Systems biology approach to study permeability of paracetamol and its solid dispersion

Physiological changes that take place at cellular level are usually reflective of their level of gene expression. Different formulation excipients have an impact on physiological behavior of the exposed cells and in turn affect transporter genes, enterocyte-mediated metabolism and toxicity biomarkers. The aim of this study was to prepare solid dispersion of paracetamol and evaluate genetic changes that occur in Caco-2 cell lines during the permeability of paracetamol alone and paracetamol solid dispersion formulations. Paracetamol-PEG 8000 solid dispersion was prepared by melt fusion method and the formulation was characterised using differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). Formulation of solid dispersion resulted in the conversion of crystalline drug into an amorphous form. Permeability studies showed that paracetamol absorption was higher from the solid dispersion formulation. DNA microarrays analysis was carried out in order to investigate the involvement of any efflux/uptake transporters in paracetamol or its solid dispersion permeability. Neither transporter carriers nor efflux proteins were found to be involved in the absorption of paracetamol or its PEG solid dispersion. Gene expression analysis established that paracetamol toxicity was potentially reduced upon formulation into solid dispersion when ATP binding cassette (ABC) and solute carrier transporter (SLC) genes were analyzed.

Dissolution rate enhancement, in vitro evaluation and investigation of drug release kinetics of chloramphenicol and sulphamethoxazole solid dispersions

Formulation of solid dispersions is one of the effective methods to increase the rate of solubilization and dissolution of poorly soluble drugs. Solid dispersions of chloramphenicol (CP) and sulphamethoxazole (SX) as model drugs were prepared by melt fusion method using polyethylene glycol 8000 (PEG 8000) as an inert carrier. The dissolution rate of CP and SX were rapid from solid dispersions with low drug and high polymer content. Characterization was performed using fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). FTIR analysis for the solid dispersions of CP and SX showed that there was no interaction between PEG 8000 and the drugs. Hyper-DSC studies revealed that CP and SX were converted into an amorphous form when formulated as solid dispersion in PEG 8000. Mathematical analysis of the release kinetics demonstrated that drug release from the various formulations followed different mechanisms. Permeability studies demonstrated that both CP and SX when formulated as solid dispersions showed enhanced permeability across Caco-2 cells and CP can be classified as well-absorbed compound when formulated as solid dispersions. © 2013 Informa Healthcare USA, Inc.

Physicochemical characterisation, drug polymer dissolution and in vitro evaluation of phenacetin and phenylbutazone solid dispersions with polyethylene glycol 8000

Poor water solubility leads to low dissolution rate and consequently, it can limit bioavailability. Solid dispersions, where the drug is dispersed into an inert, hydrophilic polymer matrix can enhance drug dissolution. Solid dispersions were prepared using phenacetin and phenylbutazone as model drugs with polyethylene glycol (PEG) 8000 (carrier), by melt fusion method. Phenacetin and phenylbutazone displayed an increase in the dissolution rate when formulated as solid dispersions as compared with their physical mixture and drug alone counterparts. Characterisation of the solid dispersions was performed using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). DSC studies revealed that drugs were present in the amorphous form within the solid dispersions. FTIR spectra for the solid dispersions of drugs suggested that there was a lack of interaction between PEG 8000 and the drug. However, the physical mixture of phenacetin with PEG 8000 indicated the formation of hydrogen bond between phenacetin and the carrier. Permeability of phenacetin and phenylbutazone was higher for solid dispersions as compared with that of drug alone across Caco-2 cell monolayers. Permeability studies have shown that both phenacetin and phenylbutazone, and their solid dispersions can be categorised as well-absorbed compounds.

Genomic evaluation during permeability of indomethacin and its solid dispersion

Drug resistance was first identified in cancer cells that express proteins known as multidrug resistance proteins that extrude the therapeutic agents out of the cells resulting in alteration of pharmacokinetics, tissue distribution, and pharmacodynamics of drugs. To this end studies were carried out to investigate the role of pharmacological inhibitors and pharmaceutical excipients with a primary focus on P-glycoprotein (P-gp). The aim of this study was to investigate holistic changes in transporter gene expression during permeability upon formulation of indomethacin as solid dispersion. Initial characterization studies of solid dispersion of indomethacin showed that the drug was dispersed within the carrier in amorphous form. Analysis of permeability data across Caco-2 monolayers revealed that drug absorption increased by 4-fold when reformulated as solid dispersion. The last phase of the work involved investigation of gene expression changes of transporter genes during permeability. The results showed that there were significant differences in the expression of both ATP-binding cassette (ABC) transporter genes as well as solute carrier transporter (SLC) genes suggesting that the inclusion of polyethylene glycol as well as changes in molecular form of drug from crystalline to amorphous have a significant bearing on the expression of transporter network genes resulting in differences in drug permeability. © 2011 Informa UK, Ltd.

