Grace Hatton - Academia.edu (original) (raw)

Papers by Grace Hatton

eJHaem

There is sparse evidence of how well haematological targets are met in practice for essential thr... more There is sparse evidence of how well haematological targets are met in practice for essential thrombocythemia (ET) and polycythaemia vera (PV) patients. Patient data was collected between 2008 and 2020 from two UK NHS Trusts for ET and PV patients. Longitudinal changes in peripheral blood counts, including the proportion of patients meeting peripheral blood count remission, was modelled. Relative risk of cardiovascular-related events for patients achieving remission within 3-months was estimated. A total of 620 ET and 429 PV patients were analysed. For high-risk patients, haematological parameters decreased in the first months of observation then stabilised within normal reference ranges until year 5. Total time spent in peripheral blood count remission was 39.2% for ET and 29.1% for PV. A lower proportion of ET patients reached target platelet counts (48.3%) compared to WBC (79.1%), whilst PV patients were less likely to reach target haematocrit levels (56.9%) compared to platelets (77.3%) or WBC (74.6%). There was no statistically significant association between reaching target blood counts within 3-months and cardiovascular risk. Complete haematological remission remains a challenging target in managing PV and ET, however this study was unable to show statistically-significant evidence that this was associated with increased risk of cardiovascular events. K E Y W O R D S epidemiology, essential thrombocythaemia, polycythaemia vera 1 INTRODUCTION Essential thrombocythemia (ET) and polycythaemia vera (PV) are myeloproliferative neoplasms (MPNs) [1], characterised by abnormal proliferation of one or more cell lineages in the bone marrow [2]. Clinical manifestations of ET and PV include increased risk of thrombosis, This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

AAPS Advances in the Pharmaceutical Sciences Series, 2018

The use of general descriptive names, registered names, trademarks, service marks, etc. in this p... more The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Journal of Controlled Release

Expert Review of Gastroenterology & Hepatology, 2018

ABSTRACT Introduction: Pediatric nonalcoholic fatty liver disease (NAFLD) is common disorder that... more ABSTRACT Introduction: Pediatric nonalcoholic fatty liver disease (NAFLD) is common disorder that has complex pathophysiology and unquantified clinical significance. Though there have been major advances in the field, there is much yet to be understood. Areas covered: PubMed/MEDLINE and Embase were searched for articles related to pediatric NAFLD and nonalcoholic steatohepatitis (NASH) between January 1998 and January 2018. The areas considered to be ‘unmet needs’ were the relationship between the intestinal microbiome and perinatal events, clinical event risk stratification, and mechanisms underlying portal inflammation. Expert commentary: In utero and ex utero factors have been associated with NAFLD and also with the intestinal microbiome, but it is not yet known how intestinal dysbiosis can be reversed and whether intervention in high-risk neonates could alter their propensity for the metabolic syndrome. Children with NAFLD are at increased risk of cardiovascular, diabetic, and hepatic diseases, but it is unclear how best to stratify children into appropriate risk groups for targeted interventions. Finally, the immune processes underlying pediatric NASH are thought to differ to those in adult NASH, yet the events surrounding activation of periportal lymphocytes are poorly understood. Deepening our understanding of these topics may lead to novel therapeutic targets.

The Lancet Planetary Health, 2020

COVID-19 and clean air: an opportunity for radical change The COVID-19 pandemic has caused more t... more COVID-19 and clean air: an opportunity for radical change The COVID-19 pandemic has caused more than 30 million infections and 960 000 deaths, causing disease in almost every country worldwide. Like all pandemics, it has laid bare and exploited social inequalities, and caused disproportionate damage to low-income families, people with poor health, and minority and marginalised groups. A further consequence of this pandemic has been economic havoc of a magnitude not seen since 1932. This downturn is projected to wipe out 200 million jobs worldwide. The previously unimaginable prospect of a second Great Depression seems possible. Yet, among all this suffering, two events have unfolded that suggest that this time of crisis could also be a time of fundamental, even revolutionary, change. The first has been the global rise of the Black Lives Matter movement. In the aftermath of the killings of Ahmaud Arbery and George Floyd, millions of people in countries across the globe have risen together as one to denounce hatred and racism and to call for an end to the social and economic inequalities-the structural violence-that underlie the disproportionate effects of COVID-19 on people of low-income and racial minority backgrounds. The second has been a remarkable worldwide reduction in ambient air pollution. These decreases are so great that they can be seen from outer space (figure). In northern India, air pollution is at a 20-year low and concentrations of fine particulate matter (PM 2•5) in New Delhi have fallen by more than 50%. 1 In Europe, nitrogen dioxide concentrations have fallen by 40% and PM 2•5 concentrations by 10%. 2 In New York and Los Angeles, PM 2•5 concentrations are 25-30% lower than concentrations from the same month a year ago. 3 Ambient air pollution is responsible for more than 5 million deaths annually-deaths caused by heart disease, stroke, chronic obstructive pulmonary disease, lung cancer, diabetes, pneumonia, and premature birth. 4 COVID-19-related improvements in air quality translate into fewer deaths from pollution-related disease. Thus, cleaner air is estimated to have saved 11 000 lives (95% CI 7000-21 000) in Europe in April, 2020, 2 and 77 000 lives in China in January and February. 5 These great gains show that cleaner air is possible. They enable us to imagine a world in which We declare no competing interests.

