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https://www.readbyqxmd.com/read/28204967/advantageous-solubility-permeability-interplay-when-using-amorphous-solid-dispersion-asd-formulation-for-the-bcs-class-iv-p-gp-substrate-rifaximin-simultaneous-increase-of-both-the-solubility-and-the-permeability
#1
Avital Beig, Noa Fine-Shamir, David Lindley, Jonathan M Miller, Arik Dahan
Rifaximin is a BCS class IV (low-solubility, low-permeability) drug and also a P-gp substrate. The aims of this work were to assess the efficiency of different rifaximin amorphous solid dispersion (ASDs) formulations in achieving and maintaining supersaturation and to investigate the consequent solubility-permeability interplay. Spray-dried rifaximin ASDs were prepared with different hydrophilic polymers and their ability to achieve and maintain supersaturation was assessed. Then, rifaximin's apparent intestinal permeability was investigated as a function of increasing supersaturation both in vitro using the parallel artificial membrane permeability assay (PAMPA) and in vivo using the single-pass rat intestinal perfusion (SPIP) model...
February 15, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28197827/phloretin-prevents-high-fat-diet-induced-obesity-and-improves-metabolic-homeostasis
#2
Sary Alsanea, Mingming Gao, Dexi Liu
Reactive oxygen species generated as a by-product in metabolism play a central role in the development of obesity and obesity-related metabolic complications. The objective of the current study is to explore the possibility to block obesity and improve metabolic homeostasis via phloretin, a natural antioxidant product from apple tree leaves and Manchurian apricot. Both preventive and therapeutic activities of phloretin were assessed using a high-fat diet-induced obesity mouse model. Phloretin was injected intraperitoneally twice weekly into regular and obese mice fed a high-fat diet...
February 14, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28194704/challenges-and-future-prospects-for-the-delivery-of-biologics-oral-mucosal-pulmonary-and-transdermal-routes
#3
Javier O Morales, Kristin R Fathe, Ashlee Brunaugh, Silvia Ferrati, Song Li, Miguel Montenegro-Nicolini, Zeynab Mousavikhamene, Jason T McConville, Mark R Prausnitz, Hugh D C Smyth
Biologic products are large molecules such as proteins, peptides, nucleic acids, etc., which have already produced many new drugs for clinical use in the last decades. Due to the inherent challenges faced by biologics after oral administration (e.g., acidic stomach pH, digestive enzymes, and limited permeation through the gastrointestinal tract), several alternative routes of administration have been investigated to enable sufficient drug absorption into systemic circulation. This review describes the buccal, sublingual, pulmonary, and transdermal routes of administration for biologics with relevant details of the respective barriers...
February 13, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28188574/reliable-rate-measurements-for-active-and-passive-hepatic-uptake-using-plated-human-hepatocytes
#4
Yi-An Bi, Renato Scialis, Sarah Lazzaro, Sumathy Mathialagan, Emi Kimoto, Julie Keefer, Hui Zhang, Anna M Vildhede, Chester Costales, A David Rodrigues, Larry M Tremaine, Manthena V S Varma
Transporter-mediated hepatic uptake is proven to be the rate-determining step in the systemic clearance of several drugs. Therefore, accurate measurement of active and passive uptake clearances in vitro is critical to facilitate pharmacokinetics and drug-drug interaction predictions. Here, we evaluated the plated human hepatocytes (PHH) and studied the effect of incubation temperature and inhibitor concentration on uptake measurements, in order to reliably estimate hepatic uptake components. Uptake rates measured using PHH, at 37°C without and with rifamycin SV, were comparable with those obtained from suspension hepatocytes and sandwich-cultured hepatocytes for a set of 10-13 compounds...
February 10, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28160164/liposomal-drug-product-development-and-quality-current-us-experience-and-perspective
#5
Mamta Kapoor, Sau L Lee, Katherine M Tyner
Research in the area of liposomes has grown substantially in the past few decades. Liposomes are lipid bilayer structures that can incorporate drug substances to modify the drug's pharmacokinetic profile thereby improving drug delivery. The agency has received over 400 liposomal drug product submissions (excluding combination therapies), and there are currently eight approved liposomal drug products on the US market. In order to identify the pain points in development and manufacturing of liposomal drug products, a retrospective analysis was performed from a quality perspective on submissions for new and generic liposomal drug products...
