility and physical stability of these formulations need to be revisited. This work focused on understanding the solubility behavior of various CsA forms in different media, including water, castor oil, and selected cosolvent micellar systems. In water, form 2 was approximately 8-9 times less soluble than form 1 (aka. tetragonal dihydrate). In neat nonaqueous solvent, for example, castor oil, form 3 (aka. orthorhombic hydrate) was found to have the lowest solubility and therefore the most stable form. In addition, the solubility-temperature relationship of CsA is complex and solvent-dependent. In aqueous vehicles, retrograde temperature dependence of solubility was observed in aqueous vehicles, that is, the solubility of CsA decreased with temperature, which was attributed to the effect of temperature on the strength of hydrogen bonding interactions; conversely, the solubility of CsA increased with temperature in nonaqueous solvents. In addition, the solubility of these CsA forms was very sensitive to temperature. Temperature-dependent form transformation was also observed in the media studied, with faster form conversion occurring at elevated temperatures. These studies provided key information to support the risk assessment for topical ophthalmic formulation development of CsA.
       
  • In Vitro and In Vivo Evaluation of Core–Shell Mesoporous Silica as a
           Promising Water-Insoluble Drug Delivery System: Improving the Dissolution
           Rate and Bioavailability of Celecoxib With Needle-Like Crystallinity
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Cuiyan Han, Shanqiang Zhang, Haitao Huang, Yan Dong, Xiaoyu Sui, Baiyu Jian, Wenquan Zhu The objective of our study was to prepare mesoporous silica nanoparticles with a core–shell structure (CSMSNs) and improve the dissolution and bioavailability of celecoxib (Cxb), a water-insoluble drug, by changing its needle-like crystal form. CSMSNs are prepared by a core-shell segmentation self-assembly method. The SBET and Vt of CSMSNs were 890.65 m2/g and 1.23 cm3/g, respectively. Cxb was incorporated into CSMSNs by the solvent evaporation method. The gastrointestinal irritancy of the CSMSNs was evaluated by a gastric mucosa irritation test. In vitro dissolution and in vivo pharmacokinetic tests were carried out to study the improvement in the dissolution behavior and oral bioavailability of Cxb. In conclusion, gastric mucosa irritation study indicated the good biocompatibility of CSMSNs. The cumulative dissolution of CSMSNs-Cxb is 86.2% within 60 min in SIF solution, which may be ascribed to the crystal form change caused by control of the nanochannel for CSMSNs. Moreover, CSMSNs could enhance the 9.9-fold AUC of Cxb. The cumulative dissolution and bioavailability of Cxb were both significantly enhanced by CSMSNs. CSMSNs with a core–shell structure are suitable as a carrier for a poorly water-soluble drug (Cxb).
       
  • Synergistic Enhancement of Cellular Uptake With CD44-Expressing Malignant
           Pleural Mesothelioma by Combining Cationic Liposome and Hyaluronic
           Acid–Lipid Conjugate
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Yu Sakurai, Akari Kato, Yasuhiro Hida, Junichi Hamada, Nako Maishi, Kyoko Hida, Hideyoshi Harashima Malignant pleural mesothelioma (MPM) is a highly aggressive form of cancer, with a median survival of less than 1 year. It is well known that the hyaluronan (HA) receptor CD44 is highly expressed by MPM cells and is reported to be correlated with a poor prognosis. We herein report on the development of a new type if drug delivery system against CD44 that involves the use of lipid nanoparticles (LNPs) equipped with a new type of HA derivative. In this study, we evaluated HA-lipid conjugation (HAL) via the end of the HA molecule through reductive amination, a process that allowed the carboxylate group to remain intact. As a result, the HAL-modified LNP appears to be a potent nanoparticle for dealing with MPM. Surprisingly, the use of a combination of a cationic lipid and HAL had a synergistic effect on cellular uptake in MPM and consequently permitted an anti-cancer drug such as cis-diamminedichloro-platinum(II) (CDDP). Intrapleural injection of CDDP-loaded HAL-LNP (1.5 mg/kg as CDDP) per week significantly suppressed the progression of this type of cancer in an MPM orthotopic model. These results suggest that HAL-modified LNP represents a potent delivery system for MPM cells that express high levels of CD44.
       