Three-dimensional printing (3DP) is an entirely novel method of manufacture with its applications... more Three-dimensional printing (3DP) is an entirely novel method of manufacture with its applications only limited by the imagination. The mainstay of 3DP utilisation practically to date has been in the field of engineering, largely for the purpose of generating model prototypes. However, the potential of 3DP has increasingly been recognised in areas of commercial manufacture in medicine due to its capacity to produce materials and devices that can equal, if not surpass, the benefits of traditional consumer goods. The opportunities for future uses are innumerable ranging from tissue engineering, the on-demand fabrication of medical devices and advanced applications in other fields with the same pressing need for medical personalisation. The 3D printing arena is ultimately exciting and endless in opportunities with the FDA encouraging the development of science and risk based approaches. This chapter will discuss the existing and future medical applications of 3DP and its potential to re...

Current Hepatology Reports, 2020

Purpose of Review We examine recent developments in the treatment of cirrhosis by gut microbiome ... more Purpose of Review We examine recent developments in the treatment of cirrhosis by gut microbiome manipulation specifically focusing on the phase 1 safety and feasibility trials of faecal microbiota transplantation (FMT). We interrogate the published data so far on its feasibility, safety and efficacy. Recent Findings A large number of trials have demonstrated the efficacy of FMT in treating recurrent Clostridium difficile infection which is now considered standard of care. In cirrhosis, FMT is still being evaluated and there are a number of clinical trials underway. There are two phase 1 pilot safety studies that have been published with promising findings. However, the importance of rigorously testing donor stool for the presence of multi-drug resistant species has been highlighted and lessons have been learned. Summary For those patients with cirrhosis, replacing an unhealthy gut microbiome with a healthy one offers a promising antibiotic-free treatment that may reduce bacterial t...

American Journal of Gastroenterology, 2019

Expert Opinion on Drug Delivery, 2019

Drug Discovery Today, 2018

Teaser Systemic diseases where foci are initially unrelated to the GI tract do in fact alter GI p... more Teaser Systemic diseases where foci are initially unrelated to the GI tract do in fact alter GI physiology and function. This ultimately affects the bioavailability of orally administered drugs.

Expert Review of Gastroenterology & Hepatology, 2018

International journal of pharmaceutics, Jan 5, 2018

The term "disease" conjures a plethora of graphic imagery for many, and the use of drug... more The term "disease" conjures a plethora of graphic imagery for many, and the use of drugs to combat symptoms and treat underlying pathology is at the core of modern medicine. However, the effects of the various gastrointestinal diseases, infections, co-morbidities and the impact of gastrointestinal surgery on the pharmacokinetic and pharmacodynamic behaviour of drugs have been largely overlooked. The better elucidation of disease pathology and the role of underlying cellular and molecular mechanisms have increased our knowledge as far as diagnoses and prognoses are concerned. In addition, the recent advances in our understanding of the intestinal microbiome have linked the composition and function of gut microbiota to disease predisposition and development. This knowledge, however, applies less so in the context of drug absorption and distribution for orally administered dosage forms. Here, we revisit and re-evaluate the influence of a portfolio of gastrointestinal diseases...