February 3, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28155028/the-two-main-goals-of-bioequivalence-studies
#6
Laszlo Endrenyi, Henning H Blume, Laszlo Tothfalusi
The principal goal of bioequivalence (BE) investigations has crucial importance and has been the subject of extensive discussions. BE studies are frequently considered to serve as procedures for sensitive discrimination. The BE investigation should be able to provide methods and conditions sensitively identifying relevant differences between drug products if such differences in fact exist. Alternatively, BE studies can be deemed as surrogates of clinical investigations assessing therapeutic equivalence. Bioequivalent drug products will be provided to patients for their benefits...
February 2, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28144911/pharmacokinetic-steady-states-highlight-interesting-target-mediated-disposition-properties
#7
Johan Gabrielsson, Lambertus A Peletier
In this paper, we derive explicit expressions for the concentrations of ligand L, target R and ligand-target complex RL at steady state for the classical model describing target-mediated drug disposition, in the presence of a constant-rate infusion of ligand. We demonstrate that graphing the steady-state values of ligand, target and ligand-target complex, we obtain striking and often singular patterns, which yield a great deal of insight and understanding about the underlying processes. Deriving explicit expressions for the dependence of L, R and RL on the infusion rate, and displaying graphs of the relations between L, R and RL, we give qualitative and quantitive information for the experimentalist about the processes involved...
January 31, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28138910/spray-dried-thiolated-chitosan-coated-sodium-alginate-multilayer-microparticles-for-vaginal-hiv-microbicide-delivery
#8
Jianing Meng, Vivek Agrahari, Miezan J Ezoulin, Sudhaunshu S Purohit, Tao Zhang, Agostino Molteni, Daniel Dim, Nathan A Oyler, Bi-Botti C Youan
It is hypothesized that novel thiolated chitosan-coated multilayer microparticles (MPs) with enhanced drug loading are more mucoadhesive than uncoated MPs and safe in vivo for vaginal delivery of topical anti-HIV microbicide. Formulation optimization is achieved through a custom experimental design and the alginate (AG) MPs cores are prepared using the spray drying method. The optimal MPs are then coated with the thiolated chitosan (TCS) using a layer-by-layer method. The morphological analysis, in situ drug payload, in vitro drug release profile, and mucoadhesion potential of the MPs are carried out using scanning electron microscopy, solid-state (31)P NMR spectroscopy, UV spectroscopy, fluorescence imaging and periodic acid Schiff method, respectively...
January 30, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28138909/colloidal-gels-with-extracellular-matrix-particles-and-growth-factors-for-bone-regeneration-in-critical-size-rat-calvarial-defects
#9
Jakob M Townsend, S Connor Dennis, Jonathan Whitlow, Yi Feng, Jinxi Wang, Brian Andrews, Randolph J Nudo, Michael S Detamore, Cory J Berkland
Colloidal gels encapsulating natural materials and exhibiting paste-like properties for placement are promising for filling complex geometries in craniofacial bone regeneration applications. Colloidal materials have demonstrated modest clinical outcomes as bone substitutes in orthopedic applications, but limited success in craniofacial applications. As such, development of a novel colloidal gel will fill a void in commercially available products for use in craniofacial reconstruction. One likely application for this technology is cranial reconstruction...
January 30, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28120254/application-of-pharmacokinetics-and-pharmacodynamics-in-product-life-cycle-management-a-case-study-with-a-carbidopa-levodopa-extended-release-formulation
#10
Nishit B Modi
Increasing costs in discovering and developing new molecular entities and the continuing debate on limited company pipelines mean that pharmaceutical companies are under significant pressure to maximize the value of approved products. Life cycle management in the context of drug development comprises activities to maximize the effective life of a product. Life cycle approaches can involve new formulations, new routes of delivery, new indications or expansion of the population for whom the product is indicated, or development of combination products...
