Understanding key parameters affecting needle-free skin penetration by a parenteral drug delivery system

This thesis seeks to resolve difficulties in the development of a parenteral needle-free drug delivery system. Analysis of the penetration performance of Glide Pharma’s Solid Dose Injector in two clinical trials on man has shown that skin, and likely its inherent variation, was the cause of incomplete deliveries. As indicated by the literature and issues with previous needle-free technologies, a more complete understanding of skin penetration is required before such systems are capable of ensuring delivery across a patient population. Exploratory skin experiments led to the justification, design and build of a novel skin penetration test rig capable of simulating the delivery of a solid dose implant. This test rig, the Penetrometer, required significant software development to both stabilise and validate its performance before use on the in vivo porcine model, an established non-clinical model for drug delivery through human skin. Two non-clinical studies have been performed using the Penetrometer to capture force displacement profiles, using a metal probe equivalent to an implant, for penetration events on multiple test sites on multiple models. Significant levels of variation in key parameters were shown to be present intra- and inter-test site, as well as intra- and inter-model. It is likely that this variation, as detected in the porcine model, was the cause of problematic system performance during human clinical trials. Penetration experiments have also been performed to establish the validity of using in vitro skin or silicone rubber as an alternative test bed to in vivo models. The key parameters measured are the peak force during penetration, the displacement of the skin at penetration and the work required to penetrate the skin, with variations observed of the order of 30%, 100% and 140%, respectively. The results indicate how challenging it will be to reliably administer drugs using needle-free injection. This information should be used to better specify the device design and implant formulation to ensure delivery success. Prior to this thesis there was no quantitative data available, either published or within the collaborator, describing the magnitude and variation of the key parameters affecting needle-free skin penetration. This thesis has used the porcine model, further work must determine the parameters for the breadth of a human patient population

Further evaluation of a novel COP container system for the cryopreservation of adherent and suspension human cell types

The commercialization of cell and gene-based therapies is driving a critical need for the refinement of handling, storage and transportation procedures to ensure the integrity of the product is maintained throughout its life cycle. One such area for refinement is in the preservation of cells that is routinely performed at cryogenic temperatures. Cells are typically stored in the vapor phase of Liquid Nitrogen (LN) at approx. -180oC to eliminate the risk of any degradation. For cryogenic storage, there are various container systems that are available for research and commercial use. These include traditional polypropylene (PP) screw-cap cryovials, and container systems with glass or polymer vials that are closed with a rubber stopper and aluminum seal. Glass/rubber vial systems, although common elsewhere in the pharmaceutical industry for drug containment, are not well suited to the challenges of cryopreservation. Even beyond risk of fracture, the differences in coefficients of thermal expansion of glass and rubber can put these systems at risk of losing container closure integrity (CCI) when stored at cryogenic temperatures. Containment systems that rely on screw-caps are also at risk, as the screw thread can create a pathway that can lead to an ingress of contaminants. In contrast, a polymer/rubber vial system, comprised of materials with more comparable coefficients of thermal expansion, closed with an aluminum seal would be a better suited alternative that could better ensure that CCI is maintained throughout a product life cycle. This research presented here is a scientific evaluation of a novel cyclic olefin polymer (COP) container system. The performance at cryogenic temperatures has been demonstrated in two separate studies. An investigation conducted without cells but measuring CCI via Oxygen Headspace of vials stored at -180°C over a 90-day period has been combined with a follow up study that compared performance between COP and PP-based container systems when cryopreserving two different cell types: adherent type human mesenchymal stem cells (MSCs) and suspension type umbilical cord hematopoietic (CD34+) stem cells. The results showed that the polymer/rubber-based container closure system maintains CCI at -180°C, and that the cells were preserved well, as demonstrated by their viability, morphology and biomarker expression post-thaw. These findings, when combined with previously reported advantages of the novel COP container system [1], show that it is a highly suitable alternative to traditional packaging systems for cryopreservation in the field of cell and gene-based therapies. [1] E.J. Woods, A. Bagchi, R. Nase and V. Vilivalam, Container System for Enabling Commercial Production of Cryopreserved Cell Therapy Products, Regenerative Medicine, 5(4) (2010), 659-66

Overcoming the translational challenges of the effective administration and delivery of cells

Of the few cell-based therapies widely available today the most mature are the treatment of blood-borne cancers and wound healing. The routes of administration for these applications are well understood and a great deal of research has resolved the many biological, pharmacological and engineering challenges associated with the delivery of cells by these methods. These delivery methods are only suitable for a small proportion of the possible cell therapies. Many other treatments under development for illnesses that affect organs – such as diabetes, dermatological conditions and degenerative diseases – require more complex tools and methods to ensure cells are efficiently and effectively delivered to structures such as the pancreas, skin and brain. Injuries to musculoskeletal tissues such as cartilage, intra-vertebral disc and bone may be more easily accessed; however, they present different challenges, as the delivery methods must not reduce the long-term mechanical function of the tissue the treatment is attempting to repair. Oversights can occur due to the reliance on existing and often unsuitable pre-clinical models for delivery and experimental methods and data that cannot be readily translated into the clinic. Different cell types and their behaviours will also lead to complications, so too will engineering challenges such as dosing accuracy, delivery to the appropriate site, engraftment and cell viability after shear and thermal stresses. The delivery method and device used should be considered a crucial part of the cell therapy as a whole. Many companies in regenerative medicine have designed their own delivery device often in series, not in parallel, with the development of their product. As more treatments get closer to clinic many more different devices will be required, thus presenting opportunities for those who understand the generic delivery challenges in the field

Towards micropump- and microneedle-based drug delivery using Micro Transdermal Interface Platforms (MicroTIPs)