Journal of Drug Delivery Science and Technology, 2015

Corticosteroids form an important component of drug-based therapeutic strategies in both Crohn's ... more Corticosteroids form an important component of drug-based therapeutic strategies in both Crohn's disease and ulcerative colitis. Here, we investigated the intestinal release behaviour of two commonly-used corticosteroids-prednisolone and budesonide-from various commercial modified-release formulations. We evaluated the release characteristics using a novel in vitro model that simulates the dynamic intestinal environment by employing bicarbonate buffers representative of the conditions and contents of the gastrointestinal lumen. The performance of the model was validated with an in-house enteric dual layer prednisolone formulation (internal standard) where in vitro release behaviour closely correlated with in vivo targeting performance in humans. The commercial prednisolone product coated with the pH responsive polymer polyvinyl acetate phthalate released its payload promptly on transfer to the upper small intestinal compartment of the test. In contrast, the budesonide products, Entocort ® and Budenofalk ® , although showing differences in product performance and delayed release characteristics, both demonstrated some suggestion of extended release behaviour. The proposed dissolution method provided a realistic and discriminative in vitro assessment of the release of corticosteroids from different oral formulations. These results demonstrate that this model can be used to aid the rational design of products developed to target different sites of the gut.

International journal of pharmaceutics, Jan 16, 2015

The aim of this work was to explore the feasibility of using fused deposition modelling (FDM) 3D ... more The aim of this work was to explore the feasibility of using fused deposition modelling (FDM) 3D printing (3DP) technology with hot melt extrusion (HME) and fluid bed coating to fabricate modified-release budesonide dosage forms. Budesonide was sucessfully loaded into polyvinyl alcohol filaments using HME. The filaments were transfomed into capsule-shaped tablets (caplets) containing 9mg budesonide using a FDM 3D printer; the caplets were then overcoated with a layer of enteric polymer. The final printed formulation was tested in a dynamic dissolution bicarbonate buffer system, and two commercial budesonide products, Cortiment(®) (Uceris(®)) and Entocort(®), were also investigated for comparison. Budesonide release from the Entocort(®) formulation was rapid in conditions of the upper small intestine while release from the Cortiment(®) product was more delayed and prolonged. In contrast, the new 3D printed caplet formulation started to release in the mid-small intestine but release t...

Journal of pharmaceutical sciences, Jan 24, 2015

All animals are equal, but some are more equal than others" was the illustrious quote derived fro... more All animals are equal, but some are more equal than others" was the illustrious quote derived from British writer George Orwell's famed work, Animal Farm. Extending beyond the remit of political allegory, however, this statement would appear to hold true for the selection of appropriate animal models to simulate human physiology in preclinical studies. There remain definite gaps in our current knowledge with respect to animal physiology, notably those of intra-and inter-species differences in gastrointestinal (GI) function, which may affect oral drug delivery and absorption. Factors such as cost and availability have often influenced the choice of animal species without clear justification for their similarity to humans, and lack of standardization in techniques employed in past studies using various animals may also have contributed to the generation of contradictory results. As it stands, attempts to identify a single animal species as appropriately representative of human physiology and which may able to adequately simulate human in vivo conditions are limited. In this review, we have compiled and critically reviewed data from numerous studies of GI anatomy and physiology of various animal species commonly used in drug delivery modeling, commenting on the appropriateness of these animals for in vivo comparison and extrapolation to humans.

International Journal of Pharmaceutics, 2013

Gastrointestinal physiology is dynamic and complex at the best of times, and a multitude of known... more Gastrointestinal physiology is dynamic and complex at the best of times, and a multitude of known variables can affect the overall bioavailability of drugs delivered via the oral route. Yet while the influences of food and beverages, including alcohol, intake as just two of these variables on oral drug delivery have been extensively documented in the wider literature, specific information on their effects remains sporadic, and is not so much contextually reviewed. Food co-ingestion with oral dosage forms can mediate several changes to drug bioavailability, yet the precise mechanisms underlying this have yet to be fully elucidated. Likewise, alcohol (ethanol) effects on drug delivery have been observed experimentally and clinically, and often to the detriment of dosage form performance. Here, we attempt to piece together the available subject matter relating to effects mediated by both solid and liquid foodstuffs on the gastrointestinal milieu and the implications for oral drug delivery, with particular emphasis on the behaviour of modified-release dosage forms, formulation robustness and drug absorption. Providing better insight into these influences and exemplifying cases where formulations have been developed or modified to circumvent their associated problems can help to appropriately direct the design of better in vitro digestive modelling systems and future oral dosage forms resilient to these effects. Moreover, it will expand on our understanding of the impact of food and alcohol intake on normal gut behaviour/function.

