Drug dissolution from mesoporous silica systems

Mesoporous silica materials have been investigated as novel formulation aids for oral drug delivery due to their drug solubility enhancing characteristics. However, the mechanism of drug release from these systems is not well understood. Several studies have reported unexplained incomplete release from mesoporous silica carriers. It has been reported, in other research fields, that passive drug adsorption onto the silica surface is possible. However, the implications for this behaviour on drug release from silica systems has not been considered to date. Dissolution studies involving these formulations are generally conducted using Type II dissolution apparatus under sink conditions with traditional simple buffer media. In this thesis, the suitability of this dissolution approach for mesoporous silica systems is considered. The overall aim of this thesis was to investigate factors influencing drug adsorption and release from mesoporous silica systems to enhance understanding of their drug release profiles. This thesis began with a comprehensive overview of the literature which identified the gaps in knowledge in this area. Based on these findings, the hypothesis, aims and objectives were developed. The four research chapters were each dedicated to factors which could potentially affect drug release; formulation excipients, dissolution medium, drug/silica interactions and dissolution apparatus. The role of drug adsorption on the silica surface was explored across several of the chapters using adsorption isotherms, adsorption models and spectroscopic techniques. Several aspects of dissolution experimental design were investigated including sink and supersaturating conditions, traditional simple buffer media versus biorelevant media and Type II (paddle) apparatus versus Type IV (flow-through cell) and a Transfer model (incorporating an SGF to FaSSIF-V2 media transfer). Finally, the results of in vitro dissolution studies were compared to in vivo performance in a fasting pig model. The literature review demonstrated the gap in knowledge concerning the mechanism of drug release from mesoporous silica systems. This informed the central themes of the thesis which were explored in four research chapters. In Chapter 3, it was determined that formulation excipients which can reduce surface tension of the dissolution media (e.g. surfactants) can significantly increase drug release from mesoporous silica carriers. Passive drug adsorption and competitive adsorption involving drug and surfactant molecules on the silica surface was also observed. Chapter 4 built on work from the previous chapter and demonstrated that components of biorelevant media that reduced surface tension can also enhance drug release from silica systems. This chapter established that the influence of biorelevant media extends beyond its impact on drug supersaturation promotion and that its use should also be recommended under sink conditions. In Chapter 5, the focus was placed on investigating drug/silica interactions under supersaturating conditions. It was determined these interactions occur through a hydrogen bonding process and not via non-specific hydrophobic interactions. It was determined that the dynamic equilibrium which exists between adsorbed and free drug during passive adsorption and dissolution can be related to the drug’s activity in solution. Finally, in Chapter 6, it was observed that dissolution experimental design can influence in vitro drug release from mesoporous silica systems. It was established that the Type IV apparatus incorporating an SGF -> FaSSIF-V2 transfer is the best predictor of in vivo performance. The findings of this thesis have made a significant contribution to enhancing knowledge on drug release from mesoporous silica systems. It provides robust recommendations for the design of in vitro dissolution studies involving mesoporous silica formulations including choice of dissolution media, drug supersaturation level and dissolution apparatus. Interesting results concerning the influence of drug activity in solution on the equilibrium process observed during drug adsorption and dissolution from mesoporous silica materials were documented. These findings open up interesting new avenues for future research in the field of mesoporous silica carriers for oral drug delivery

Increasing Actual and Perceived Burden of Tick-Borne Disease in Maine

Introduction: The burden of tick-borne disease (TBD) in Maine has steadily increased since the first case of Lyme disease was reported in the late 1980s. The emergence of five different agents of TBD in Maine has been challenging and confusing for clinicians and the public. Methods: We reviewed the ecology of emerging of tick -borne disease, then reviewed risk factors for tick bites and tick-borne disease in Maine. We then compared the burden of TBD versus community-acquired comparison infections in terms of hospitalizations, deaths, and media attention. Results and Discussion: In Maine, risk of exposure to bites from the vector blacklegged or “deer tick”, Ixodes scapularis, is a reality in most of the state. In New England, resurgence of white-tailed deer attending reforestation and suburbanization of the landscape and climate change have contributed to geographic expansion of the deer tick from relict populations in southern New England. TBDs have emerged as a significant health burden in Maine, but compared with other infections of public health importance, receive disproportionately high media attention. Measures of tick-borne disease severity provide a necessary context for individual and public health decision making. Mass media reports and social networking inform much public debate regarding TBDs, but in many instances, do not accurately reflect their actual prevalence or expected outcome. Conclusion: Reducing actual and perceived risks associated with TBD will require well-supported information paired with an appreciation for how interpersonal communication and social media drive community perceptions and responses to the emergence of TBDs

