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Journal of Pharmaceutical Sciences

Hélène Chapy, Leonid Kagan
With a long half-life, pharmacokinetic evaluation of monoclonal antibodies in rodents lasts multiple weeks during which the animals may grow significantly. We evaluated the impact of weight, age and previous drug exposure on the pharmacokinetics of rituximab. Serum concentrations of rituximab were measured after intravenous and subcutaneous dosing, in Sprague-Dawley rats between 7 to 21 weeks old and weighing between 200 to 600 g. The growth of rats during the study was incorporated into the model through the increase of the volumes of compartments in relation to the rats total body weight...
March 15, 2018: Journal of Pharmaceutical Sciences
Ting Zhang, Liping Wang, Ying Bao, Qi Yang, Lina Zhou, Hongxun Hao, Chuang Xie
Polymorphic forms of etoricoxib have been reported in the literature and form I was considered to be the most stable one. However, in this work, it was found that form I and form V are enantiotropic by DSC analysis, solubility measurements and solution-mediated polymorphic transformation experiments with form V being more stable than form I at room temperature. Thermodynamic transition temperature is determined as (353.45 ± 0.10) K. Besides, form V would transform to form I with the seeding effect of form I at high temperature below the melting point of form V...
March 15, 2018: Journal of Pharmaceutical Sciences
C M Chavez-Eng, R W Lutz, D Goykhman, K P Bateman
Methodology for analysis of a microdosing drug cocktail designed to evaluate the contribution of drug transporters and drug metabolizing enzymes to disposition was developed using LC-MS based detection. Fast and sensitive methods were developed and qualified for the quantification of statins (pitavastatin, pitavastain lactone, rosuvastatin, atorvastatin, 2-hydroxy, and 4-hydroxy atorvastatin), midazolam, and dabigatran in human plasma. Chromatographic separation was accomplished using reversed phase liquid chromatography or HILIC with gradient elution and detection by MS/MS in the positive ionization mode using electrospray ionization...
March 13, 2018: Journal of Pharmaceutical Sciences
Shaoxin Feng, Nathaniel D Catron, Alan Donghua Zhu, John M Lipari, Jianwei Wu, Yi Gao, Geoff G Z Zhang
Micellar solubilization is an important concept in the delivery of poorly water-soluble drugs. The rational selection of the type and the amount of surfactant to be incorporated in a formulation require comprehensive solubility studies. These studies are time and material demanding, both of which are scarce, especially during late discovery and early development stages. We hypothesized that, if the solubilization mechanism or molecular interaction is similar, the solubilization capacity ratio (SCR, a newly defined parameter) is dictated by micellar structures, independent of drugs...
March 13, 2018: Journal of Pharmaceutical Sciences
Lisa A Mcconnachie, Loren M Kinman, Josefin Koehn, John C Kraft, Sarah Lane, Wonsok Lee, Ann C Collier, Rodney J Y Ho
Daily oral antiretroviral therapy (ART) regimens produce limited drug exposure in tissues where residual HIV persists, and suffer from poor patient adherence and disparate drug kinetics, which all negatively impact outcomes. To address this, we developed a tissue- and cell-targeted long-acting 4-in-1 nanosuspension composed of lopinavir (LPV), ritonavir (RTV), tenofovir (TFV), lamivudine (3TC). In four macaques dosed subcutaneously, drug levels over 5 weeks in plasma, lymph node, and peripheral blood mononuclear cells (LNMCs, PBMCs) were analyzed by LC-MS/MS...
March 13, 2018: Journal of Pharmaceutical Sciences
Takehisa Nakajima, Issei Takeuchi, Hiroyuki Ohshima, Hiroshi Terada, Kimiko Makino
First, an elementary osmotic pump (EOP) with a simple structure was prepared using polyethylene oxide (PEO) and NaCl as an excipient, and the influence of the molecular-weight of PEO on drug-release was investigated. In the dissolution test of EOP, it was observed that the gelated core tablet was pushed out through the orifice. The dissolution profile of EOP was sigmoidal, and despite the short time, a zero-order release region was observed. The gel swelling rate in the zero-order region was independent of the molecular-weight of PEO...
March 13, 2018: Journal of Pharmaceutical Sciences
Hojun Song, Cheol Moon, Beom-Jin Lee, Euichaul Oh
Herein, we aimed to prepare porous granules of pravastatin and evaluate their applicability to orally disintegrating tablets (ODTs). Pravastatin solid dispersion granules (PSDGs-A) were prepared by dispersing pravastatin sodium in D-mannitol (the dispersion medium) in the presence of ammonium bicarbonate (the sublimation agent) using a spray-drying process. The PSDGs-A were round, irregularly shaped, mesoporous agglomerates with appropriate particle size, bulk density, and flowability for the tableting process...