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, Jan 9, 2014

The aim of this study was to explore the potential of fused-deposition 3-dimensional printing (FD... more The aim of this study was to explore the potential of fused-deposition 3-dimensional printing (FDM 3DP) to produce modified-release drug loaded tablets. Two aminosalicylate isomers used in the treatment of inflammatory bowel disease (IBD), 5-aminosalicylic acid (5-ASA, mesalazine) and 4-aminosalicylic acid (4-ASA), were selected as model drugs. Commercially produced polyvinyl alcohol (PVA) filaments were loaded with the drugs in an ethanolic drug solution. A final drug-loading of 0.06% w/w and 0.25% w/w was achieved for the 5-ASA and 4-ASA strands, respectively. 10.5mm diameter tablets of both PVA/4-ASA and PVA/5-ASA were subsequently printed using an FDM 3D printer, and varying the weight and densities of the printed tablets was achieved by selecting the infill percentage in the printer software. The tablets were mechanically strong, and the FDM 3D printing was shown to be an effective process for the manufacture of the drug, 5-ASA. Significant thermal degradation of the active 4-A...

European Journal of Pharmaceutics and Biopharmaceutics, 2013

The in vivo proof of concept of a novel double-coating system, based on enteric polymers, which a... more The in vivo proof of concept of a novel double-coating system, based on enteric polymers, which accelerated drug release in the ileo-colonic region, was investigated in humans. Prednisolone tablets were coated with a double-coating formulation by applying an inner layer composed of EUDRAGIT S neutralised to pH 8.0 and a buffer salt (10% KH₂PO₄), which was overcoated with layer of standard EUDRAGIT S organic solution. For comparison, a single coating system was produced by applying the same amount of EUDRAGIT S organic solution on the tablet cores. Dissolution tests on the tablets were carried out using USP II apparatus in 0.1N HCl for 2 h and subsequently in pH 7.4 Krebs bicarbonate buffer. For comparison, tablets were also tested under the USP method established for modified release mesalamine formulations. Ten fasted volunteers received the double-coated and single-coated tablets in a two-way crossover study. The formulations were radiolabelled and followed by gamma scintigraphy; the disintegration times and positions were recorded. There was no drug release from the single-coated or double-coated tablets in 0.1N HCl for 2h. The single-coated tablets showed slow release in subsequent Krebs bicarbonate buffer with a lag time of 120 min, while in contrast drug release from the double-coated tablets was initiated at 60 min. In contrast, using the USP dissolution method, normally employed for modified release mesalamine products, no discrimination was attained. The in vivo disintegration of the single-coated EUDRAGIT S tablets in the large intestine was erratic. Furthermore, in 2 volunteers, the single-coated tablet was voided intact. Double-coated tablets disintegrated in a more consistent way, mainly in the ileo-caecal junction or terminal ileum. The accelerated in vivo disintegration of the double-coating EUDRAGIT S system can overcome the limitations of conventional enteric coatings targeting the colon and avoid the pass-through of intact tablets. Moreover, Krebs bicarbonate buffer has the ability to discriminate between formulations designed to target the ileo-colonic region.

International journal of pharmaceutics, Jan 23, 2015

The aminosalicylate mesalazine (mesalamine) forms the mainstay of treatment in ulcerative colitis... more The aminosalicylate mesalazine (mesalamine) forms the mainstay of treatment in ulcerative colitis (UC); a disease for which many commercial modified-release products have been developed with the aim of providing targeted gastrointestinal release. The release profiles of five of these commercial formulations were evaluated in bicarbonate buffer using a novel dissolution model that mimics the dynamic conditions of the gastrointestinal tract. Monolithic and multi-particulate mesalazine formulations with pH-dependent and/or independent release mechanisms were evaluated (Asacol(®) 800, Octasa(®), Mezavant(®) XL, Salofalk(®), Pentasa(®)), and each of the products displayed a distinctive dissolution profile. The dissolution results for Mezavant(®) XL (Lialda(®)) (lag time 290min) demonstrated good correlation with previously reported in vivo disintegration times assessed by gamma-scintigraphy in humans. Octasa(®) showed a similar lag time to Mezavant(®) XL. Drug release from Asacol(®) 800 ...

International Journal of Pharmaceutics, 2013

Gastrointestinal physiology is dynamic and complex at the best of times, and a multitude of known... more Gastrointestinal physiology is dynamic and complex at the best of times, and a multitude of known variables can affect the overall bioavailability of drugs delivered via the oral route. Yet while the influences of food and beverage intake as just two of these variables on oral drug delivery have been extensively documented in the wider literature, specific information on their effects remains sporadic, and is not so much contextually reviewed. Food co-ingestion with oral dosage forms can mediate several changes to drug bioavailability, yet the precise mechanisms underlying this have yet to be fully elucidated. Likewise, the often detrimental effects of alcohol (ethanol) on dosage form performance have been widely observed experimentally, but knowledge of which has only moderately impacted on clinical practice. Here, we attempt to piece together the available subject matter relating to the influences of both solid and liquid foodstuffs on the gastrointestinal milieu and the implicati...

