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Emerging nanomedicine applications and manufacturing: progress and challenges
APS 6th International PharmSci Conference 2015 7–9 September 2015 East Midlands Conference Centre, University of Nottingham, Nottingham, UK As part of the 6th APS International PharmSci Conference, a nanomedicine session was organised to address challenges and share experiences in this field. Topics ranged from the reporting on latest results and advances in the development of targeted therapeutics to the needs that the community faces in how to progress these exciting proof of concept results into products. Here we provide an overview of the discussion and highlight some of the initiatives that have recently been established to support the translation of nanomedicines into the clinic. </jats:p
The emerging role of physiologically based pharmacokinetic modelling in solid drug nanoparticle translation.
The use of solid drug nanoparticles (SDN) has become an established approach to improve drug delivery, supporting enhancement of oral absorption and long-acting administration strategies. A broad range of SDNs have been successfully utilised for multiple products and several development programmes are currently underway across different therapeutic areas. With some approaches, a large range of material space is available with diversity in physical characteristics, excipient choice and pharmacological behaviour. The selection of SDN lead candidates is a complex process including a broad range of in vitro and in vivo data, and a better understanding of how physical characteristics relate to performance is required. Physiologically-based pharmacokinetic (PBPK) modelling is based upon a comprehensive integration of experimental data into a mathematical description of drug distribution, allowing simulation of SDN pharmacokinetics that can be qualified in vivo prior to human prediction. This review aims to provide a description of how PBPK can find application into the development of SDN. Integration of predictive PBPK modelling into SDN development allows a better understanding of the SDN dose-response relationship, supporting a framework for rational optimisation while reducing the risk of failure in developing safe and effective nanomedicines
Role of highly branched, high molecular weight polymer structures in directing uniform polymer particle formation during nanoprecipitation
The new macromolecular architecture, hyperbranched polydendrons, are composed of a broad distribution of molecular weights and architectural variation; however, nanoprecipitation of these materials yields highly uniform, dendron-functional nanoparticles. By isolating different fractions of the diverse samples, the key role of the most highly branched structures in directing nucleation and growth has been explored and determined.</div
Use of a physiologically-based pharmacokinetic model to simulate artemether dose adjustment for overcoming the drug-drug interaction with efavirenz
PURPOSE: To treat malaria, HIV-infected patients normally receive artemether (80Â mg twice daily) concurrently with antiretroviral therapy and drug-drug interactions can potentially occur. Artemether is a substrate of CYP3A4 and CYP2B6, antiretrovirals such as efavirenz induce these enzymes and have the potential to reduce artemether pharmacokinetic exposure. The aim of this study was to develop an in vitro in vivo extrapolation (IVIVE) approach to model the interaction between efavirenz and artemether. Artemether dose adjustments were then simulated in order to predict optimal dosing in co-infected patients and inform future interaction study design. METHODS: In vitro data describing the chemical properties, absorption, distribution, metabolism and elimination of efavirenz and artemether were obtained from published literature and included in a physiologically based pharmacokinetic model (PBPK) to predict drug disposition simulating virtual clinical trials. Administration of efavirenz and artemether, alone or in combination, were simulated to mirror previous clinical studies and facilitate validation of the model and realistic interpretation of the simulation. Efavirenz (600Â mg once daily) was administered to 50 virtual subjects for 14Â days. This was followed by concomitant administration of artemether (80Â mg eight hourly) for the first two doses and 80Â mg (twice daily) for another two days. RESULTS: Simulated pharmacokinetics and the drug-drug interaction were in concordance with available clinical data. Efavirenz induced first pass metabolism and hepatic clearance, reducing artemether C(max) by 60% and AUC by 80%. Dose increases of artemether, to correct for the interaction, were simulated and a dose of 240Â mg was predicted to be sufficient to overcome the interaction and allow therapeutic plasma concentrations of artemether. CONCLUSIONS: The model presented here provides a rational platform to inform the design for a clinical drug interaction study that may save time and resource while the optimal dose is determined empirically. Wider application of IVIVE could help researchers gain a better understanding of the molecular mechanisms underpinning variability in drug disposition
Direct synthesis of nanoparticles with spatial heterogeneity for tailored cellular interactions
Long-Acting Injectable Statins-Is It Time for a Paradigm Shift?
