19 research outputs found
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Effect of bore fluid composition on microstructure and performance of a microporous hollow fibre membrane as a cation-exchange substrate
This is the author accepted manuscript. The final version is available via Elsevier at http://www.sciencedirect.com/science/article/pii/S002196731500432X.Micro-capillary film (MCF) membranes are effective platforms for bioseparations and viable alternatives to established packed bed and membrane substrates at the analytical and preparative chromatography scales. Single hollow fibre (HF) MCF membranes with varied microstructures were produced in order to evaluate the effect of the bore fluid composition used during hollow fibre extrusion on their structure and performance as cation-exchange adsorbers. Hollow fibres were fabricated from ethylene-vinyl alcohol (EVOH) copolymer through solution extrusion followed by nonsolvent induced phase separation (NIPS) using bore fluids of differing composition (100wt.% N-methyl-2-pyrrolidone (NMP), 100wt.% glycerol, 100wt.% water). All HFs displayed highly microporous and mesoporous microstructures, with distinct regions of pore size <1μm, 5-15μm and up to 50μm in diameter, depending upon proximity to the bore fluid. Scanning electron microscopy (SEM) revealed skins of pore size <1μm at the inner surface of HFs produced with water and glycerol, while NMP bore fluid resulted in a skinless inner HF surface. The HFs were modified for chromatography by functionalising the polymer surface hydroxyl groups with sulphonic acid (SP) groups to produce cation-exchange adsorbers. The maximum binding capacities of the HFs were determined by frontal analysis using lysozyme solutions (0.05-100mgml(-1)) for a flow rate of 1.0mlmin(-1). The NMP-HF-SP module displayed the largest maximum lysozyme binding capacity of all the fibres produced (40.3mg lysozyme/ml adsorbent volume), a nearly 2-fold increase over the glycerol and 10-fold increase over the water variants at the same sample flow rate. The importance of NMP as a bore fluid to hollow fibre membrane performance as a result of inner surface porosity was established with a view to applying this parameter for the optimisation of multi-capillary MCF performance in future studies.The authors would like to acknowledge the financial support of the University of Cambridge CHESS scheme. The authors would like to thank Dr. Jeremy Skepper for help with SEM imaging and assistance by Dr. Bart Hallmark and Matthew Townsend
Salidroside as a Novel Protective Agent to Improve Red Blood Cell Cryopreservation.
Glycerol and trehalose have been widely examined as protective agents in the cryopreservation of red blood cells (RBCs). However, the effectiveness of these reagents alone on cell viability is moderate. Here, the addition of salidroside attenuated oxidative damage of sheep RBCs prior to and post cryostorage. The supplementation of salidroside to the cryopreservation media containing 10% glycerol improved RBC survival by approximately 61.1±4.8% vs 37.9±4.6%. A smaller effect was seen in RBCs cryopreserved in 300 mM trehalose where the addition of salidroside improved survival by 7.6±0.3%. Furthermore, the addition of salidroside to cold storage solution demonstrated a significant reduction of haemolysis after 4 days for RBCs loaded with either glycerol or trehalose, compared to cells incubated without salidroside. RBCs survival was 2-fold greater following freezing in trehalose, compared with glycerol. After 10 days, salidroside enabled a lower haemolysis of 16.7±1.3% compared to 29.0±8.4% for cells incubated without salidroside. However, salidroside had no effect on RBCs which had been frozen in glycerol as the resulting haemolysis rate by day 10 was approximately 60%. Salidroside increased glutathione reductase activity and decreased lactate dehydrogenase activity. Furthermore, it led to reduced carbonylation of proteins in both glycerol and trehalose loaded cells. Finally, no effect on lipid peroxidation was found in the glycerol loaded RBCs although this was reduced in RBCs loaded with trehalose and salidroside. The present findings confirm the potential use of salidroside as a novel protective agent in cryopreservation and refrigerated storage of sheep RBCs.King AbdulAziz City for Science and Technology (KACST), NASAThis is the final version of the article. It first appeared from the Public Library of Science via https://doi.org/10.1371/journal.pone.016274
Mimicking the Impact of Infant Tongue Peristalsis on Behavior of Solid Oral Dosage Forms Administered During Breastfeeding.
An in vitro simulation system was developed to study the effect of an infant's peristaltic tongue motion during breastfeeding on oral rapidly disintegrating tablets in the mouth, for use in rapid product candidate screening. These tablets are being designed for use inside a modified nipple shield worn by a mother during breastfeeding, a proposed novel platform technology to administer drugs and nutrients to breastfeeding infants. In this study, the release of a model compound, sulforhodamine B, from tablet formulations was studied under physiologically relevant forces induced by compression and rotation of a tongue mimic. The release profiles of the sulforhodamine B in flowing deionized water were found to be statistically different using 2-way ANOVA with matching, when tongue mimic rotation was introduced for 2 compression levels representing 2 tongue strengths (p = 0.0013 and p < 0.0001 for the lower and higher compression settings, respectively). Compression level was found to be a significant factor for increasing model compound release at rotational rates representing nonnutritive breastfeeding (p = 0.0162). This novel apparatus is the first to simulate the motion and pressures applied by the tongue and could be used in future infant oral product development.This work was made possible through the generous support of the Saving Lives at Birth partners: the United States Agency for International Development (USAID), the Government of Norway, the Bill & Melinda Gates Foundation (grant number: OPP1129832), Grand Challenges Canada, and the UK Department for International Development (DFID); as well as the Gates Cambridge Trust.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.xphs.2016.08.00
Nano toolbox in immune modulation and nanovaccines.
