347 research outputs found
Letter from J. E. Gavin (for Senator Hayden) to Roy W. James, Michael Hanley and H. A. Montgomery
No full textLetter from J. E. Gavin on behalf of Carl Hayden writing in regards to the insurance claims filed with the National Park
The Social Construction of the Child Sex Offender Explored by Narrative
No full textThe notion of "child sex offender" provokes aversion, but it may be that it is a social construction. We suggest that a Dominant narrative, in which child sex offenders are constructed as irredeemable, persists, despite the emergence of assumption challenging Alternative narratives. A story completion method was used to elicit themes of Dominant or Alternative narratives, theory-led thematic analysis was used to identify them. The use and analysis of narrative and free-form stories are well established in social research, but remain a novel concept in the study of offenders. The results support the persistence of the Dominant narrative with two notable exceptions. Conclusions centre on utility of the narrative method to examine offender constructions, and the pervasiveness of Dominant narratives. Key Words: Dominant and Alternative Narrative, Social Construction, Child Sex Offenders, and Thematic Analysi
A comparative analysis of two different analysers used for determination of the Total Organic Carbon in pharmaceutical grade water
No full textTotal Organic Carbon (TOC) is a routine test for pharmaceutical grade water. Several manufacturers supply equipment of different designs but there is a dearth of published, peer-reviewed, information evaluating the various analysers. In this study, we compared two TOC analysers, both validated to the same pharmacopoeial criteria, but with different oxidation and detection methods. The results in this paper show that there were no unexplained out-of-specification results and that both analysers operated equivalently in terms of the pharmacopoeial 500ppb pass/fail limits. However, significant differences between the TOC levels reported from paired samples were observed, two paired samples recorded a pass/fail conflict (albeit flagged with an overestimation warning), as well as differences in analyser responses between spiked samples that contained low levels of nitro- and chloro-carbon compounds
An Novel Additive Manufacturing Micro-factory: Overcoming limitations of pharmaceutical formulations
No full text3D printing (3DP) of pharmaceutical formulations via commercially available FDM printers has gained interest in recent years, enabling personalisation of medicines. It also facilitates advanced control of the micro-structure of the tablet core, permitting fine tuning of product release characteristics with a single formulation. In addition, the technology also offers a platform for dose escalation studies employing a single formulation and single manufacturing step. FDM printers utilise filament feedstock material of specific diameter, which is conveyed by a drive gear, molten in the hot end and extruded via the nozzle of the printer. Suitable mechanical properties of the filament and physical properties of the formulation are paramount in this process. Print failure can be associated with (brittle) filament breaking in the drive gear or soft (ductile) filaments buckling in the drive gear or hot end [1, 2, 3]. The formulation space for pharmaceutical additive manufacturing is therefore very limited, since most immediate release polymers are very brittle. In this study we present a novel, filament free FDM 3D printing system (Intellectual Property Office UK, patent application number 2101534.2), overcoming limitations of unsuitable filament properties and opening up the pharmaceutical formulation space in FDM of pharmaceutical oral solid dose forms. Prasad et al reported on a 30% w/w Paracetamol (PCM) - Affinisol™ 15 LV (hydroxypropyl methylcellulose, HPMC) formulation, not printable on a conventional FDM printer [1]. This formulation was processed on the filament free FDM printer to successfully print oral solid dose forms (OSDs). In initial rheological screening tests, process conditions for initial printing trials were identified. The operating space of the printer and slicer settings in this process were investigated as well as the uniformity of mass and dimensions of printed OSDs. A relationship of Slicer Infill percentage (microstructure) and tablet core weight was also assessed, demonstrating the ability to create patient centred dose forms. Material reconciliation showed good traceability of material during the manufacturing process. This study demonstrates how an integrated HME-3DP opens up the pharmaceutical formulation space for additive manufacturing, allowing for a wider range of pharmaceutically approved polymers (and formulations) employed in additive manufacturing and personalisation of dose forms. 