In recent years, advances in pharmaceutical processing technologies have resulted in development of medicines that provide therapeutic pharmacokinetic exposure for a period ranging from weeks to months following a single parenteral administration. Benefits for adherence, dose and patient satisfaction have been witnessed across a range of indications from contraception to schizophrenia, with a range of long-acting medicines also in development for infectious diseases such as HIV. Existing drugs that have successfully been formulated as long-acting injectable formulations have long pharmacokinetic half-lives, low target plasma exposures, and low aqueous solubility. Of the statins that are clinically used currently, atorvastatin, rosuvastatin, and pitavastatin may have compatibility with this approach. The case for development of long-acting injectable statins is set out within this manuscript for this important class of life-saving drugs. An overview of some of the potential development and implementation challenges is also presented
Layer by layer self-assembly for coating a nanosuspension to modify drug release and stability for oral delivery
Mucus-responsive functionalized emulsions: design, synthesis and study of novel branched polymers as functional emulsifiers
Mucus lines the moist cavities throughout the body, acting as barrier by protecting the underlying cells against the external environment, but it also hinders the permeation of drugs and drug delivery systems. As the rate of diffusion is low, the development of a system which could increase retention time at the mucosal surface would prove beneficial. Here, we have designed a range of branched copolymers to act as functional mucus-responsive oil-in-water emulsifiers comprising the hydrophilic monomer oligo(ethylene glycol) methacrylate and a hydrophobic dodecyl initiator. The study aimed to investigate the importance of chain end functionality on successful emulsion formation, by systematically replacing a fraction of the hydrophobic chain ends with a secondary poly(ethylene glycol) based hydrophilic initiator in a mixed-initiation strategy; a decrease of up to 75 mole percent of hydrophobic chain ends within the branched polymer emulsifiers was shown to maintain comparative emulsion stability. These redundant chain ends allowed for functionality to be incorporated into the polymers via a xanthate based initiator containing a masked thiol group; thiol groups are known to have mucoadhesive character, due to their ability to form disulfide bonds with the cysteine rich areas of mucus. The mucoadhesive nature of emulsions stabilised by thiol-containing branched copolymers was compared to non-functional emulsions in the presence of a biosimilar mucosal substrate and enhanced adherence to the mucosal surface was observed. Importantly, droplet rupture and mucus triggered release of dye-containing oil was seen from previously highly-stable thiol-functional emulsions; this observation was not mirrored by non-functional emulsions where droplet integrity was maintained even in the presence of mucus
Cryphonectria nitschkei chrysovirus 1 with unique molecular features and a very narrow host range
Cryphonectria nitschkei chrysovirus 1 (CnCV1), was described earlier from an ascomycetous fungus, Cryphonectria nitschkei strain OB5/11, collected in Japan; its partial sequence was reported a decade ago. Complete sequencing of the four genomic dsRNA segments revealed molecular features similar to but distinct from previously reported members of the family Chrysoviridae. Unique features include the presence of a mini-cistron preceding the major large open reading frame in each genomic segment. Common features include the presence of CAA repeats in the 5′-untranslated regions and conserved terminal sequences. CnCV1-OB5/11 could be laterally transferred to C. nitschkei and its relatives C. radicalis and C. naterciae via coculturing, virion transfection and protoplast fusion, but not to fungal species other than the three species mentioned above, even within the genus Cryphonectria, suggesting a very narrow host range. Phenotypic comparison of a few sets of CnCV1-infected and -free isogenic strains showed symptomless infection in new hosts
Understanding the Degradation of Core-Shell Nanogels Using Asymmetrical Flow Field Flow Fractionation
Nanogels are candidates for biomedical applications, and core-shell nanogels offer the potential to tune thermoresponsive behaviour with the capacity for extensive degradation. These properties were achieved by the combination of a core of poly(N-isopropylmethacrylamide) and a shell of poly(N-isopropylacrylamide), both crosslinked with the degradable crosslinker N,N'-bis(acryloyl)cystamine. In this work, the degradation behaviour of these nanogels was characterised using asymmetric flow field flow fractionation coupled with multi-angle and dynamic light scattering. By monitoring the degradation products of the nanogels in real-time, it was possible to identify three distinct stages of degradation: nanogel swelling, nanogel fragmentation, and nanogel fragment degradation. The results indicate that the core-shell nanogels degrade slower than their non-core-shell counterparts, possibly due to a higher degree of self-crosslinking reactions occurring in the shell. The majority of the degradation products had molecule weights below 10 kDa, which suggests that they may be cleared through the kidneys. This study provides important insights into the design and characterisation of degradable nanogels for biomedical applications, highlighting the need for accurate characterisation techniques to measure the potential biological impact of nanogel degradation products
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