NOVEL ORAL DELIVERY OF IBUPROFEN SOLUTION IN HARD GELATIN CAPSULES

Objective: The primary objective of the project was to formulate and evaluate hard capsule containing the solution of ibuprofen. It also included enhancement of solubility of ibuprofen in hydrophilic solvents to obtain a unit dose capsule acceptable for human consumption. Methods: Solution of ibuprofen was developed by the salt formation of partial drug using potassium hydroxide in PEG 600 and water. The solution was encapsulated in hard capsules with band sealing. The final formulation was evaluated for uniformity of weight, disintegration, drug content and stability. The dissolution profile was compared with that of available marketed tablets and softgels. Results: The capsules were evaluated and found compliant as per specifications mentioned in general monograph of capsules in IP 2014. The uniformity of weight of the batch of capsules was found to be 734.8 mg (±0.58). The disintegration time of these capsules was observed to be 4.45 min. The drug content was found to be 100.03% and the product is stable over three months of test period under room temperature as well as accelerated conditions. The dissolution profile showed that softgels take longer time to release the drug whereas marketed tablets showed a dissolution profile comparable with that of formulated capsules. Conclusion: The developed capsule is a unit dose of liquid containing solubilized ibuprofen delivering the drug directly into the gastrointestinal tract (GIT). These are newer solid oral dosage forms with higher patient compliance and ease in manufacturing. They require lesser steps and manufacturing area when compared to the manufacturing of compressed tablets

Effect of Levodopa-Carbidopa Intestinal Gel on Non-Motor Symptoms in Patients with Advanced Parkinson\u27s Disease

Background: Levodopa-carbidopa intestinal gel (LCIG; carbidopa-levodopa enteral suspension in the United States), delivered via percutaneous gastrojejunostomy (PEG-J) and titrated in the inpatient setting, is an established treatment option for advanced Parkinson\u27s disease (PD) patients with motor fluctuations. However, long-term prospective data on the efficacy of LCIG on non-motor symptoms and the safety of outpatient titration are limited. Methods: In this 60-week, open-label phase 3b study, LCIG titration was initiated in an outpatient setting following PEG-J placement in PD patients. The efficacy of LCIG on motor and non-motor symptoms, quality of life, and safety was assessed. Results: Thirty-nine patients were enrolled in the study and 28 patients completed the treatment. A majority of patients (54%) completed outpatient titration within the first week of LCIG infusion. LCIG led to significant reductions from baseline in Non-Motor Symptom Scale (NMSS) total score (least squares mean ± SE = −17.6 ± 3.6, P \u3c 0.001) and 6 of the NMSS domain scores (sleep/fatigue, attention/memory, gastrointestinal tract, urinary, sexual function, miscellaneous) at week 12. These reductions were maintained at week 60 with the exception of the urinary domain. “Off” time (−4.9 ± 0.5 hours/day, P \u3c 0.001) and “On” time without troublesome dyskinesia (−4.3 ± 0.6 hours/day, P \u3c 0.001) were improved at week 60. Adverse events (AEs) were reported in 37 (95%) patients. Conclusions: LCIG treatment led to reductions in non-motor symptom burden and motor fluctuations in advanced PD patients. The safety profile was consistent with previous studies that used inpatient titration and outpatient titration did not appear to pose additional risk

The Cost Effectiveness of Levodopa-Carbidopa Intestinal Gel in the Treatment of Advanced Parkinson’s Disease in England

Background: Parkinson’s disease is a progressive neurodegenerative disease, which significantly impacts patients’ quality of life and is associated with high treatment and direct healthcare costs. In England, levodopa/carbidopa intestinal gel (LCIG) is indicated for the treatment of levodopa-responsive advanced Parkinson’s disease with troublesome motor fluctuations when available combinations of medicinal products are unsatisfactory. Objective: We aimed to determine the cost effectiveness of LCIG compared to the standard of care for patients with advanced Parkinson’s disease in England, using real-world data. Methods: A Markov model was adapted from previous published studies, using the perspective of the English National Health System and Personal and Social Services to evaluate the cost effectiveness of LCIG compared to standard of care in patients with advanced Parkinson’s disease over a 20-year time horizon. The model comprised 25 health states, defined by a combination of the Hoehn and Yahr scale, and waking time spent in OFF-time. The base case considered an initial cohort of patients with an Hoehn and Yahr score of ≥ 3, and > 4 h OFF-time. Standard of care comprised standard oral therapies, and a proportion of patients were assumed to be treated with subcutaneous apomorphine infusion or injection in addition to oral therapies. Efficacy inputs were based on LCIG clinical trials where possible. Resource use and utility values were based on results of a large-scale observational study, and costs were derived from the latest published UK data, valued at 2017 prices. The EuroQol five-dimensions-3-level (EQ-5D-3L) instrument was used to measure utilities. Costs and quality-adjusted life-years were discounted at 3.5%. Both deterministic and probabilistic sensitivity analyses were conducted. Results: Total costs and quality-adjusted life-years gained for LCIG vs standard of care were £586,832 vs £554,022, and 2.82 vs 1.43, respectively. The incremental cost-effectiveness ratio for LCIG compared to standard of care was £23,649/quality-adjusted life-year. Results were sensitive to the healthcare resource utilisation based on real-world data, and long-term efficacy of LCIG. Conclusions: The base-case incremental cost-effectiveness ratio was estimated to be within the acceptable thresholds for cost effectiveness considered for England