In vitro dissolution models for the prediction of in vivo performance of an oral mesoporous silica formulation

Drug release from mesoporous silica systems has been widely investigated in vitro using USP Type II (paddle) dissolution apparatus. However, it is not clear if the observed enhanced in vitro dissolution can forecast drug bioavailability in vivo. In this study, the ability of different in vitro dissolution models to predict in vivo oral bioavailability in a pig model was examined. The fenofibrate-loaded mesoporous silica formulation was compared directly to a commercial reference product, Lipantil Supra®. Three in vitro dissolution methods were considered; USP Type II (paddle) apparatus, USP Type IV (flow-through cell) apparatus and a USP IV Transfer model (incorporating a SGF to FaSSIF-V2 media transfer). In silico modelling, using a physiologically based pharmacokinetic modelling and simulation software package (Gastroplus™), to generate in vitro/in vivo relationships was also investigated. The study demonstrates that the in vitro dissolution performance of a mesoporous silica formulation varies depending on the dissolution apparatus utilised and experimental design. The findings show that the USP IV transfer model was the best predictor of in vivo bioavailability. The USP Type II (paddle) apparatus was not effective at forecasting in vivo behaviour. This observation is likely due to hydrodynamic differences between the two apparatus and the ability of the transfer model to better simulate gastrointestinal transit. The transfer model is advantageous in forecasting in vivo behaviour for formulations which promote drug supersaturation and as a result are prone to precipitation to a more energetically favourable, less soluble form. The USP IV transfer model could prove useful in future mesoporous silica formulation development. In silico modelling has the potential to assist in this process. However, further investigation is required to overcome the limitations of the model for solubility enhancing formulations

Role of drug adsorption onto the silica surface in drug release from mesoporous silica systems.

Factors contributing to incomplete drug release from a number of mesoporous silica formulations are not well understood. This study aims to address this gap in knowledge by exploring the role of drug adsorption onto silica substrates during the drug release process in dissolution media. Adsorption isotherms were generated to understand drug adsorption behavior onto the silica surface. Two silica materials were selected (SBA-15 (mesoporous) and Aerosil 200 (nonporous)) to investigate the influence of porous architecture on the adsorption/dissolution processes. The ability of the dissolution medium to wet the silica surface, particularly the porous network, was investigated by the addition of a surfactant to the dissolution medium. The results demonstrated that a larger amount of drug was bound/m2 to the nonporous surface than to the mesoporous material. Adsorption isotherms proved useful in understanding drug adsorption/release behavior for the nonporous silica formulation. However, the quantity of drug remaining on the mesoporous silica surface after dissolution was significantly higher than the amount predicted using adsorption isotherm data. These results suggest that a fraction of loaded drug molecules were tightly bound to the silica surface or attached to sites which are inaccessible for the dissolution media. The presence of surfactant, sodium dodecyl sulfate, in the media enhanced drug release from the silica surface. This behavior can be attributed to both the improved wetting characteristics of the media and adsorption of the surfactant to the silica surface. The findings of this study reinforce the significance of the role that silica porous architecture plays in the dissolution process and indicates that accessible surface area is an important parameter to consider for mesoporous systems in relation to drug release

Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study.