Solid dispersions: formulation, characterisation, permeability and genomic evaluation

Poor water solubility is characterised by low dissolution rate and consequently reduced bioavailability. Formulation of solid dispersion of the drug has attracted considerable interest as a means of improving dissolution process of a range of poorly water soluble drugs. This current study investigates the formulation of solid dispersion for a range of poorly water soluble drugs with varying physicochemical properties including paracetamol, sulphamethoxazole, phenacetin, indomethacin, chloramphenicol, phenylbutazone and succinylsulphathiazole. Solid dispersions were prepared using various drugs to polymer ratios. PEG 8000 was selected as a carrier in the solid dispersions. The study revealed that inclusion of drug within the polymeric matrix, ratio of drug to polymer and physicochemical properties of the drug molecules enhance the dissolution rate. Characterisations of the solid dispersions were performed using DSC, FTIR and SEM. These studies revealed that all seven drugs were present in the amorphous form within the solid dispersions and there was a lack of interaction between the PEG 8000 and drug. Stability studies for solid dispersions showed that all seven drugs studied were unstable at accelerated conditions (40°C±2°C/75%RH±5%RH) whereas, they were found to be stable for 12 months at room conditions. Permeability of indomethacin, phenacetin, phenylbutazone and paracetamol were higher for solid dispersions as compared to drug alone across Caco-2 cell monolayers. From the cell uptake studies it was shown that PEG 8000 enhanced rhodamine123 uptake which suggested that PEG 8000 may increase the permeability of these drugs in solid dispersions. Gene expression profiles analyzing the expression changes in the ABC and solute carrier transporter during permeability studies.ABCA10, ABCB4, ABCC12, SLC12A6, MCT13, SLC22A12 and SLC6A6 gene expression were increased by indomethacin alone whereas solid dispersion of indomethacin resulted in a slight increase in expression. ABCC12 and SAMC gene expression was increased in case of paracetamol alone but slightly increased when exposed to solid dispersion of paracetamol.

The creep behaviour of pressure diecast zinc-aluminium based alloys

The creep behaviour of three pressure diecast commercial zinc-aluminium based alloys: Mazak 3, corresponding to BS 1004A, and the new alloys ZA.8 and ZA.27 with a series of alloys with compositions ranging from 0% to 30% aluminium was investigated. The total creep elongation of commercial alloys was shown to be well correlated using an empirical equation. Based on this a parametrical relationship was derived which allowed the total creep extension to be related to the applied stress, the temperature and the time of test, so that a quantitative assessment of creep of the alloys could be made under different conditions. Deviation from the normal creep kinetics occurred in alloys ZA.8 and ZA.27 at very low stresses, 150°C, due to structural coarsening combined with partial transformation of ε -phase into T' phase. The extent of primary creep was found to increase with aluminium content, but secondary creep rates decreased in the order Mazak 3, ZA.8 and ZA.27. Thus, based on the above equation, ZA.8 was found to have a substantially better total creep resistance than ZA.27, which in turn was marginally better than Mazak 3 for strains higher than 0.5%, but inferior for smaller strains, due to its higher primary creep extension. The superior creep resistance of ZA.8 was found to be due to the presence of strictly-orientated, thin plate-like precipitates of ε(CuZn4) phase in the zinc matrix of the eutectic and the lamellarly decomposed β phase, in which the precipitation morphology and orientation of ε in the zinc matrix was determined. Over broad ranges of temperature and stresses, the stress exponents and activation energies for creep were found to be consistent with some proposed creep rate mechanisms; i.e. viscous glide for Mazak 3, dislocation climb over second phase particles for ZA.8 and dislocation climb for ZA.27, controlled by diffusion in the zinc-rich phase. The morphology of aluminium and copper-rich precipitates formed from the solid solution of zinc was clearly revealed. The former were found to further increase the creep rate of inherently low creep resistant zinc, but the latter contributed significantly to the creep resistance. Excess copper in the composition, however, was not beneficial in improving the creep resistance. Decomposition of β in copper-containing alloys was found to be through a metastable Zn-Al phase which is strongly stabilised by copper, and the final products of the decomposition had a profound effect on the creep strength of the alloys. The poor creep resistance of alloy ZA.27 was due to the presence of particulate products derived from decomposed β-phase and a large volume of fine, equiaxed products of continuously decomposed α-dendrites.