1.Prasad E, Islam MT, Goodwin DJ, Megarry AJ, Halbert GW, Florence AJ, Robertson J 2019. Development of a hot-melt extrusion (HME) process to produce drug loaded Affinisol™ 15LV filaments for fused filament fabrication (FFF) 3D printing. Additive Manufacturing 29:100776. 2.Zhang J, Feng X, Patil H, Tiwari RV, Repka MA 2017. Coupling 3D printing with hot-melt extrusion to produce controlled-release tablets. Int J Pharm 519(1-2):186-197. 3.Prasad, E., Robertson, J., Halbert, G.W., 2022. Mefenamic acid solid dispersions: Impact of formulation composition on processing parameters, product properties and performance. Int J Pharm 616, 121505. 10.1016/j.ijpharm.2022.12150
Manometric Temperature Measurement (MTM) lyophilisation of a challenging clinical trial pharmaceutical
No full textINTRODUCTION Cancer Research UK Formulation Unit The Formulation Unit based at the University of Strathclyde in Glasgow has a research and development history in excess of 25 years, being funded by, and working in partnership with, firstly Cancer Research Campaign, and since 2002, with Cancer Research UK. The Unit is based in an entirely academic University setting, and since 2004 has been licensed by the UK government Medicines and Healthcare products Regulatory Agency (MHRA) for research, development and manufacture of Phase I/II novel small molecule cancer therapeutics and diagnostics. Research programs have delivered new formulations to clinical trial as either sterile or non-sterile presentations. However, the Unit’s specialty is based around small volume parenteral product manufacture. Boronophenylalanine (L-BPA) in Boron Neutron Capture Therapy (BNCT) L-BPA is the premier pharmaceutical selection in BNCT in treatment of selected head and neck tumours. BNCT relies on localisation of boron 10 within a tumour mass, made possible by the amino acid carrier portion of the L-BPA molecule. Phenylalanine is selectively transported across the blood brain barrier and then into astrocytic cells by a LAT-1 transporter system that is up-regulated in tumour. A targeted external neutron beam activates the accumulated L-BPA. In brief, neutron capture by boron causes nuclear re-arrangement and formation of a high linear energy transfer alpha particle and lithium 7 nuclei. Thus the patient is dosed with localised radiotherapy. OLD FORMULATION Issues existed with the previous standard formulation of L-BPA in fructose. L-BPA complexed with fructose has low solubility of around 30mg/mL. Consequently, large administration volumes are required to achieve clinical dosing in tens of grams of drug per patient. Moreover, L-BPA in fructose solutions must be freshly prepared and administered within 48 hours for reasons of product instability (Henriksson et al, 2008). Although rare, hereditary fructose intolerance needs to be considered. Taken together, L-BPA production, preparation and patient dosing is highly challenging. NEW FORMULATION Restrictions The Formulation Unit developed a new improved formulation; the drug product was a lyophilized pH8 solution of L-BPA at 100mg/mL in 110mg/mL mannitol (Schmidt et al, 2011). When lyophilised, a shelf life of 48 months was supported for the drug product. Whilst a three times increase in solubility, and a significantly enhanced product lifetime were worthy formulation enhancements, a new restriction emerged; the solution for lyophilisation contained 21% w/v solids far exceeding the ‘normal’ region of 2% w/v to 5% w/v (Boylan and Nail, 2009). Moreover, the lyophilisation cycle of 6 days was considered commercially unfavourable. A shortened drying cycle of 1 to 3 days would be preferred. Research was therefore initiated to reduce drying cycle time utilising Manometric Temperature Measurement (MTM) technology. MTM Studies MTM controlled freeze drying systems were originally marketed in the first decade of the new millennium. The ability to use software to calculate the performance at the freeze-drying front in real time is scientifically and commercially appealing. The possibility to optimize processing conditions at that same time as data is being received invites the prospect of a reduced experimentation phase thereby rapidly reaching the goal of a maximally efficient freeze drying cycle. In theory, even a minimally experienced operator could achieve this outcome. In summary, MTM functions by taking pressure rise information at regular intervals (Giesler et al, 2007). Based on SMART® software (SP Scientific, Stone Ridge, NY, USA), hourly pressure rise data are taken at a rate of 10 samples per second. The system