January 24, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28116678/inclusion-of-digestible-surfactants-in-solid-smedds-formulation-removes-lag-time-and-influences-the-formation-of-structured-particles-during-digestion
#11
Kapilkumar Vithani, Adrian Hawley, Vincent Jannin, Colin Pouton, Ben J Boyd
Solid self-microemulsifying drug delivery systems (SMEDDS) have received considerable attention in recent times attempting to overcome the drawbacks of liquid SMEDDS. Earlier literature reports on solid SMEDDS have focussed on formulation development; however, the digestibility and propensity for self-assembly of the digested components with endogenous bile salts and phospholipids are unknown. Therefore, as a starting point, previously reported solid SMEDDS containing Gelucire® 44/14 (GEL) and the non-digestible surfactants, Vitamin E TPGS (TPGS) and Lutrol® F 127 (F 127), were prepared, and their dispersion and digestion behaviours were studied using an in vitro lipolysis model, coupled with small-angle X-ray scattering (SAXS) to determine the formed colloidal structures during digestion in real time...
January 23, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28116677/a-heparin-purification-process-removes-spiked-transmissible-spongiform-encephalopathy-agent
#12
Cyrus Bett, Ksenija Grgac, Dianna Long, Michael Karfunkle, David A Keire, David M Asher, Luisa Gregori
In 2000, bovine heparin was withdrawn from the US market for fear of contamination with bovine spongiform encephalopathy (BSE) agent, the cause of variant Creutzfeldt-Jakob disease in humans. Thus, US heparin is currently sourced only from pig intestines. Availability of alternative sources of crude heparin, a life-saving drug, would benefit public health. Bovine heparin is an obvious option, but BSE clearance by the bovine heparin manufacturing process should be evaluated. To this end, using hamster 263K scrapie as a surrogate for BSE agent, we applied a four-step bench-scale heparin purification protocol resembling a typical heparin manufacturing process to investigate removal of the spiked scrapie agent...
January 23, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28116676/scientific-and-regulatory-considerations-for-generic-complex-drug-products-containing-nanomaterials
#13
Nan Zheng, Dajun D Sun, Peng Zou, Wenlei Jiang
In the past few decades, the development of medicine at the nanoscale has been applied to oral and parenteral dosage forms in a wide range of therapeutic areas to enhance drug delivery and reduce toxicity. An obvious response to these benefits is reflected in higher market shares of complex drug products containing nanomaterials than that of conventional formulations containing the same active ingredient. The surging market interest has encouraged the pharmaceutical industry to develop cost-effective generic versions of complex drug products based on nanotechnology when the associated patent and exclusivity on the reference products have expired...
January 23, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28097629/radiomitigation-and-tissue-repair-activity-of-systemically-administered-therapeutic-peptide-tp508-is-enhanced-by-pegylation
#14
Scott D McVicar, Kempaiah Rayavara, Darrell H Carney
TP508 is a synthetically derived tissue repair peptide that has previously demonstrated safety and potential efficacy in phase I/II clinical trials for the treatment of diabetic foot ulcers. Recent studies show that a single injection of TP508 administered 24 h after irradiation significantly increases survival and delays mortality in murine models of acute radiation mortality. Thus, TP508 is being developed as a potential nuclear countermeasure. Because of the short plasma half-life of TP508, we hypothesize that increasing the peptide bioavailability would increase TP508 efficacy or reduce the dosage required for therapeutic effects...
January 17, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28097628/erratum-to-optimal-affinity-of-a-monoclonal-antibody-guiding-principles-using-mechanistic-modeling
#15
Abhinav Tiwari, Anson K Abraham, John M Harrold, Anup Zutshi, Pratap Singh
No abstract text is available yet for this article.