Thermal treatment of biomass

A biomass pyrolysis process is provided in which biomass feedstock is mixed with a heat carrier. The heat carrier at least partly comprises char. The ratio by weight of biomass to char is in the range 1:1 to 1:20. The process may be carried out by in a screw/auger pyrolysis reactor in which the solid feedstock components are conveyed along the reactor by a first screw. A second screw conveys at least a portion of the solid products of the biomass pyrolysis back to a heat transfer medium input port. Thus, the heat transfer medium includes char from the biomass pyrolysis.

The development of a sustainable agricultural industry through the application of biochar and pyroligneous acid

This paper marks the first in a series of studies into the potential use of pyrolysis products in the development of more sustainable practices within the agricultural industry. In this study, the immediate benefits of the application of biochar to crop yields of Raphanus sativus (radishes) are assessed. Furthermore, the study reports on the preliminary findings into the potential application of pyroligneous acid (wood vinegar) as a biocidal agent against crop disease. Although germination tests undertaken on biochar/compost blends of up to 1: 2, by weight, showed no significant adverse effect from the addition of the nutrient rich carbonaceous solid, evidence of substantial increases in crop yield through the addition of biochar were not observed. In sharp contrast, zones of inhibition were observed at 3-10 vol. % upon application of pyroligneous acid to two causal agents responsible for certain diseases in vegetable and fruit crops, i.e. Rhizobium radiobacter (agrobacterium tumefaciens) and Xanthomonas campestris, highlighting the versatility in the application of pyrolysis products and avenues for exploration in the development of this biomass conversion technology.

A biological-inspired support frame for an artificial cornea

Bilateral corneal blindness represents a quarter of the total blind, world-wide. The artificial cornea in assorted forms, was developed to replace opaque non-functional corneas and to return sight in otherwise hopeless cases that were not amenable to corneal grafts; believed to be 2% of corneal blind. Despite technological advances in materials design and tissue engineering no artificial cornea has provided absolute, long-term success. Formidable problems exist, due to a combination of unpredictable wound healing and unmanageable pathology. To have a solid guarantee of reliable success an artificial cornea must possess three attributes: an optical window to replace the opaque cornea; a strong, long term union to surrounding ocular tissue; and the ability to induce desired host responses. A unique artificial cornea possesses all three functional attributes- the Osteo-odonto-keratoprosthesis (OOKP). The OOKP has a high success rate and can survive for up to twenty years, but it is complicated both in structure and in surgical procedure; it is expensive and not universally available. The aim of this project was to develop a synthetic substitute for the OOKP, based upon key features of the tooth and bone structure. In doing so, surgical complexity and biological complications would be reduced. Analysis of the biological effectiveness of the OOKP showed that the structure of bone was the most crucial component for implant retention. An experimental semi-rigid hydroxyapatite framework was fabricated with a complex bone-like architecture, which could be fused to the optical window. The first method for making such a framework, was pressing and sintering of hydroxyapatite powders; however, it was not possible to fabricate a void architecture with the correct sizes and uniformity of pores. Ceramers were synthesised using alternative pore forming methods, providing for improved mechanical properties and stronger attachment to the plastic optical window. Naturally occurring skeletal structures closely match the structural features of all forms of natural bone. Synthetic casts were fabricated using the replamineform process, of desirable natural artifacts, such as coral and sponges. The final method of construction by-passed ceramic fabrication in favour of pre-formed coral derivatives and focused on methods for polymer infiltration, adhesion and fabrication. Prototypes were constructed and evaluated; a fully penetrative synthetic OOKP analogue was fabricated according to the dimensions of the OOKP. Fabrication of the cornea shaped OOKP synthetic analogue was also attempted.