eJHaem

There is sparse evidence of how well haematological targets are met in practice for essential thr... more There is sparse evidence of how well haematological targets are met in practice for essential thrombocythemia (ET) and polycythaemia vera (PV) patients. Patient data was collected between 2008 and 2020 from two UK NHS Trusts for ET and PV patients. Longitudinal changes in peripheral blood counts, including the proportion of patients meeting peripheral blood count remission, was modelled. Relative risk of cardiovascular-related events for patients achieving remission within 3-months was estimated. A total of 620 ET and 429 PV patients were analysed. For high-risk patients, haematological parameters decreased in the first months of observation then stabilised within normal reference ranges until year 5. Total time spent in peripheral blood count remission was 39.2% for ET and 29.1% for PV. A lower proportion of ET patients reached target platelet counts (48.3%) compared to WBC (79.1%), whilst PV patients were less likely to reach target haematocrit levels (56.9%) compared to platelets (77.3%) or WBC (74.6%). There was no statistically significant association between reaching target blood counts within 3-months and cardiovascular risk. Complete haematological remission remains a challenging target in managing PV and ET, however this study was unable to show statistically-significant evidence that this was associated with increased risk of cardiovascular events. K E Y W O R D S epidemiology, essential thrombocythaemia, polycythaemia vera 1 INTRODUCTION Essential thrombocythemia (ET) and polycythaemia vera (PV) are myeloproliferative neoplasms (MPNs) [1], characterised by abnormal proliferation of one or more cell lineages in the bone marrow [2]. Clinical manifestations of ET and PV include increased risk of thrombosis, This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

AAPS Advances in the Pharmaceutical Sciences Series, 2018

The use of general descriptive names, registered names, trademarks, service marks, etc. in this p... more The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Journal of Controlled Release

Expert Review of Gastroenterology & Hepatology, 2018

ABSTRACT Introduction: Pediatric nonalcoholic fatty liver disease (NAFLD) is common disorder that... more ABSTRACT Introduction: Pediatric nonalcoholic fatty liver disease (NAFLD) is common disorder that has complex pathophysiology and unquantified clinical significance. Though there have been major advances in the field, there is much yet to be understood. Areas covered: PubMed/MEDLINE and Embase were searched for articles related to pediatric NAFLD and nonalcoholic steatohepatitis (NASH) between January 1998 and January 2018. The areas considered to be ‘unmet needs’ were the relationship between the intestinal microbiome and perinatal events, clinical event risk stratification, and mechanisms underlying portal inflammation. Expert commentary: In utero and ex utero factors have been associated with NAFLD and also with the intestinal microbiome, but it is not yet known how intestinal dysbiosis can be reversed and whether intervention in high-risk neonates could alter their propensity for the metabolic syndrome. Children with NAFLD are at increased risk of cardiovascular, diabetic, and hepatic diseases, but it is unclear how best to stratify children into appropriate risk groups for targeted interventions. Finally, the immune processes underlying pediatric NASH are thought to differ to those in adult NASH, yet the events surrounding activation of periportal lymphocytes are poorly understood. Deepening our understanding of these topics may lead to novel therapeutic targets.

The Lancet Planetary Health, 2020

COVID-19 and clean air: an opportunity for radical change The COVID-19 pandemic has caused more t... more COVID-19 and clean air: an opportunity for radical change The COVID-19 pandemic has caused more than 30 million infections and 960 000 deaths, causing disease in almost every country worldwide. Like all pandemics, it has laid bare and exploited social inequalities, and caused disproportionate damage to low-income families, people with poor health, and minority and marginalised groups. A further consequence of this pandemic has been economic havoc of a magnitude not seen since 1932. This downturn is projected to wipe out 200 million jobs worldwide. The previously unimaginable prospect of a second Great Depression seems possible. Yet, among all this suffering, two events have unfolded that suggest that this time of crisis could also be a time of fundamental, even revolutionary, change. The first has been the global rise of the Black Lives Matter movement. In the aftermath of the killings of Ahmaud Arbery and George Floyd, millions of people in countries across the globe have risen together as one to denounce hatred and racism and to call for an end to the social and economic inequalities-the structural violence-that underlie the disproportionate effects of COVID-19 on people of low-income and racial minority backgrounds. The second has been a remarkable worldwide reduction in ambient air pollution. These decreases are so great that they can be seen from outer space (figure). In northern India, air pollution is at a 20-year low and concentrations of fine particulate matter (PM 2•5) in New Delhi have fallen by more than 50%. 1 In Europe, nitrogen dioxide concentrations have fallen by 40% and PM 2•5 concentrations by 10%. 2 In New York and Los Angeles, PM 2•5 concentrations are 25-30% lower than concentrations from the same month a year ago. 3 Ambient air pollution is responsible for more than 5 million deaths annually-deaths caused by heart disease, stroke, chronic obstructive pulmonary disease, lung cancer, diabetes, pneumonia, and premature birth. 4 COVID-19-related improvements in air quality translate into fewer deaths from pollution-related disease. Thus, cleaner air is estimated to have saved 11 000 lives (95% CI 7000-21 000) in Europe in April, 2020, 2 and 77 000 lives in China in January and February. 5 These great gains show that cleaner air is possible. They enable us to imagine a world in which We declare no competing interests.