Applying modern soil mechanics to small mobile robots

Developing a robot that can traverse diffcult terrain requires many decisions to be made during the design stages. Numerous locomotion strategies exist and many architectures of each strategy can be created. We introduce a model that provides a platform for comparing these locomotion methods by calculating their expected energy use in traversing compliant terrain. Furthermore, our method can be used to aid the operation of a robot. A large proportion of the locomotion strategies in the literature include additional methods to improve their effcacy in diffcult terrain. A wheel-leg hybrid robot is a point in case. Our model can be used to determine when it is most effcient to employ these augmentations. To fnd the energy requirements of a terrain, the resistance-to-motion the robot faces is determined. Our model focuses on two locomotion mechanisms, wheels, and singlelink single-joint rotary legs. The method developed within this thesis also shows much promise for the analysis of other locomotion strategies. For wheeled locomotion this approach allows the modelling of the terrain interaction with both driven or towed wheels. Our model is a signifcant improvement for small mobile robots, those weighing less than 50 kilograms and with a wheel diameter or leg length under half a metre, for which the state of the art fails to accurately determine dynamic sinkage or the resistance to motion. The proposed model addresses many of the issues apparent with the classical terramechanics approach to calculating resistance to motion. Primarily these models were created for large agricultural or military vehicles, those with wheel diameters greater than half a metre and weighing over half a tonne. Additionally the classical model decouples the effects of multi-directional loading on the terrain. These both contribute to inaccurate predictions of the terrain interaction for small mobile robots. We address these problems by utilising the soil strength failure envelope method to determine bearing capacity. This approach more accurately models the interlinked forces and moments that exist at the soil-wheel/soil-leg interface. The solution amalgamates various physical phenomenon previously calculated independently, such as compaction, bulldozing, and rolling resistance, greatly simplifying the analysis. The number of parameters is also signifcantly reduced to a single term for undrained soils and two terms for drained soils. These parameters are well established in the soil mechanics literature. The model is augmented with a term that evaluates the work required to overcome unavoidable, small, repeated obstacles found in diffcult terrain such as uneven ground or fora. A natural scaling law is used to predict the distribution of various sized obstacles and the equivalent average resistance-to-motion that these obstacles present. As a whole, the model predicts the minimum work needed to traverse a particular terrain populated with repetitive obstacles as might be found in environments of interest such as forests, felds, rubble, deserts, or tundra. Additionally, feld testing in a forested environment with a wheeled robot and the development of a wheel-leg unit during the undertaking of this research ensures the model has a practical framing. Within this thesis is presented a novel method to evaluate a robot’s resistance-tomotion. This model represents a signifcant contribution to the feld as it replaces terramechanics models which have little practical use due to their inaccuracy and which are misleading for small robots. Our model can be utilised to select physical robot parameters such as wheel radius, or width as well as aiding in the operation of locomotion augmentations. Additionally, our model provides a platform for comparison of different robot architectures where no previous adequate platform exists. We believe our model will prove useful to the robotics community as it is the frst application of modern soil mechanics to determine resistance-to-motion. The increased fdelity to the soil interaction enables such a model to be utilised in both design and operation of small mobile robots

Determining resistance to motion for small wheeled robots using soil strength failure envelopes