  • Co-Processed Particles: An Approach to Transform Poor Tableting Properties
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Rahul Roopwani, Ira S. Buckner The role of co-processing in improving tablet mechanical properties was investigated in this work. Gabapentin was used as the model compound owing to its poor tableting properties such as low tensile strength, strain rate sensitivity, high ejection force, and tablet capping. Gabapentin was blended with hydroxypropyl methylcellulose (Methocel®) in a high shear mixer to obtain an interactive mixture consisting of finer hydroxypropyl methylcellulose particles adsorbed onto the surface of larger gabapentin particles. Interactive mixture containing
       
  • Kinetics Study of Cocrystal Formation Between Indomethacin and Saccharin
           Using High-Shear Granulation With In Situ Raman Spectroscopy
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Ryoma Tanaka, Yusuke Hattori, Kazuhide Ashizawa, Makoto Otsuka Pharmaceutical manufacturing processes are necessary to make solid dosage form even in cocrystal formation. In an effort to reduce the number of unit operations, high-shear wet granulation with cocrystallization system was proposed. In the present study, indomethacin-saccharin was chosen as a model compound, and the cocrystal formation kinetics was investigated during the consistent process. The role of each initial indomethacin crystal state (γ-form, α-form, or amorphous) for the kinetics was explored using in situ Raman spectroscopy with multivariate curve resolution by alternating least-squares analysis as a chemometrics. Obtained granules were characterized by X-ray diffraction and tablet dissolution testing. The Raman peaks assigned to indomethacin-saccharin cocrystal were increased with granulation when ethanol was used as a binding solvent. In addition, the reaction kinetics of run samples which had different indomethacin forms was distinguished by best fitting using Avrami–Erofeev or Ginstling–Brounshtein model. The kinetic variance depended on the initial thermodynamic state of indomethacin because they had a different crystallization mechanism for the cocrystal. The scalable and feasible granulation method is required in the pharmaceutical industry.
       
  • Cyclization of N-Terminal Glutamic Acid to pyro-Glutamic Acid Impacts
           Monoclonal Antibody Charge Heterogeneity Despite Its Appearance as a
           Neutral Transformation
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Zhihua Liu, Joseph Valente, Shujie Lin, Naresh Chennamsetty, Difei Qiu, Mark Bolgar Pyroglutamic acid (pyroGlu) is commonly observed at the N-terminus of therapeutic monoclonal antibodies. Notably, the term “pyroGlu” refers to a single product that could originate from the cyclization of either an N-terminal glutamine or an N-terminal glutamic acid. This is an important and easily overlooked distinction that has major implications on the charge variant nature of a pyroGlu relative to its uncyclized form. Cyclization of an N-terminal glutamine for instance clearly produces an acidic variant with a lower isoelectric point owing to the loss of the positively charged N-terminal amine. In this report, we demonstrate that cyclization of an N-terminal glutamic acid on the other hand produces a basic variant with a higher isoelectric point contrary to the typical assumption that the simultaneous loss of the N-terminal amine and the carboxylic acid side-chain would negate the formation of a charge variant. The results of our investigation demonstrate the need to consider the relative strengths of the acidic and basic functional groups which are altered when assessing whether the product will be a charge variant. This study also adds new knowledge and experimental evidence to understand charge heterogeneity in monoclonal antibodies.
       