Micro Transdermal Interface Platforms (MicroTIPs) will combine minimally invasive microneedle arrays with highly miniaturized sensors, actuators, control electronics, wireless communications and artificial intelligence. These patch-like devices will be capable of autonomous physiological monitoring and transdermal drug delivery, resulting in increased patient adherence and devolved healthcare. In this paper, we experimentally demonstrate the feasibility of controlled transdermal drug delivery using a combination of 500 μm tall silicon microneedles, a commercial micropump, pressure and flow sensors, and bespoke electronics. Using ex-vivo human skin samples and a customized application/retraction system, leak-free delivery of volumes ranging from 0.7-1.1 mL has been achieved in under one hour. Clinical Relevance — This work experimentally confirms the feasibility of combining micropumps with microneedle arrays for applications in transdermal drug delivery

A comparison of flow- and pressure-controlled infusion strategies for microneedle-based transdermal drug delivery

Microneedle-based transdermal drug delivery is considered an attractive alternative to conventional injections using hypodermic needles due to its minimally invasive and painless nature; this has the potential to improve patient adherence to medication regimens. Hollow microneedles (MNs) are sharp, sub-millimeter protrusions with a channel that serves as a fluidic interface with the skin. This technology could be coupled with micro-pumps, embedded sensors, actuators and electronics to create Micro Transdermal Interface Platforms - smart, wearable infusion systems capable of delivering precise microdoses over a prolonged period. Using 500 µm tall hollow microneedles, ex-vivo human skin and a customized application/retraction device, this work focuses on comparing two infusion control strategies, namely ‘set pressure’ (SP) and ‘set flow’ (SF) infusion. It was found that flow-controlled infusion was capable of delivering higher volumes than pressure-driven delivery, and a mean volume of 3.8 mL was delivered using a set flowrate of 50 µL/minute. This suggests that flow driven delivery is a better control strategy and confirms that MN array retraction is beneficial for transdermal MN infusion

Quadrature by Expansion: A New Method for the Evaluation of Layer Potentials

Integral equation methods for the solution of partial differential equations, when coupled with suitable fast algorithms, yield geometrically flexible, asymptotically optimal and well-conditioned schemes in either interior or exterior domains. The practical application of these methods, however, requires the accurate evaluation of boundary integrals with singular, weakly singular or nearly singular kernels. Historically, these issues have been handled either by low-order product integration rules (computed semi-analytically), by singularity subtraction/cancellation, by kernel regularization and asymptotic analysis, or by the construction of special purpose "generalized Gaussian quadrature" rules. In this paper, we present a systematic, high-order approach that works for any singularity (including hypersingular kernels), based only on the assumption that the field induced by the integral operator is locally smooth when restricted to either the interior or the exterior. Discontinuities in the field across the boundary are permitted. The scheme, denoted QBX (quadrature by expansion), is easy to implement and compatible with fast hierarchical algorithms such as the fast multipole method. We include accuracy tests for a variety of integral operators in two dimensions on smooth and corner domains

The personality domains and styles of the Five-Factor Model are related to incident depression in Medicare recipients aged 65 to 100

OBJECTIVES: Few prospective studies have examined personality and depression in older adults. We investigated whether the Five Factor Model (FFM) of personality traits --- Neuroticism, Extraversion, Openness to Experience, Agreeableness, and Conscientiousness --- and trait combinations (styles) are related to incident major or minor depression. PARTICIPANTS/SETTING: Prospective data were gathered on a community sample of 512 older adults with disability and a history of significant health care utilization who were enrolled in a Medicare Demonstration Project. MEASUREMENTS: Depression and personality traits and styles were assessed at baseline; depression was assessed again at approximately 12 and 22 months. DESIGN: Participants who developed incident major depression were compared to those free of depression at all three assessments. Similar analyses were done for minor depression. RESULTS: High Neuroticism and low Conscientiousness were risk factors for both major and minor depression. Combinations of high Neuroticism with low or high Extraversion or high Openness conferred risk for major depression. Other novel findings for major depression revealed new trait combinations of low Conscientiousness with low or high Extraversion, high Openness, or low Agreeableness. Three trait combinations, all involving low Conscientiousness, predicted risk for minor depression: high Neuroticism, high Agreeableness, and low Openness. CONCLUSION: The present findings highlight the importance of examining combinations of personality traits or personality styles when identifying those who are most at-risk for geriatric depression. Since other personality domains may modify the risk related to high Neuroticism and low Conscientiousness, the prevention, diagnosis, and treatment of depression could be greatly improved by assessing older patients not only on all five domains of personality but in terms of their combinations

Leveraging the macro-level environment to balance work and life: an analysis of female entrepreneurs' job satisfaction

This study investigates the interactive effect of female entrepreneurs’ experience of work–life imbalance and gender-egalitarian macro-level conditions on their job satisfaction, with the prediction that the negative linear relationship between work–life imbalance and job satisfaction may be buffered by the presence of women-friendly action resources, emancipative values, and civic entitlements. Data pertaining to 7,392 female entrepreneurs from 44 countries offer empirical support for these predictions. Female entrepreneurs who are preoccupied with their ability to fulfill both work and life responsibilities are more likely to maintain a certain level of job satisfaction, even if they experience significant work–life imbalances, to the extent that they operate in supportive macro-level environments

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. Methods: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. Findings: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96–1·28). Interpretation: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. Funding: National Institute for Health Research Health Services and Delivery Research Programme

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

BACKGROUND: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. METHODS: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. FINDINGS: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96-1·28). INTERPRETATION: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. FUNDING: National Institute for Health Research Health Services and Delivery Research Programme