To accurately determine sinkage and resistance to motion, we use modern soil mechanics theory which utilises soil strength failure envelopes. This method allows the modelling of the terrain interaction with both driven or towed wheels. Our model is a significant improvement for small mobile robots, those weighing less than 50 kilograms and with a wheel diameter under half a metre, for which state of the art fails to properly determine dynamic sinkage or the resistance to motion. Small mobile robots are an area of great interest with applications in difficult terrain including; search and rescue, mapping, security, exploration, and agriculture. Our model describes the motion resistance faced during locomotion in these difficult terrains dependent solely on the structural parameters of the robot, the soil’s type and its shear strength. The proposed model addresses many of the issues apparent with the classical terramechanics approach to calculating resistance to motion. Primarily, these models were created for large agricultural or military vehicles. Additionally, they decouple the effects of multi-directional loading on the terrain. These both contribute to inaccurate predictions of the terrain interaction for small mobile robots. We address these problems by using the failure envelope method. This approach more accurately models the interlinked forces and moments that exist at the soil-wheel interface. The solution amalgamates various physical phenomenon previously calculated independently, such as compaction and rolling resistance, greatly simplifying the analysis. The number of empirical soil parameters is also significantly reduced to a single term in undrained soils and two in drained soils. These parameters are well established in the literature.A failure envelope defines the bearing capacity of a soil at a particular footing. To find parameters centred around the axle, the failure envelope must be transformed from an approximated footing to one that is described by the weight, towing force and torque applied at the wheel’s axle. Our model uses the property of the failure envelope surface which defines the type of failure the soil experiences under the applied forces and moments. Solving numerically for a given weight, wheel radius, wheel width and soil strength, gives a single solution for steady state locomotion where there is no vertical deformation in the soil. Our approach can be applied for both a driven or towed wheel, returning a required torque or towing force respectively. The model is augmented with a term that evaluates the work required to overcome unavoidable small, repeated obstacles found in difficult terrain such as uneven ground or flora. A natural scaling law is used to predict the distribution of various sized obstacles and the equivalent average resistance to motion that these obstacles present. As a whole, the model predicts the minimum required work needed to traverse a particular terrain populated with repetitive obstacles as might be found in terrains of interest such as forests, fields, rubble, desserts, or tundra.<br/

The Role of Health-Related Lifestyle Attitudes in Understanding Health Behaviors and Outcomes