calculates the product temperature at the sublimation interface and mass transfer resistance of the product. Adjustments are then automatically made to the shelf temperature and system pressure to achieve a calculated target product temperature. The end of primary drying can be determined by comparing the vapour pressure of ice with the system chamber pressure. Input data is minimal, such as vial number, inner vial area, fill volume and weight, concentration, product critical temperature. MATERIALS AND METHODS Chemicals Syntagon AB, Södertälje, Sweden manufactured BPA raw material according to EU current Good Manufacturing Practice (cGMP). D-mannitol (Ph. Eur) was sourced from Sigma-Aldrich, Poole, UK, and fuming hydrochloric acid and sodium hydroxide pellets (both extra pure Ph. Eur., BP, JP, NF) were obtained from VWR International, Lutterworth, UK. Water for Irrigation (WFI) in bulk was acquired from Baxter’s Healthcare Ltd., Norfolk, UK. Type 1 clear glass 50mL vials with 20mm butyl rubber stoppers (proved clean), crimped with 20mm tear off aluminium overseals were all from Adelphi Healthcare Packaging, Haywards Heath, UK. Lyophilisation equipment MTM software (SMART®) was operated on an FTS Systems Lyostar II drier (Biopharma, Winchester, UK). CONCLUSION A new improved L-BPA formulation in mannitol has been developed and used in human clinical trial. Further research using MTM technology succeeded in reducing a 6 day drug product drying cycle to 53 hours. The formulation exhibited non-ideal behaviour, and MTM failed to predict drying parameters, e.g., base of vial temperature, that are more closely replicated in ‘ideal’ test articles such as a 5% mannitol comparator. Further test lyophilisations are required to reach ideal. ACKNOWLEDGMENTS This research is funded by Cancer Research UK. REFERENCES 1. Boylan, J.C. and Nail, S.L. Parenteral Products, in: Florence, A.T. and Siepman, J. (Eds.), Modern Pharmaceutics. Informa Healthcare, New York, 565-609 (2009). 2. Giesler, H.; Kramer, T. and Pikal, M. J. Use of manometric temperature measurement (MTM) and SMART freeze dryer technology for development of an optimised freeze drying cycle. J. Pharm Sci. 96(12), 3402-3418 (2007). 3. Henriksson, R.; Capala, J.; Michanek, A.; Lindahl, S.A.; Satford, L.G.; Franzen, L.; Blomquist, E.; Westlin, J.E. and Bergenheim, A.T. Boron neutron capture therapy (BNCT) for glioblastoma multiforme: A phase II study evaluating a prolonged high-dose of boronophenylalanine (BPA). Radiotherapy and Oncology 88, 183-191 (2008). 4. Schmidt, E.; Dooley, N.; Ford, S. J.; Elliott, M. and Halbert, G. W. Physicochemical investigation of the influence of saccharide based parenteral formulation excipients on L-p-boronphenylalanine solubilisation for Boron Neutron Capture Therapy. J. Pharm. Sci. 101(1), 223-232 (2011)
Mefenamic acid solid dispersions : impact of formulation composition on processing parameters, product properties and performance
No full textThe objective of this study was to develop an immediate release (IR), crystalline solid dispersion (CSD) formulation of Mefenamic acid (MFA) by hot-melt-extrusion (HME) and assess the impact of drug loading on process parameters, product physico-chemical properties and product performance. An HME process to produce a range of MFA-Soluplus®-Sorbitol polymer matrix CSD formulations was developed based on rheological screening assays of physical mixtures (PM). The impact of drug loading on process parameters was compared to the impact of drug loading on the physico-chemical properties of formulations. Based on process and product data, three groupings of API drug loading were identified: sub-saturated, saturated, and supersaturated systems. CSD formulations were obtained for 20 - 50% (w/w) drug loading containing the stable polymorphic form I of MFA. CSD formulations predominantly improved the consistency of the product performance. An Amorphous Solid Dispersion (ASD) was obtained for 10% (w/w) drug loading, exhibiting faster drug release even at physiologically relevant pH. This study illustrates the impact of drug loading on process and product characteristics and how a better understanding of maximum API solubility in a given polymer system can improve targeted formulation development
Social and Virtual Networks: Evaluating Synchronous Online Interviewing Using Instant Messenger
No full textThis paper describes an evaluation of the quality and utility of
synchronous online interviewing for data collection in social network
research. Synchronous online interviews facilitated by Instant Messenger
as the communication medium, were undertaken with ten final year
university students. Quantitative and qualitative content analysis of