  • Identification of an Adduct Impurity of an Active Pharmaceutical
           Ingredient and a Leachable in an Ophthalmic Drug Product Using LC-QTOF
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Ramarao Gollapalli, Gagandeep Singh, Alejandro Blinder, Jeremiah Brittin, Arijit Sengupta, Bikash Mondal, Milan Patel, Biswajit Pati, James Lee, Amit Ghode, Mahesh Kote Impurity investigations are important in pharmaceutical development to ensure drug purity and safety for the patient. The impurities typically found in drug products are degradants or reaction products of the active pharmaceutical ingredient (API) or leachable compounds from the container closure system. However, secondary reactions may also occur between API degradants, excipient impurities, residual solvents, and leachables to form adduct impurities. We hereby report an adduct-forming interaction of API (moxifloxacin) with a leachable compound (ethylene glycol monoformate) in moxifloxacin ophthalmic solution. The leachable compound originated from a low-density polyethylene bottle used in the packaging of drug products. The adduct impurity was tentatively identified as 1-cyclopropyl-6-fluoro-7-(1-(2-(formyloxy)ethyl) octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (C24H28FN3O6, MW = 473.19621) using accurate mass LC-QTOF analysis. The mass accuracy error between the theoretical mass and the experimental mass of an impurity was found to be 0.2 ppm. An MS/MS analysis was utilized to provide mass spectrometry fragments to support verification of the proposed structure.
       
  • De-Risking Early-Stage Drug Development With a Bespoke Lattice Energy
           Predictive Model: A Materials Science Informatics Approach to Address
           Challenges Associated With a Diverse Chemical Space
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Tiffany Lai, Klimentina Pencheva, Ernest Chow, Robert Docherty The solid-state properties of new chemical entities are critical to the stability and bioavailability of pharmaceutical drug products. The stability of the solid-state packing is described by the packing energy and an accurate prediction of this property for drug molecules would therefore be desirable. However, this has been difficult to achieve because of the lack of fundamental thermodynamic data on drug molecules. A potential solution would be to use calculated lattice energies to build a model and design molecules with desired physicochemical properties from an early stage, aligning with a “design by first intent” strategy for physicochemical properties. We first demonstrate the high correlation and interchangeability between QSPR models built using calculated lattice energies and experimental sublimation enthalpies for small organic molecules. We then present a QSPR model trained on in-house molecules using lattice energies calculated from crystal structures. The result is a model that enables fast prediction of the lattice energies of in-house molecules from 2-D molecular structure with reasonable accuracy (R2 = 0.92, root mean square error = 3.58 kcal/mol). We explore the model elements to improve our understanding of the molecular properties that contribute to lattice energy and then suggest potential cross-industry aspects that may enhance the application of the concept.
       
  • Translating Cell and Gene Biopharmaceutical Products for Health and Market
           Impact. Product Scaling From Clinical to Marketplace: Lessons Learned and
           Future Outlook
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Annette Bak, Kristina Pagh Friis, Yan Wu, Rodney J.Y. Ho Cell and gene therapies have the potential to be curative for severe disease states such as cancer or incurable orphan genetic diseases. Despite the promise, there are only few such therapies available, although more are appearing in pharmaceutical pipelines. A major culprit limiting a fast translation from preclinical research to the clinic and the market is chemistry, manufacturing and control. The root cause is that most cell and gene therapies currently are personalized in form of ex vivo manipulated cells. This approach stands in sharp contrast to the population-based approach seen for small molecules and protein therapeutics. Therefore, it warrants a different approach to product manufacturing, testing, release, regulatory submissions, and product distribution. In this commentary, we highlight opportunities to solve these issues already in progress in industry and at academic institutions, but in addition call for expert contributions to a future cluster of articles in Journal of Pharmaceutical Sciences to illuminate additional solutions. Finally, we are also providing a perspective on future directions including expanding from current approaches of gene modification via viral vectors to for example gene editing, approaches that may lend themselves better toward allogenic and in vivo therapies and more typical chemistry, manufacturing and control approaches.
       
  • Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms:
           Ondansetron
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Gopal Singh Rajawat, Tejashree Belubbi, Mangal S. Nagarsenker, Bertil Abrahamsson, Rodrigo Cristofoletti, Dirk W. Groot, Peter Langguth, Alan Parr, James E. Polli, Mehul Mehta, Vinod P. Shah, Tomokazu Tajiri, Jennifer Dressman Literature data pertaining to the physicochemical, pharmaceutical, and pharmacokinetic properties of ondansetron hydrochloride dihydrate are reviewed to arrive at a decision on whether a marketing authorization of an immediate release (IR) solid oral dosage form can be approved based on a Biopharmaceutics Classification System (BCS)-based biowaiver. Ondansetron, a 5HT3 receptor antagonist, is used at doses ranging from 4 mg to 24 mg in the management of nausea and vomiting associated with chemotherapy, radiotherapy, and postoperative treatment. It is a weak base and thus exhibits pH-dependent solubility. However, it is able to meet the criteria of “high solubility” as well as “high permeability” and can therefore be classified as a BCS class I drug. Furthermore, ondansetron hydrochloride 8 mg IR tablets (Zofran® 8 mg) and multiples thereof (16 mg = Zofran® 8 mg × 2 tablets and 24 mg = Zofran® 8 mg × 3 tablets) meet the criteria of “rapidly dissolving” in dissolution testing. Ondansetron hydrochloride has a wide therapeutic window and is well-tolerated after oral administration. Based on its favorable physicochemical properties, pharmacokinetic data and the minimal risks associated with an incorrect bioequivalence decision, the BCS-based biowaiver procedure can be recommended for ondansetron hydrochloride dihydrate IR tablets.
       
  • Editorial Advisory Board
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s):
       
  • Preincubation With Everolimus and Sirolimus Reduces Organic
           Anion-Transporting Polypeptide (OATP)1B1- and 1B3-Mediated Transport
           Independently of mTOR Kinase Inhibition: Implication in Assessing OATP1B1-
           and OATP1B3-Mediated Drug-Drug Interactions
    • Abstract: Publication date: October 2019Source: Journal of Pharmaceutical Sciences, Volume 108, Issue 10Author(s): Taleah Farasyn, Alexandra Crowe, Oliver Hatley, Sibylle Neuhoff, Khondoker Alam, Jean Kanyo, TuKiet T. Lam, Kai Ding, Wei Yue Organic anion transporting polypeptides (OATP)1B1 and OATP1B3 mediate hepatic uptake of many drugs including lipid-lowering statins. Current studies determined the OATP1B1/1B3-mediated drug-drug interaction (DDI) potential of mammalian target of rapamycin (mTOR) inhibitors, everolimus and sirolimus, using R-value and physiologically based pharmacokinetic models. Preincubation with everolimus and sirolimus significantly decreased OATP1B1/1B3-mediated transport even after washing and decreased inhibition constant values up to 8.3- and 2.9-fold for OATP1B1 and both 2.7-fold for OATP1B3, respectively. R-values of everolimus, but not sirolimus, were greater than the FDA-recommended cutoff value of 1.1. Physiologically based pharmacokinetic models predict that everolimus and sirolimus have low OATP1B1/1B3-mediated DDI potential against pravastatin. OATP1B1/1B3-mediated transport was not affected by preincubation with INK-128 (10 μM, 1 h), which does however abolish mTOR kinase activity. The preincubation effects of everolimus and sirolimus on OATP1B1/1B3-mediated transport were similar in cells before preincubation with vehicle control or INK-128, suggesting that inhibition of mTOR activity is not a prerequisite for the preincubation effects observed for everolimus and sirolimus. Nine potential phosphorylation sites of OATP1B1 were identified by phosphoproteomics; none of these are the predicted mTOR phosphorylation sites. We report the everolimus/sirolimus-preincubation-induced inhibitory effects on OATP1B1/1B3 and relatively low OATP1B1/1B3-mediated DDI potential of everolimus and sirolimus.
       
  • Overall similarities and a possible factor affecting plasma metabolome
           profiles between venous and capillary blood samples from 20 healthy human
           males
    • 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.
       
 
 
JournalTOCs
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
 
About JournalTOCs
API
Help
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-