Health systems throughout the world increasingly recognize health-related quality of life (HRQoL) as a key patient-centered health outcome. HRQoL is particularly important in conditions which impair daily living (e.g. Parkinson’s Disease) and in those that are largely subjective in nature (e.g. pain). HRQoL, when assessed using a preference-based measure, is an essential component in the calculation of quality adjusted life years (QALYs). QALYs gained form the denominator in an incremental cost-effectiveness ratio (ICER), which is the most common result derived in a cost-utility analysis and is used to inform patient and system-level decisions and incorporated into pricing and reimbursement decisions. HRQoL can be viewed as an individual’s perception of his/her own health. An individual’s perception is often influenced by attitudes and beliefs, which in turn also influence health behaviors and overall health. This dissertation examines the role of health and life-style related attitudes (HLA) in understanding health behaviors and outcomes through three separate studies. The studies evaluated the validity of measures of HRQoL and HLA in a community population and examined the relationship between HLA and health behaviors, self-assessment of health and life-satisfaction. The first chapter introduces key study concepts including HLA, self-assessment and life-satisfaction along with a conceptual framework that facilitates the understanding of the relationship between HLA, health behaviors and outcomes (including self-assessment of health and life satisfaction). The introductory chapter highlights the gaps in the evidence, research objectives and hypotheses that were examined in subsequent chapters, and explains the significance of the research. All the studies are based on secondary analyses from a large scale community health study conducted in Kirklees, United Kingdom, in 2012. The second chapter examines the properties of the recently developed EQ-5D-5L as a measure of population health in a large community-based survey. The assessment of the construct validity of the EQ-5D-5L in a community sample helps to facilitate in the use of EQ-5D-5L in general population health studies. A secondary aim of the study was to compare EQ-5D-5L summary scores based on an English value set (5L-ENG), crosswalk scores based on 3L values (XW), and scores based on equal weighting (5L-EWS). Properties of the EQ-5D-5L that were examined included discriminative ability, strength of correlations with related measures of health, and statistical efficiency, as assessed with relative efficiency (RE) ratios between summary scores from known group comparisons, using the XW as the referent. Correlations between EQ-5D dimensions and other measures of health ranged from r =0.56-0.73. Compared to the XW, the RE of the 5L-ENG and 5L-EWS were similar or higher (Age:RE5L-ENG=0.96,RE5L-EWS=1.36; BMI:RE5L-ENG=1.00,RE5L-EWS=1.0; Number of prescription medications:RE5L-ENG=1.00,RE5L-EWS=1.18; Number of Chronic conditions:RE5L-ENG=1.00,RE5L-EWS=1.61; General Health:RE5L-ENG=1.13,RE5L-EWS=1.20). The results provided evidence to support the validity of EQ-5D-5L in large community based surveys. If statistical efficiency of a summary score is a desirable property, the EWS should be considered for non-QALY purposes. The third chapter describes the second study which sought to determine the extent to which health and lifestyle related attitudes (HLA) explained health behaviors and outcomes. If certain HLAs are associated with specific health behaviors, it raises the possibility of using HLA based segmentation to improve the uptake of health interventions designed, for instance, to reduce drug abuse. Individuals were characterized based on HLA using two different approaches: (1) as five discrete segments; and (2) as 3 single-item scales (“importance of health”, “involvement in health” and “control of health”). The association between each HLA approach and several potentially modifiable behaviors/conditions was assessed using logistic regression. When respondents were categorized according to HLA segments, 30.8% were health conscious realists, 15.0% balanced compensators, 17.7% life-for-todays, 10.0% hedonistic immortals and 26.4% unconfident fatalists. Correlational analysis between HLA segments and trait scales produced low scores and moderate negative correlations between specific HLA traits and segments, which indicated the approaches were complementary. The model fit between HLA and health behaviors/conditions was weak and except for mental health problems, was similar across the approaches. Both approaches demonstrated convergent and divergent validity, e.g. unconfident fatalists and those with low levels of the trait “involvement in health” were significantly more likely to report poor diet [OR=2.27 (95%CI: 2.02, 2.55), OR=1.59 (95%CI: 1.45, 1.74), respectively. The HLA segmentation approach performed better as a predictor of certain behaviors (e.g. tobacco use) than others (e.g. exercise). Both the segment and the trait methods had comparable performance in explaining health behaviors and outcomes. Thus, both provided viable approaches to identify sub-groups of the population who are more likely to engage in certain negative health behaviors that could be targeted for tailored healthcare interventions. The fourth chapter describes the third study, which examined the relationship between HLA and self-assessment of health and life-satisfaction. Evaluation of the relationship between HLA and health behaviors and self-assessment of HRQoL and life satisfaction may help to identify groups which systematically differ in their valuation of health, despite of being in similar health state. In this study, individuals were characterized based on HLA segments [Health Conscious Realists(HCR), Balanced Compensators(BC), Live for Todays(LFT), Hedonistic Immortals(HI), and Unconfident Fatalists(UF)] using an algorithm for the 19-item Healthy Foundations Lifestyle Segmentation questionnaire. Associations between HLA and outcomes of interest [(i) self-assessment of health (EQ-VAS), (ii) differences between personal (i.e. EQ-VAS) and societal valuation of health (Dev), and (iii) life-satisfaction] were examined by multivariate regression analyses, adjusting for current health and relevant individual characteristics. The societal valuation was based on the preference-based algorithm for the EQ-5D-5L. Dev was examined to evaluate if HLA segments differ systematically between personal valuation of health and societal valuation of the health state. In the analytical sample (n=9,130), compared to HCR respondents (reference): (i) mean VAS scores for UF, LFT and BC respondents were 9.02 (p<0.001) and 1.96 points lower (p=0.002) and 1.15 points higher (p<0.01) respectively; (ii) Dev score in UF respondents was 0.027 lower (p<0.001), and (iii) BC respondents were less likely (OR:0.8,95%CI:0.6, 0.9), while UF were more likely (OR:3.5, 95%CI: 2.9, 4.2) to report low lifesatisfaction. Thus, HLA were associated with systematic differences in self-assessment of health and life-satisfaction, most notably UF, who rated their health much more negatively and had much lower life satisfaction, even after adjusting for characteristics such as age and gender. Results suggest that unconfident fatalists, who compromised 30% of survey respondents, are an important subgroup in the community who may need to be separately targeted for health care interventions, particularly behavioral. Importantly from a health services research perspective, the assessment of self reported HRQoL in this subgroup using measures of health and well-being may need to be separately considered in analysis and interpretation. Further research on this topic is warranted given the increasing use of patient-reported outcomes in health systems, particularly in conditions in which UF are disproportionately represented. The fifth chapter provides an overall conclusion to the dissertation. The characterization of individuals based on HLA's implications for health promotion and self assessment of health is discussed, and future research directions are proposed