respondent and researcher evaluation of the quality and utility of IM
indicated that IM was an integral part of student university life and also
an excellent and innovative communication platform; a potential
advancement for research interviewing. IM was subsequently compared
with face-to-face communication in terms of gains and losses for research
interviewing. The efficacy of the method of online interviewing using IM in
this context is discussed. Key Words: Synchronous Online Interviewing,
Instant Messenger, Social Support Networks, Virtual Networks, and
Content Analysi
Solid dispersions : improving drug performance through tablet micro-structure design
No full textPurpose Solid dispersions formulations manufactured by Hot-Melt-Extrusion (HME) have shown to improve drug release for BCS class II drugs, such as Mefenamic acid (MFA). Drug release for MFA is highly dependent on particle size. Commercially available MFA capsules have shown high variability in their drug release profile which may lead to variable efficacy. This study shows how solid dispersion formulations and microstructure design significantly improve product performance. Methods Solid dispersion formulation of 50% w/w Mefenamic acid (MFA, Sigma Aldrich) and Soluplus (BASF) containing 15% w/w Sorbitol (Merck) as plasticiser (SOL15) was prepared by HME (Process 11, Thermofisher). The formulation was a) pelletised and hand filled into size 0 hard gelatine capsules and b) 3D printed (3DP) with a porous core exposed to the surface (Figure 1) to achieve a MFA dose of 250mg. Neat MFA powder and a physical mixture (PM) of 50% (w/w) MFA and SOL15 powder were also hand filled into size 0 hard gelatine capsules to generate a MFA dose of 250mg. Pellets were prepared by cutting the HME filament (~2 mm diameter) to the length of approximately ~2mm. The 3DP tablets were printed with a novel in-house designed integrated HME-3D printer (Intellectual Property Office UK, patent application number 2101534.2). The 3D printed tablet shape was elliptical with a length of 22 mm, width of 12 mm and height of 5mm. The Infill % was set to 47.3%, which equated to an infill line distance of 0.85 mm (gap between infill lines). No top or bottom layer were printed to create a porous tablet core. Drug release profiles of all three formulations were established by performing a Dissolution test based on USP 37 of Mefenamic acid capsules (n=6) in Tris buffer pH 9 and UV analysis. The % drug release (normalised to tablet weight) was calculated and reported. Results Whilst MFA powder achieved a very consistent released, it failed to release >85 % content within 60 minutes (Figure 2A). The physical mixture showed greater variation between the 6 tablets, but released >85% content at 55 minutes. The pelletised solid dispersion formulation significantly improved drug release compared to neat MFA powder and the PM, >85% drug release within 35 minutes and therefore complying with pharmacopeial release requirements (>85% at 45 minutes) (Figure 2B). The variation between individual tablets was also lower compared to the PM. The 3DP tablet, with a highly controlled microstructure, achieved complete drug release at 20 minutes (91.6%). The variation in drug release was very high at 10 minutes only and very low at all other data points. Conclusions Solid dispersion formulation significantly improved the drug release profile by increasing the consistency and reducing the time to achieve complete drug release (>85%) to 35 minutes and 20 minutes for the 3DP tablet. This demonstrates the possibility of fine tuning drug release profiles through micro-structure control by 3DP
Erratum to: Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos (Nature Cell Biology, (2018), 20, 2, (144-151), 10.1038/s41556-017-0017-8)
No full textIn the version of this Letter originally published, an author error led to the affiliations for Brendan Payne, Jonathan Coxhead and Gavin Hudson being incorrect. The correct affiliations are: Brendan Payne:3Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.6Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK; this is a new affiliation 6 and subsequent existing affiliations have been renumbered. Jonathan Coxhead:11Genomic Core Facility, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK; this is a new affiliation 11 and subsequent existing affiliations have been renumbered. Gavin Hudson:3Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. In addition, in Fig. 2d, the numbers on the x-axis of the left plot were incorrectly labelled as negative; they should have been positive. These errors have now been corrected in all online versions of the Letter
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