New methods for the production of oral dosage forms

This thesis was previously held under moratorium from 18/11/19 to 18/11/21Oral drug delivery remains the preferred method of API administration, but Biopharmaceutical Classification System Class II drugs are not ideally suited to this due to their inherent poor solubility. The current study aims to utilise the innovative formulation technique of aerosol jet printing to increase the dissolution capability of poorly soluble drugs. Aerosol jet printing Class II drugs with an appropriate stabilising polymer reduces crystallinity, increasing drug solubility. Furthermore, in the presence of sufficient polymer content, fully amorphous products can be produced resulting in enhanced dissolution capabilities. The intrinsic dissolution rate of fenofibrate was found to increase by 10-fold on printing with PVP K30. A lesser increase was typically seen on printing the materials as separate layers, but a slight loss of crystallinity does suggest that there are some interactions happening at the interface. Printing with PVP K30 was also found to increase the intrinsic dissolution rate of ibuprofen, with 3-fold increase on formation of amorphous material. Aerosol jet printing also allows a high degree of precision, enabling control of drug location to the micrometre, production of scalable dosage forms and control of drug distribution within solid dispersions. This high degree of precision has also enabled design of more complex dosage forms with a view to generating a pulsatile release profile in an entirely novel manner. Scale up of printing was attempted to allow demonstration of high precision printing of a full-size tablet. Unfortunately, dissolution testing of the full-size tablet failed but it is hoped this technology could be developed further in the future. Overall this thesis demonstrates the ability of the aerosol jet technology to be applied to pharmaceutical manufacturing in a precise manner to increase dissolution of poorly soluble compounds. Future work could include development of the technique for use in production of more complex customisable dosage forms.Oral drug delivery remains the preferred method of API administration, but Biopharmaceutical Classification System Class II drugs are not ideally suited to this due to their inherent poor solubility. The current study aims to utilise the innovative formulation technique of aerosol jet printing to increase the dissolution capability of poorly soluble drugs. Aerosol jet printing Class II drugs with an appropriate stabilising polymer reduces crystallinity, increasing drug solubility. Furthermore, in the presence of sufficient polymer content, fully amorphous products can be produced resulting in enhanced dissolution capabilities. The intrinsic dissolution rate of fenofibrate was found to increase by 10-fold on printing with PVP K30. A lesser increase was typically seen on printing the materials as separate layers, but a slight loss of crystallinity does suggest that there are some interactions happening at the interface. Printing with PVP K30 was also found to increase the intrinsic dissolution rate of ibuprofen, with 3-fold increase on formation of amorphous material. Aerosol jet printing also allows a high degree of precision, enabling control of drug location to the micrometre, production of scalable dosage forms and control of drug distribution within solid dispersions. This high degree of precision has also enabled design of more complex dosage forms with a view to generating a pulsatile release profile in an entirely novel manner. Scale up of printing was attempted to allow demonstration of high precision printing of a full-size tablet. Unfortunately, dissolution testing of the full-size tablet failed but it is hoped this technology could be developed further in the future. Overall this thesis demonstrates the ability of the aerosol jet technology to be applied to pharmaceutical manufacturing in a precise manner to increase dissolution of poorly soluble compounds. Future work could include development of the technique for use in production of more complex customisable dosage forms

Pharmacotherapies for COPD

This review article summarizes the main treatments for chronic obstructive pulmonary disease, their mechanisms, and the key evidence from trials supporting their use. Drug classes covered were short acting beta agonists (SABA), short acting muscarinic antagonists (SAMA), long acting beta agonists (LABA), long acting antimuscarinics (LAMA), inhaled corticosteroids (ICS), LABA/ ICS combinations, specific phosphodiesterase (PDE4) inhibitors, non-specific PDE inhibitors, mucolytics, and oxygen. Non-specific therapies, such as opiates for relief of dyspnoea and therapies for smoking cessation, are also covered briefly. For each class of drug, mechanisms of action are described, key clinical trial results are reported, and available agents compared. Finally, the place of each drug in therapy is compared between current worldwide guidelines

Modelling long term digital preservation costs: a scientific data case study

In recent years there has been increasing UK Government pressure on publicly funded researchers to plan the preservation and ensure the accessibility of their data for the long term. A critical challenge in implementing a digital preservation strategy is the estimation of such a programme’s cost. This pa-per presents a case study based on the cost estimation of preserving scientific data produced in the ISIS facility based at The Science and Technology Facilities Council (STFC) Rutherford Appleton Laboratory UK. The model for cost estimation for long term digital preservation is presented along with an outline of the development and validation activities undertaken as part of this project. The framework and methodology from this research provide an insight into the task of costing long term digital preservation processes, and can potentially be adapted to deliver benefits to other organisa-tions

Pulmonary MicroRNA changes alter angiogenesis in chronic obstructive pulmonary disease and lung cancer

The pulmonary endothelium is dysfunctional in chronic obstructive pulmonary disease (COPD), a known risk factor for lung cancer. The pulmonary endothelium is altered in emphysema, which is disproportionately affected by cancers. Gene and microRNA expression differs between COPD and non-COPD lung. We hypothesised that the alteration in microRNA expression in the pulmonary endothelium contributes to its dysfunction. A total of 28 patients undergoing pulmonary resection were recruited and endothelial cells were isolated from healthy lung and tumour. MicroRNA expression was compared between COPD and non-COPD patients. Positive findings were confirmed by quantitative polymerase chain reaction (qPCR). Assays assessing angiogenesis and cellular migration were conducted in Human Umbilical Vein Endothelial Cells (n = 3–4) transfected with microRNA mimics and compared to cells transfected with negative control RNA. Expression of miR-181b-3p, miR-429 and miR-23c (all p < 0.05) was increased in COPD. Over-expression of miR-181b-3p was associated with reduced endothelial sprouting (p < 0.05). miR-429 was overexpressed in lung cancer as well and exhibited a reduction in tubular formation. MicroRNA-driven changes in the pulmonary endothelium thus represent a novel mechanism driving emphysema. These processes warrant further study to determine if they may be therapeutic targets in COPD and lung cancer