March 9, 2018: Journal of Pharmaceutical Sciences
John M Hickey, Vishal M Toprani, Kawaljit Kaur, Ravi P N Mishra, Akshay Goel, Natalia Oganesyan, Andrew Lees, Robert Sitrin, Sangeeta B Joshi, David B Volkin
CRM197 , a single amino acid mutant of diphtheria toxoid, is a commonly used carrier protein in commercial polysaccharide-protein conjugate vaccines. In this study, CRM197 proteins from three different expression systems and five different manufacturers were obtained for an analytical comparability assessment using a wide variety of physicochemical and in vitro antigenic binding assays. A comprehensive analysis of the five CRM197 molecules demonstrate that recombinant CRM197 's expressed in heterologous systems (E...
March 8, 2018: Journal of Pharmaceutical Sciences
Franck Da-Silva, Xavier Boulenc, Hélène Vermet, Pauline Compigne, Sabine Gerbal-Chaloin, Martine Daujat-Chavanieu, Sylvie Klieber, Patrick Poulin
The objective was to compare, with the same dataset, the predictive performance of three in vitro assays of hepatic clearance (CL), namely, micropatterned cocultures (MPCC) (also referring to HepatoPac® ) and suspension as well as monolayer hepatocytes to define which assay is the most accurate. Furthermore, existing in vitro-to-in vivo extrapolation (IVIVE) methods were challenged to verify which method is the most predictive (i.e., direct scaling method without binding correction, conventional method based either on the unbound fraction in plasma (fup ) according to the free drug hypothesis, or based on an fup value adjusted for the albumin (ALB)-facilitated hepatic uptake phenomenon)...
March 7, 2018: Journal of Pharmaceutical Sciences
Hui-Lin Chen, Chen-Chen Cai, Jun-Yuan Ma, Mei-Ling Yu, Mei-Hui Zhao, Jian-Bo Guo, Hui Xu
The objective of this study was to investigate the effect of dispersion states of azone in gels on the transdermal permeation of levamisole hydrochloride (LH). LH hydro-alcoholic gels containing azone of different dispersion states were prepared by varying the contents of azone and Tween80, and the in vitro transdermal permeation of LH across excised rat skin was evaluated. Depending on the content of azone, mixed solvents and solubilizer used, azone presented as dissolved molecules, solubilized in micelles, and fine or coarse emulsion droplets in gels...
March 5, 2018: Journal of Pharmaceutical Sciences
Guo-Fu Li, Guo Yu, Yanfei Li, Yi Zheng, Qing-Shan Zheng, Hartmut Derendorf
Quantitative prediction of unbound drug fraction (fu ) is essential for scaling pharmacokinetics through physiologically-based approaches. However, few attempts have been made to evaluate the projection of fu values under pathological conditions. The primary objective of this study was to predict fu values (n=105) of 56 compounds with or without the information of predominant binding protein in patients with varying degrees of hepatic insufficiency by accounting for quantitative changes in molar concentrations of either the major binding protein or albumin plus alpha 1-acid glycoprotein (AAG) associated with differing levels of hepatic dysfunction...
March 5, 2018: Journal of Pharmaceutical Sciences
Veronika Hampl, Xinghua Guo, Christian Ehrenstrasser, Martin Viertler, Lucy Rayner, Giusy Campanelli, Reinhard Schipflinger, Karine Thewes, Alessandra Cerreti, Stephan Boehm, Corinna Sonderegger
Visible particles linked to polysorbates used in biopharmaceutical drug products have been observed repeatedly in recent years as an industry-wide issue, with polysorbate degradation and insoluble degradation products, especially fatty acids and fatty acid esters, being suspected as root-cause. We have shown that the visible particles observed in a monoclonal antibody (mAB) drug product solution in vials after 18 months of long-term storage at 5 ± 3°C were neither linked to reduction in polysorbate (PS80) concentration nor to any known polysorbate degradation product, but consist of 12-tricosanone, an impurity present in the raw material PS80, not a degradation product...
February 27, 2018: Journal of Pharmaceutical Sciences
Morgan E Gibbs, Laura A Wilt, Kaitlyn V Ledwitch, Arthur G Roberts
P-glycoprotein (Pgp) is a multidrug resistance transporter that limits the penetration of a wide range of neurotherapeutics into the brain including opioids. The diphenylpropylamine opioids methadone and loperamide are structurally similar, but loperamide has about a 4-fold higher Pgp-mediated transport rate. In addition to these differences, they showed significant differences in their effects on Pgp-mediated ATP hydrolysis. The activation of Pgp-mediated ATP hydrolysis by methadone was monophasic, while loperamide activation of ATP hydrolysis was biphasic implying methadone has a single binding site and loperamide has two binding sites on Pgp...
February 27, 2018: Journal of Pharmaceutical Sciences
Frank Karkossa, Sandra Klein
Drug release and availability at the site of action are the major factors determining the clinical response for locally-acting gastrointestinal (GI) drug products. The present work focused on the prediction of site and extent of in vivo mesalazine release after oral administration to a variety of subjects using individualized in vitro drug release experiments. First, experiments mimicking GI passages in average adult subjects were performed. Then, results from a study screening fasted in vivo pH- and transit profiles in individual subjects were translated into a novel in vitro dissolution model enabling to mimic individual GI pH-profiles and transit times with physiologically relevant dissolution media...