Three-dimensional printing (3DP) is an entirely novel method of manufacture with its applications... more Three-dimensional printing (3DP) is an entirely novel method of manufacture with its applications only limited by the imagination. The mainstay of 3DP utilisation practically to date has been in the field of engineering, largely for the purpose of generating model prototypes. However, the potential of 3DP has increasingly been recognised in areas of commercial manufacture in medicine due to its capacity to produce materials and devices that can equal, if not surpass, the benefits of traditional consumer goods. The opportunities for future uses are innumerable ranging from tissue engineering, the on-demand fabrication of medical devices and advanced applications in other fields with the same pressing need for medical personalisation. The 3D printing arena is ultimately exciting and endless in opportunities with the FDA encouraging the development of science and risk based approaches. This chapter will discuss the existing and future medical applications of 3DP and its potential to re...

Current Hepatology Reports, 2020

Purpose of Review We examine recent developments in the treatment of cirrhosis by gut microbiome ... more Purpose of Review We examine recent developments in the treatment of cirrhosis by gut microbiome manipulation specifically focusing on the phase 1 safety and feasibility trials of faecal microbiota transplantation (FMT). We interrogate the published data so far on its feasibility, safety and efficacy. Recent Findings A large number of trials have demonstrated the efficacy of FMT in treating recurrent Clostridium difficile infection which is now considered standard of care. In cirrhosis, FMT is still being evaluated and there are a number of clinical trials underway. There are two phase 1 pilot safety studies that have been published with promising findings. However, the importance of rigorously testing donor stool for the presence of multi-drug resistant species has been highlighted and lessons have been learned. Summary For those patients with cirrhosis, replacing an unhealthy gut microbiome with a healthy one offers a promising antibiotic-free treatment that may reduce bacterial t...

American Journal of Gastroenterology, 2019

Expert Opinion on Drug Delivery, 2019

Drug Discovery Today, 2018

Teaser Systemic diseases where foci are initially unrelated to the GI tract do in fact alter GI p... more Teaser Systemic diseases where foci are initially unrelated to the GI tract do in fact alter GI physiology and function. This ultimately affects the bioavailability of orally administered drugs.

Expert Review of Gastroenterology & Hepatology, 2018

International journal of pharmaceutics, Jan 5, 2018

The term "disease" conjures a plethora of graphic imagery for many, and the use of drug... more The term "disease" conjures a plethora of graphic imagery for many, and the use of drugs to combat symptoms and treat underlying pathology is at the core of modern medicine. However, the effects of the various gastrointestinal diseases, infections, co-morbidities and the impact of gastrointestinal surgery on the pharmacokinetic and pharmacodynamic behaviour of drugs have been largely overlooked. The better elucidation of disease pathology and the role of underlying cellular and molecular mechanisms have increased our knowledge as far as diagnoses and prognoses are concerned. In addition, the recent advances in our understanding of the intestinal microbiome have linked the composition and function of gut microbiota to disease predisposition and development. This knowledge, however, applies less so in the context of drug absorption and distribution for orally administered dosage forms. Here, we revisit and re-evaluate the influence of a portfolio of gastrointestinal diseases...

Journal of Drug Delivery Science and Technology, 2015

Corticosteroids form an important component of drug-based therapeutic strategies in both Crohn's ... more Corticosteroids form an important component of drug-based therapeutic strategies in both Crohn's disease and ulcerative colitis. Here, we investigated the intestinal release behaviour of two commonly-used corticosteroids-prednisolone and budesonide-from various commercial modified-release formulations. We evaluated the release characteristics using a novel in vitro model that simulates the dynamic intestinal environment by employing bicarbonate buffers representative of the conditions and contents of the gastrointestinal lumen. The performance of the model was validated with an in-house enteric dual layer prednisolone formulation (internal standard) where in vitro release behaviour closely correlated with in vivo targeting performance in humans. The commercial prednisolone product coated with the pH responsive polymer polyvinyl acetate phthalate released its payload promptly on transfer to the upper small intestinal compartment of the test. In contrast, the budesonide products, Entocort ® and Budenofalk ® , although showing differences in product performance and delayed release characteristics, both demonstrated some suggestion of extended release behaviour. The proposed dissolution method provided a realistic and discriminative in vitro assessment of the release of corticosteroids from different oral formulations. These results demonstrate that this model can be used to aid the rational design of products developed to target different sites of the gut.