RESONATE-2 is a phase 3 study of first-line ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged ≥65 years (n = 269) were randomized 1:1 to once-daily ibrutinib 420 mg continuously or chlorambucil 0.5-0.8 mg/kg for ≤12 cycles. With a median (range) follow-up of 60 months (0.1-66), progression-free survival (PFS) and overall survival (OS) benefits for ibrutinib versus chlorambucil were sustained (PFS estimates at 5 years: 70% vs 12%; HR [95% CI]: 0.146 [0.098-0.218]; OS estimates at 5 years: 83% vs 68%; HR [95% CI]: 0.450 [0.266-0.761]). Ibrutinib benefit was also consistent in patients with high prognostic risk (TP53 mutation, 11q deletion, and/or unmutated IGHV) (PFS: HR [95% CI]: 0.083 [0.047-0.145]; OS: HR [95% CI]: 0.366 [0.181-0.736]). Investigator-assessed overall response rate was 92% with ibrutinib (complete response, 30%; 11% at primary analysis). Common grade ≥3 adverse events (AEs) included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), and hyponatremia (6%); occurrence of most events as well as discontinuations due to AEs decreased over time. Fifty-eight percent of patients continue to receive ibrutinib. Single-agent ibrutinib demonstrated sustained PFS and OS benefit versus chlorambucil and increased depth of response over time

Childcare, choice and social class: Caring for young children in the UK

This paper draws on the results of two qualitative research projects examining parental engagements with the childcare market in the UK. Both projects are located in the same two London localities. One project focuses on professional middle class parents, and the other on working class families, and we discuss the key importance of social class in shaping parents' differential engagement with the childcare market, and their understandings of the role childcare plays in their children's lives. We identify and discuss the different "circuits" of care (Ball et al 1995) available to and used by families living physically close to each other, but in social class terms living in different worlds. We also consider parents' relationships with carers, and their social networks. We conclude that in order to fully understand childcare policies and practices and families' experiences of care, an analysis which encompasses social class and the workings of the childcare market is needed

Comparing motor-­vehicle crash risk of EU and US vehicles

This study examined the hypotheses that vehicles meeting EU safety standards perform similarly to US-­‐regulated vehicles in the US driving environment, and vice versa. The analyses used three statistical approaches to “triangulate” evidence regarding differences in crash and injury risk. Separate analyses assessed crash avoidance technologies, including headlamps and mirrors. The results suggest that when controlling for differences in environment and exposure, vehicles meeting EU standards offer reduced risk of serious injury in frontal/side crashes and have driver-­‐side mirrors that reduce risk in lane-­‐change crashes better, while vehicles meeting US standards provide a lower risk of injury in rollovers and have headlamps that make pedestrians more conspicuous.Alliance of Automobile Manufacturershttp://deepblue.lib.umich.edu/bitstream/2027.42/112977/1/103199.pd

Geological Field Trips

This field trip guide organized in the framework of the Goldschmidt Conference 2013, held in Florence from August 25 to 30, 2013, is here presented. The two-days field trip, shows some of the many geological, naturalistic and cultural features in the Fiorano area (Modena), in which history, geology and passion for Ferrari come together in a perfect marriage. The first excursion day is dedicated to visit the Natural Reserve of Salse di Nirano, where the mud volcanoes, produced by the cold mud, salt water and hydrocarbons - mainly methane- can be observed. The second day is devoted to visit the Ferrari Museum and goes on at the Spezzano Castle, hosting the Ceramics Museum. Clays are, in fact, abundant in the hilly margin, where they form badlands, characteristic narrow crests washed out by running waters. In the Castle there is also a Balsamic Vinegar producing Consortium, it’s a peculiar and typical product of Modena province. The itinerary ends with the tour to Enzo Ferrari’s Birthplace at Modena

Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study

RESONATE-2 is a phase 3 study of first-line ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged >= 65 years (n = 269) were randomized 1:1 to once-daily ibrutinib 420 mg continuously or chlorambucil 0.5-0.8 mg/kg for = 3 adverse events (AEs) included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), and hyponatremia (6%); occurrence of most events as well as discontinuations due to AEs decreased over time. Fifty-eight percent of patients continue to receive ibrutinib. Single-agent ibrutinib demonstrated sustained PFS and OS benefit versus chlorambucil and increased depth of response over time