February 27, 2018: Journal of Pharmaceutical Sciences
Kazue Kimura, Saho Onishi, Kei Moriyama
The present study reports a high-throughput screening method for the salt formation of amine-containing active pharmaceutical ingredients (APIs) based on fluorescence measurements. A free form amine API was alkynylated by a solid-vapor reaction using propargyl bromide, and a fluorescent compound was produced by a subsequent reaction using 9-azidomethylanthracene. In contrast, salts were inert to propargyl bromide; thus, no fluorescence was observed. Samples for salt screening were prepared by grinding haloperidol with various counter acids, and these mixtures were derivatized in a 96-well microplate to determine whether the salt formation had occurred between haloperidol and the counter acids...
February 27, 2018: Journal of Pharmaceutical Sciences
Rajneet K Oberoi, Weihan Zhao, Dilraj S Sidhu, Rolando M Viani, Roger Trinh, Wei Liu
Glecaprevir (GLE) and pibrentasvir (PIB) are direct-acting antivirals coformulated as a combination tablet for once-daily treatment of chronic hepatitis C virus infection. The objective of this study was to evaluate the effect of different methods of tablet manipulations - cutting in half, grinding into powder, or crushing- on the bioavailability of GLE and PIB relative to whole film-coated bilayer tablets. This was a Phase 1, single-dose, open-label, randomized, five-period, nonfasting, crossover study in 25 healthy adult male and female subjects...
February 21, 2018: Journal of Pharmaceutical Sciences
Yunseok Oh, Yoo-Seong Jeong, Min-Soo Kim, Jee Sun Min, Gongmi Ryoo, Ji Eun Park, Yearin Jun, Yoo-Kyung Song, Se-Eun Chun, Songhee Han, Soo Kyung Bae, Suk-Jae Chung, Wooin Lee
Betulinic acid (BA), a plant-derived pentacyclic triterpenoid, may interact with the members of the organic anion transporting polypeptide 1B subfamily. Here, we investigated the interactions of BA and its analogs with OATP1B1/3 and rat Oatp1b2 in vitro and in vivo. BA inhibited the activity of OATP1B1/3 and rat Oatp1b2 in vitro. Systemic exposure of atorvastatin was substantially altered with the intravenous co-administration of BA (20 mg/kg). Pre-incubation (incubation with inhibitors, followed by washout) with BA led to a sustained inhibition of OATP1B3, which recovered rapidly in the media containing 10% fetal bovine serum...
February 17, 2018: Journal of Pharmaceutical Sciences
Joanne Heade, Sam Maher, Sinead B Bleiel, David J Brayden
In addition to their solubilising properties, excipients used in lipid-based formulations (LBFs) can improve intestinal permeability of macromolecules. We determined whether ad-mixing of medium chain fatty acid (MCFA) permeation enhancers (PEs) with a lipoidal excipient (Labrasol®) could potentiate trans-epithelial flux of a poorly permeable macromolecule (FITC-dextran 4 kDa, FD4) across rat intestinal mucosae mounted in Ussing chambers. Low concentrations of sodium caprate (C10 ), sodium undecylenate (C11:1 ), or sodium laurate (C12 ) combined with Labrasol® increased the Papp of FD4 to values typically seen with higher concentrations of MCFAs or Labrasol® alone...
February 17, 2018: Journal of Pharmaceutical Sciences
Battini Swapna, M K Chaitanya Mannava, Ashwini Nangia
The classic FDC of four TB drugs, namely Rifampicin (RIF), Isoniazid (INH), Pyrazinamide (PZA) and Ethambutol Dihydrochloride (EDH) has the twin issues of physical stability and rifampicin cross-reaction in the 4FDC. The major reason for these quality issues is the interaction between RIF and INH to yield isonicotinyl hydrazone (HYD) in drug tablets. Pharmaceutical cocrystals of INH with caffeic acid (PZA + EDH + RIF + INH-CFA cocrystal) and vanillic acid (PZA + EDH + RIF + INH-VLA cocrystal) are able to stabilize the FDC formulation compared to the reference batch (PZA + EDH + RIF + INH)...
February 17, 2018: Journal of Pharmaceutical Sciences
Muralikrishnan Angamuthu, Vijay Kumar Shankar, S Narasimha Murthy
Unique properties of thermodynamic activity of solvents in topical semisolids and its effects on in vitro product performance has not been fully understood. Mechanistic investigation was undertaken to demonstrate the significance of thermodynamic potential of solvents [water activity (aw ) or solvent activity (as )] on in vitro performance of model topical formulations. Drug transport across synthetic membranes was found to decrease with decreasing water activity of formulations. Similarly, in vitro permeation of model permeant (caffeine) across porcine epidermis was found to decrease with decreasing water activity of formulations...
February 17, 2018: Journal of Pharmaceutical Sciences
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