International journal of pharmaceutics, Jan 16, 2015

The aim of this work was to explore the feasibility of using fused deposition modelling (FDM) 3D ... more The aim of this work was to explore the feasibility of using fused deposition modelling (FDM) 3D printing (3DP) technology with hot melt extrusion (HME) and fluid bed coating to fabricate modified-release budesonide dosage forms. Budesonide was sucessfully loaded into polyvinyl alcohol filaments using HME. The filaments were transfomed into capsule-shaped tablets (caplets) containing 9mg budesonide using a FDM 3D printer; the caplets were then overcoated with a layer of enteric polymer. The final printed formulation was tested in a dynamic dissolution bicarbonate buffer system, and two commercial budesonide products, Cortiment(®) (Uceris(®)) and Entocort(®), were also investigated for comparison. Budesonide release from the Entocort(®) formulation was rapid in conditions of the upper small intestine while release from the Cortiment(®) product was more delayed and prolonged. In contrast, the new 3D printed caplet formulation started to release in the mid-small intestine but release t...

Journal of pharmaceutical sciences, Jan 24, 2015

All animals are equal, but some are more equal than others" was the illustrious quote derived fro... more All animals are equal, but some are more equal than others" was the illustrious quote derived from British writer George Orwell's famed work, Animal Farm. Extending beyond the remit of political allegory, however, this statement would appear to hold true for the selection of appropriate animal models to simulate human physiology in preclinical studies. There remain definite gaps in our current knowledge with respect to animal physiology, notably those of intra-and inter-species differences in gastrointestinal (GI) function, which may affect oral drug delivery and absorption. Factors such as cost and availability have often influenced the choice of animal species without clear justification for their similarity to humans, and lack of standardization in techniques employed in past studies using various animals may also have contributed to the generation of contradictory results. As it stands, attempts to identify a single animal species as appropriately representative of human physiology and which may able to adequately simulate human in vivo conditions are limited. In this review, we have compiled and critically reviewed data from numerous studies of GI anatomy and physiology of various animal species commonly used in drug delivery modeling, commenting on the appropriateness of these animals for in vivo comparison and extrapolation to humans.

International Journal of Pharmaceutics, 2013

Gastrointestinal physiology is dynamic and complex at the best of times, and a multitude of known... more Gastrointestinal physiology is dynamic and complex at the best of times, and a multitude of known variables can affect the overall bioavailability of drugs delivered via the oral route. Yet while the influences of food and beverages, including alcohol, intake as just two of these variables on oral drug delivery have been extensively documented in the wider literature, specific information on their effects remains sporadic, and is not so much contextually reviewed. Food co-ingestion with oral dosage forms can mediate several changes to drug bioavailability, yet the precise mechanisms underlying this have yet to be fully elucidated. Likewise, alcohol (ethanol) effects on drug delivery have been observed experimentally and clinically, and often to the detriment of dosage form performance. Here, we attempt to piece together the available subject matter relating to effects mediated by both solid and liquid foodstuffs on the gastrointestinal milieu and the implications for oral drug delivery, with particular emphasis on the behaviour of modified-release dosage forms, formulation robustness and drug absorption. Providing better insight into these influences and exemplifying cases where formulations have been developed or modified to circumvent their associated problems can help to appropriately direct the design of better in vitro digestive modelling systems and future oral dosage forms resilient to these effects. Moreover, it will expand on our understanding of the impact of food and alcohol intake on normal gut behaviour/function.