Damping in zinc-based alloys

The damping behaviour of the cold chamber pressure-die-casting alloy: M3, ZA8, ZA27, ZM11, Cosmal, Supercosmal and newly developed ZA27H1 and ZA27H2 was investigated at room temperature and elevated temperatures of up to 90 degrees C. The damping properties of the alloys were established at all temperatures. Formulas were established to predict damping properties of each alloy at any given temperature. The prediction formulae were found to be very accurate. All of the experimental alloys were heterogenous with varying microstructure and grain size; this was the major contribution and dominated the damping properties of the alloys. Super cosmal and ZA27 possessed the highest tensile strength but ZA27H1, ZA27H2 and ZM11 showed the highest damping properties. The relationship between microstructure and damping capacity of all alloys was also examined using back-scattered electron on the SEM. Further more detailed examinations of the microstructures of alloys ZM11, Cosmal and Supercosmal were carried out on the transmission electron microscope in order to establish the phases present in all alloys. These helped to obtain the mechanism of damping in the experimental alloys. The main damping mechanism in most of the experimental alloys was due to grain-boundary-sliding. Micro structural examinations also revealed the absence of -phase in the Cosmal and Supercosmal. This was thought to be due to a change in solid solubility of the alloys, which could have been caused by the addition of Si.

Employment law:an introduction for HR and business students

The Aston Centre for Human Resources (ACHR) was created at Aston Business School, Aston University, in February 2006. The mission of the Centre is both to inform and influence practice through conducting high quality, challenging research in order to extend the existing theoretical frameworks and to develop new and relevant conceptual models to represent and guide the changing realities facing businesses and the people they employ in the 21st century. * Students studying an Employment Law module on a HR or general business degree, whether undergraduate or postgraduate. * Students taking the Employment Law elective on the CIPD's Professional Development Scheme (PDS). * Students studying Employee Relations or Diversity. This new edition has been thoroughly updated, and includes expanded coverage of the impact of EU Law, and Discrimination Law including ageism, sexual orientation, religious belief, harassment and disability. The text is ideal text for those business students on undergraduate and postgraduate courses who are taking a first module in Employment Law. It covers a comprehensive range of topics enabling students to gain a solid understanding of the key principles of the subject. The engaging, authoritative writing style and range of learning features make this a refreshingly accessible and student-friendly read. Each chapter includes summaries of topical and relevant cases, direction to key sources of legal information and suggestions for further reading whilst covering the CIPD’s standards for the Employment Law elective on the Professional Development Scheme (PDS). This text includes a range of case studies, tasks and examples to consolidate learning and includes a brand new section on Employment Law study skills to help students get to grips with how to access and read law reports, understand the sources of the law, find and use up-to-date legal information (particularly websites) and how to prepare for exams and written assignments.

Precipitation studies on alloys from the system copper chromium zirconium

The precipitation reactions occurring in a series of copper-based alloys selected from the system copper-chromium-zirconium have been studied by resistometric and metallographic techniques. A survey of the factors influencing the development of copper-based alloys for high strength, high conductivity applications is followed by a more general review of contemporary materials, and illustrates that the most promising alloys are those containing chromium and zirconium. The few systematic attempts to study alloys from this system have been collated, discussed, and used as a basis for the selection of four alloy compositions viz:- Cu - 0.4% Cr Cu - 0.24. Zr Cu - 0. 3% Cr - 0.1% Zr Cu - 0.2% Cr - 0.2% Zr A description of the experimental techniques used to study the precipitation behaviour of these materials is preceeded by a discussion of the currently accepted theories relating to precipitate nucleation and growth. The experimental results are presented and discussed for each of the alloys independently, and are then treated jointly to obtain an overall assessment of the way in which the precipitation kinetics, metallography and mechanical properties vary with alloy composition and heat treatment. The metastable solid solution of copper-chromium is found to decompose by the rejection of chromium particles which maintain a coherent interface and a Kurdjumov-Sachs type crystallographic orientation relationship with the copper matrix. The addition of 0.1% zirconium to the alloy retards the rate of transformation by a factor of ten and modifies the dispersion characteristics of the precipitate without markedly altering the morphology. Further additions of zirconium lead to the growth of stacking faults during ageing, which provide favourable nucleation sites for the chromium precipitate. The partial dislocations bounding such stacking faults are also found to provide mobile heterogeneous nucleation sources for the precipitation reactions occurring in copper-zirconium.