Despite the great success of vaccines over two centuries, the conventional strategy is based on attenuated/altered microorganisms. However, this is not effective for all microbes and often fails to elicit a protective immune response, and sometimes poses unexpected safety risks. The expanding nano toolbox may overcome some of the roadblocks in vaccine development given the plethora of unique nanoparticle (NP)-based platforms that can successfully induce specific immune responses leading to exciting and novel solutions. Nanovaccines necessitate a thorough understanding of the immunostimulatory effect of these nanotools. We present a comprehensive description of strategies in which nanotools have been used to elicit an immune response and provide a perspective on how nanotechnology can lead to future personalized nanovaccines
Characterising the disintegration properties of tablets in opaque media using texture analysis.
Tablet disintegration characterisation is used in pharmaceutical research, development, and quality control. Standard methods used to characterise tablet disintegration are often dependent on visual observation in measurement of disintegration times. This presents a challenge for disintegration studies of tablets in opaque, physiologically relevant media that could be useful for tablet formulation optimisation. This study has explored an application of texture analysis disintegration testing, a non-visual, quantitative means of determining tablet disintegration end point, by analysing the disintegration behaviour of two tablet formulations in opaque media. In this study, the disintegration behaviour of one tablet formulation manufactured in-house, and Sybedia Flashtab placebo tablets in water, bovine, and human milk were characterised. A novel method is presented to characterise the disintegration process and to quantify the disintegration end points of the tablets in various media using load data generated by a texture analyser probe. The disintegration times in the different media were found to be statistically different (P<0.0001) from one another for both tablet formulations using one-way ANOVA. Using the Tukey post-hoc test, the Sybedia Flashtab placebo tablets were found not to have statistically significant disintegration times from each other in human versus bovine milk (adjusted P value 0.1685).This work was made possible through the generous support of the Saving Lives at Birth partners: the United States Agency for International Development (USAID), the Government of Norway, the Bill & Melinda Gates Foundation, Grand Challenges Canada and the UK Department for International Development (DFID).This is the accepted manuscript. The final version is available at http://www.sciencedirect.com/science/article/pii/S0378517315002392#
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Amorphous metal-organic frameworks for drug delivery.
We report the encapsulation of the hydrophilic model molecule calcein in the Zr-based MOF UiO-66, followed by amorphization of the framework by ball-milling. We show controlled release of calcein over more than 30 days, compared with the 2 day release period from crystalline UiO-66.C.A.O. thanks Becas Chile and the Cambridge Trust for funding. T.D.B. thanks Trinity Hall (University of Cambridge) for funding. D.F.-J. thanks the Royal Society (UK) for funding through a University Research Fellowship. A.K.C is grateful to the European Research Council for an Advanced Investigator Award.This is the author accepted manuscript. The final version is available from the Royal Society of Chemistry at http://dx.doi.org/10.1039/C5CC05237
Functionalized micro-capillary film for the rapid at-line analysis of IgG aggregates in a cell culture bioreactor.
A micro-capillary film has been developed that offers the potential for an at-line analytical tool for rapid aggregate analysis during biopharmaceutical antibody production. A non-porous walled micro-capillary film (NMCF) with cation exchange functionality was demonstrated to act as a chromatography medium that could be operated with high linear fluid velocities and was highly resistant to blockage by entrained particulates, including cells. The NMCF containing 19 parallel microcapillaries was prepared using a melt extrusion process from poly(ethylene-vinyl alcohol) copolymer (EVOH). The NMCF-EVOH was modified to have cation-exchange functionality (NMCF-EVOH-SP) and shown to differentially bind monomer and aggregated species of IgG antibody directly from a bioreactor. The use of NMCF-EVOH-SP to quantify aggregate concentrations in monoclonal antibody preparations in less than 20 minutes was demonstrated.The authors would like to thank the EPSRC for the provision of a CASE Award. This study was sponsored by MedImmune, the global biologics R&D arm of AstraZeneca.This is the final version of the article. It first appeared from Taylor & Francis via http://dx.doi.org/10.1080/19420862.2015.106536
Drug delivery from a solid formulation during breastfeeding-A feasibility study with mothers and infants.