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, Jan 9, 2014

The aim of this study was to explore the potential of fused-deposition 3-dimensional printing (FD... more The aim of this study was to explore the potential of fused-deposition 3-dimensional printing (FDM 3DP) to produce modified-release drug loaded tablets. Two aminosalicylate isomers used in the treatment of inflammatory bowel disease (IBD), 5-aminosalicylic acid (5-ASA, mesalazine) and 4-aminosalicylic acid (4-ASA), were selected as model drugs. Commercially produced polyvinyl alcohol (PVA) filaments were loaded with the drugs in an ethanolic drug solution. A final drug-loading of 0.06% w/w and 0.25% w/w was achieved for the 5-ASA and 4-ASA strands, respectively. 10.5mm diameter tablets of both PVA/4-ASA and PVA/5-ASA were subsequently printed using an FDM 3D printer, and varying the weight and densities of the printed tablets was achieved by selecting the infill percentage in the printer software. The tablets were mechanically strong, and the FDM 3D printing was shown to be an effective process for the manufacture of the drug, 5-ASA. Significant thermal degradation of the active 4-A...

European Journal of Pharmaceutics and Biopharmaceutics, 2013

The in vivo proof of concept of a novel double-coating system, based on enteric polymers, which a... more The in vivo proof of concept of a novel double-coating system, based on enteric polymers, which accelerated drug release in the ileo-colonic region, was investigated in humans. Prednisolone tablets were coated with a double-coating formulation by applying an inner layer composed of EUDRAGIT S neutralised to pH 8.0 and a buffer salt (10% KH₂PO₄), which was overcoated with layer of standard EUDRAGIT S organic solution. For comparison, a single coating system was produced by applying the same amount of EUDRAGIT S organic solution on the tablet cores. Dissolution tests on the tablets were carried out using USP II apparatus in 0.1N HCl for 2 h and subsequently in pH 7.4 Krebs bicarbonate buffer. For comparison, tablets were also tested under the USP method established for modified release mesalamine formulations. Ten fasted volunteers received the double-coated and single-coated tablets in a two-way crossover study. The formulations were radiolabelled and followed by gamma scintigraphy; the disintegration times and positions were recorded. There was no drug release from the single-coated or double-coated tablets in 0.1N HCl for 2h. The single-coated tablets showed slow release in subsequent Krebs bicarbonate buffer with a lag time of 120 min, while in contrast drug release from the double-coated tablets was initiated at 60 min. In contrast, using the USP dissolution method, normally employed for modified release mesalamine products, no discrimination was attained. The in vivo disintegration of the single-coated EUDRAGIT S tablets in the large intestine was erratic. Furthermore, in 2 volunteers, the single-coated tablet was voided intact. Double-coated tablets disintegrated in a more consistent way, mainly in the ileo-caecal junction or terminal ileum. The accelerated in vivo disintegration of the double-coating EUDRAGIT S system can overcome the limitations of conventional enteric coatings targeting the colon and avoid the pass-through of intact tablets. Moreover, Krebs bicarbonate buffer has the ability to discriminate between formulations designed to target the ileo-colonic region.

International journal of pharmaceutics, Jan 23, 2015

The aminosalicylate mesalazine (mesalamine) forms the mainstay of treatment in ulcerative colitis... more The aminosalicylate mesalazine (mesalamine) forms the mainstay of treatment in ulcerative colitis (UC); a disease for which many commercial modified-release products have been developed with the aim of providing targeted gastrointestinal release. The release profiles of five of these commercial formulations were evaluated in bicarbonate buffer using a novel dissolution model that mimics the dynamic conditions of the gastrointestinal tract. Monolithic and multi-particulate mesalazine formulations with pH-dependent and/or independent release mechanisms were evaluated (Asacol(®) 800, Octasa(®), Mezavant(®) XL, Salofalk(®), Pentasa(®)), and each of the products displayed a distinctive dissolution profile. The dissolution results for Mezavant(®) XL (Lialda(®)) (lag time 290min) demonstrated good correlation with previously reported in vivo disintegration times assessed by gamma-scintigraphy in humans. Octasa(®) showed a similar lag time to Mezavant(®) XL. Drug release from Asacol(®) 800 ...

International Journal of Pharmaceutics, 2013

Gastrointestinal physiology is dynamic and complex at the best of times, and a multitude of known... more Gastrointestinal physiology is dynamic and complex at the best of times, and a multitude of known variables can affect the overall bioavailability of drugs delivered via the oral route. Yet while the influences of food and beverage intake as just two of these variables on oral drug delivery have been extensively documented in the wider literature, specific information on their effects remains sporadic, and is not so much contextually reviewed. Food co-ingestion with oral dosage forms can mediate several changes to drug bioavailability, yet the precise mechanisms underlying this have yet to be fully elucidated. Likewise, the often detrimental effects of alcohol (ethanol) on dosage form performance have been widely observed experimentally, but knowledge of which has only moderately impacted on clinical practice. Here, we attempt to piece together the available subject matter relating to the influences of both solid and liquid foodstuffs on the gastrointestinal milieu and the implicati...