Association of occupational heat exposure and colorectal cancer in the MCC-Spain study

Objective Heat exposure and heat stress/strain is a concern for many workers. There is increasing interest in potential chronic health effects of occupational heat exposure, including cancer risk. We examined potential associations of occupational heat exposure and colorectal cancer (CRC) risk in a large Spanish multi-case–control study. Methods We analyzed data on 1198 histologically confirmed CRC cases and 2690 frequency-matched controls. The Spanish job-exposure matrix, MatEmEsp, was used to assign heat exposure estimates to the lifetime occupations of participants. Three exposure indices were assessed: ever versus never exposed, cumulative exposure and duration (years). We estimated odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression adjusting for potential confounders. Results Overall, there was no association of ever, compared with never, occupational heat exposure and CRC (OR 1.09, 95% CI 0.92–1.29). There were also no associations observed according to categories of cumulative exposure or duration, and there was no evidence for a trend. There was no clear association of ever occupational heat exposure and CRC in analysis conducted among either men or women when analyzed separately. Positive associations were observed among women in the highest categories of cumulative exposure (OR 1.81, 95% CI 1.09–3.03) and duration (OR 2.89, 95% CI 1.50–5.59) as well as some evidence for a trend (P<0.05). Conclusion Overall, this study provides no clear evidence for an association between occupational heat exposure and CRC.The study was partially funded by the "Accion Transversal del Cancer", approved by the Spanish Ministry Council on 11 October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/1359, PI09/00773, PI09/01286, PI09/01903, PI09/02078, PI09/01662, PI11/01403, PI11/01889, PI12/00265), the Fundación Marqués de Valdecilla (API 10/09), the Junta de Castilla y León (LE22A10-2), the Consejería de Salud of the Junta de Andalucía (2009-S0143), the Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10), the Recercaixa (2010ACUP 00310), the Regional government of the Basque Country, the Consejería de Sanidad de la Región de Murcia, the European Commission grants FOOD-CT-2006–036224-HIWATE, the Spanish Association Against Cancer (AECC) Scientific Foundation, the Catalan Government DURSI grant 2014SGR647, the support of the Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia (2017SGR1085), the Fundación Caja de Ahorros de Asturias and by the University of Oviedo. MCT is funded by a Ramón y Cajal fellowship (RYC-2017-01892) from the Spanish Ministry of Science, Innovation and Universities and co-funded by the European Social Fund. We acknowledge support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. Statistical assistance provided by Ana Espinosa Morano was greatly appreciated

Personalizing medicine for metastatic colorectal cancer: Current developments

Metastatic colorectal cancer (mCRC) is still one of the tumor types with the highest incidence and mortality. In 2012, colorectal cancer was the second most prevalence cancer among males (9%) and the third among females (8%). In this disease, early diagnosis is important to improve treatment outcomes. However, at the time of diagnosis, about one quarter of patients already have metastases, and overall survival of these patients at 5-years survival is very low. Because of these poor statistics, the development of new drugs against specific targets, including the pathway of angiogenesis, has witnessed a remarkable increase. So, targets therapies through epidermal growth factor and its receptor and also KRAS pathways modulation acquired a main role whether in association with standard chemotherapy and radiotherapy. With the current knowledge in the field of molecular biology, including genetic mutations and polymorphisms, we know better why patients respond so differently to the same treatments. So, in the future we can develop increasingly personalized treatments to the patient and not the disease. This review aims to summarize some molecular pathways and their relation to tumor growth, as well as novel targeted developing drugs and recently approved for mCRC. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.info:eu-repo/semantics/publishedVersio

Inkjet printing of oral dosage forms to solubilize BCS Class II drugs

Oral drug delivery remains the preferred method of administration but BCS Class II drugs are not ideally suited to this due to their inherent poor solubility. Although a number of methods to increase solubility already exist, there is a need for less damaging methods of production which are more flexible to the needs of the patient. The innovative formulation method of inkjet printing has been suggested for this purpose as it has the capacity to produce highly precise dosing in a continuous manner. The Optomec Aerosol Jet 200 Printer utilised in the current study has never been used in pharmaceutical research before and it is highly interesting as it functions in a manner akin to a miniaturised spray dryer. Due to the low dose content of a single layer, formulations can be easily tailored to the patient’s individual requirements by changing the size and speed of deposition, utilising different nozzle sizes and layering to increase the overall dose. Raman spectroscopy, scanning electron microscopy and powder x-ray diffraction suggest that printing the drug alone results in a crystalline product. However, in the presence of a polymer it seems to form a less crystalline product suggesting the polymer is promoting solid dispersion formation in a similar manner to a spray dryer. Completely amorphous formulations are achieved on application of a premixed "ink" with a polymer content of 75% or more, allowing up to 25% drug loading. Drug release increases 10-fold on printing relative to a comparable powder blend and thus inkjet printing can be considered to be a viable method of improving the overall performance of the drug. The next steps will be to utilize this established methodology to produce innovative controlled release on a small scale

Inkjet printing oral dosage forms

The current study aims to establish an innovative method of effectively solubilising Biopharmaceutical Classification System Class II drugs using inkjet printing. Dosage forms have been produced using an Optomec AJ200 3D Inkjet printer. Printing with an appropriate polymer seems to result in an amorphous product, which will hopefully have a greater overall solubility