Funder: University of Cambridge WD Armstrong TrustFunder: University of Cambridge Kurt Hahn TrustFunder: Studienstiftung des Deutschen Volkes; funder-id: http://dx.doi.org/10.13039/501100004350BACKGROUND: Breastfeeding is critical to health outcomes, particularly in low-resource settings where there is little access to clean water. For infants in their first twelve months of life, the delivery of medications is challenging, and use of oral syringes to deliver liquid formulations can pose both practical and emotional challenges. OBJECTIVE: To explore the potential to deliver medicine to infants via a solid formulation during breastfeeding. METHODS: Single center feasibility study within a tertiary level neonatal unit in the UK, involving twenty-six breastfeeding mother-infant dyads. A solid formulation of Vitamin B12 was delivered to infants during breastfeeding. Outcomes included the quantitative change in serum vitamin B12 and assessment of maternal expectations and experiences. RESULTS: Delivery of Vitamin B12 through a solid formulation that dissolved in human milk did not impair breastfeeding, and Vitamin B12 levels rose in all infants from a mean baseline (range) 533 pg/mL (236-925 pg/mL) to 1871 pg/mL (610-4981 pg/mL) at 6-8 hours post-delivery. Mothers described the surprising ease of 'drug' delivery, with 85% reporting a preference over the use of syringes. CONCLUSIONS: Solid drug formulations can be delivered during breastfeeding and were preferred by mothers over the delivery of liquid formulations via a syringe
Using the Slug Mucosal Irritation Assay to Investigate the Tolerability of Tablet Excipients on Human Skin in the Context of the Use of a Nipple Shield Delivery System.
PURPOSE: Neonates are particularly challenging to treat. A novel patented drug delivery device containing a rapidly disintegrating tablet held within a modified nipple shield (NSDS) was designed to deliver medication to infants during breastfeeding. However concerns exist around dermatological nipple tolerability with no pharmaceutical safety assessment guidance to study local tissue tolerance of the nipple and the areola. This is the first Slug Mucosal Irritation (SMI) study to evaluate irritancy potential of GRAS excipients commonly used to manufacture rapidly disintegrating immediate release solid oral dosage form METHODS: Zinc sulphate selected as the antidiarrheal model drug that reduces infant mortality, was blended with functional excipients at traditional levels [microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, magnesium stearate]. Slugs were exposed to blends slurried in human breast milk to assess their stinging, itching or burning potential, using objective values such as mucus production to categorize irritation potency RESULTS: Presently an in vivo assay, previously validated for prediction of ocular and nasal irritation, was used as an alternative to vertebrate models to anticipate the potential maternal dermatological tolerability issues to NSDS tablet components. The excipients did not elicit irritancy. However, mild irritancy was observed when zinc sulphate was present in blends. CONCLUSION: These promising good tolerability results support the continued investigation of these excipients within NSDS rapidly disintegrating tablet formulations. Topical local tolerance effects being almost entirely limited to irritation, the slug assay potentially adds to the existing preformulation toolbox, and may sit in between the in vitro and existing in vivo assays.This work was made possible through the support of the Saving Lives at Birth partners: the United States Agency for International Development (USAID), the Government of Norway, the Bill & Melinda Gates Foundation, Grand Challenges Canada, and the UK Department for International Development (DFID). Additional support was provided by the Gates Cambridge Trust
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Human leukemia cells (HL-60) proteomic and biological signatures underpinning cryo-damage are differentially modulated by novel cryo-additives.
BACKGROUND: Cryopreservation is a routinely used methodology for prolonged storage of viable cells. The use of cryo-protective agents (CPAs) such as dimethylsulfoxide (DMSO), glycerol, or trehalose is paramount to reducing cellular cryo-injury, but their effectiveness is still limited. The current study focuses on establishing and modulating the proteomic and the corresponding biological profiles associated with the cryo-injury of human leukemia (HL-60) cells cryopreserved in DMSO alone or DMSO +/- novel CPAs (e.g., nigerose [Nig] or salidroside [Sal]). FINDINGS: To reduce cryo-damage, HL-60 cells were cultured prior and post cryopreservation in malondialdehyde Roswell Park Memorial Institute medium-1640 media +/- Nig or Sal. Shotgun proteomic analysis showed significant alterations in the levels of proteins in cells cryopreserved in Nig or Sal compared to DMSO. Nig mostly affected cellular metabolism and energy pathways, whereas Sal increased the levels of proteins associated with DNA repair/duplication, RNA transcription, and cell proliferation. Validation testing showed that the proteome profile associated with Sal was correlated with a 2.8-fold increase in cell proliferative rate. At the functional level, both Nig and Sal increased glutathione reductase (0.0012±6.19E-05 and 0.0016±3.04E-05 mU/mL, respectively) compared to DMSO controls (0.0003±3.7E-05 mU/mL) and reduced cytotoxicity by decreasing lactate dehydrogenase activities (from -2.5 to -4.75 fold) and lipid oxidation (-1.6 fold). In contrast, only Nig attenuated protein carbonylation or oxidation. CONCLUSIONS: We have identified key molecules and corresponding functional pathways underpinning the effect of cryopreservation (+/- CPAs) of HL-60 cells. We also validated the proteomic findings by identifying the corresponding biological profiles associated with promoting an anti-oxidative environment post cryopreservation. Nig or Sal in comparison to DMSO showed differential or additive effects in regard to reducing cryo-injury and enhancing cell survival/proliferation post thaw. These results can provide useful insight to cryo-damage and the design of enhanced cryomedia formulation