January 17, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28091881/identifying-metabolites-of-meclonazepam-by-high-resolution-mass-spectrometry-using-human-liver-microsomes-hepatocytes-a-mouse-model-and-authentic-urine-samples
#16
Svante Vikingsson, Ariane Wohlfarth, Mikael Andersson, Henrik Gréen, Markus Roman, Martin Josefsson, Fredrik C Kugelberg, Robert Kronstrand
Meclonazepam is a benzodiazepine patented in 1977 to treat parasitic worms, which recently appeared as a designer benzodiazepine and drug of abuse. The aim of this study was to identify metabolites suitable as biomarkers of drug intake in urine using high-resolution mass spectrometry, authentic urine samples, and different model systems including human liver microsomes, cryopreserved hepatocytes, and a mice model. The main metabolites of meclonazepam found in human urine were amino-meclonazepam and acetamido-meclonazepam; also, minor peaks for meclonazepam were observed in three of four urine samples...
January 13, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28083797/population-pharmacokinetic-pharmacodynamic-model-of-oral-fludrocortisone-and-intravenous-hydrocortisone-in-healthy-volunteers
#17
Noureddine Hamitouche, Emmanuelle Comets, Mégane Ribot, Jean-Claude Alvarez, Eric Bellissant, Bruno Laviolle
This study aimed at describing the pharmacokinetics and the concentration-effect relationships of fludrocortisone and hydrocortisone on urinary sodium/potassium excretion in healthy volunteers. This was a placebo-controlled, randomized, double blind, crossover study, of oral fludrocortisone and intravenous hydrocortisone, given alone or in combination, in 12 healthy male volunteers. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics and pharmacokinetic-pharmacodynamic relationships on urinary sodium/potassium ratio for each drug...
January 12, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28083796/approaches-to-mitigate-the-unwanted-immunogenicity-of-therapeutic-proteins-during-drug-development
#18
Laura I Salazar-Fontana, Dharmesh D Desai, Tarik A Khan, Renuka C Pillutla, Sandra Prior, Radha Ramakrishnan, Jennifer Schneider, Alexandra Joseph
All biotherapeutics have the potential to induce an immune response. This immunological response is complex and, in addition to antibody formation, involves T cell activation and innate immune responses that could contribute to adverse effects. Integrated immunogenicity data analysis is crucial to understanding the possible clinical consequences of anti-drug antibody (ADA) responses. Because patient- and product-related factors can influence the immunogenicity of a therapeutic protein, a risk-based approach is recommended and followed by most drug developers to provide insight over the potential harm of unwanted ADA responses...
January 12, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28074350/a-comparative-study-of-the-bone-regenerative-effect-of-chemically-modified-rna-encoding-bmp-2-or-bmp-9
#19
Behnoush Khorsand, Satheesh Elangovan, Liu Hong, Alexander Dewerth, Michael S D Kormann, Aliasger K Salem
Employing cost-effective biomaterials to deliver chemically modified ribonucleic acid (cmRNA) in a controlled manner addresses the high cost, safety concerns, and lower transfection efficiency that exist with protein and gene therapeutic approaches. By eliminating the need for nuclear entry, cmRNA therapeutics can potentially overcome the lower transfection efficiencies associated with non-viral gene delivery systems. Here, we investigated the osteogenic potential of cmRNA-encoding BMP-9, in comparison to cmRNA-encoding BMP-2...
January 10, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28070717/identification-of-new-synthetic-cannabinoid-adb-chminaca-mab-chminaca-metabolites-in-human-hepatocytes
#20
Jeremy Carlier, Xingxing Diao, Cristina Sempio, Marilyn A Huestis
ADB-CHMINACA (MAB-CHMINACA) is a new synthetic cannabinoid with high potency and many reported adverse events and fatalities. The drug is currently scheduled in several countries in Europe and the USA. Analytical methods need to be developed to confirm ADB-CHMINACA intake for clinical and forensic programs. For many synthetic cannabinoids, parent compound is not detectable in biological samples after intake, making the detection of metabolites the only way to prove consumption. Therefore, detection of ADB-CHMINACA metabolites in biological specimens is critical...
January 9, 2017: AAPS Journal
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