Excipient characterization and particle engineering to develop directly compressed orally disintegrating tablets

ODTs have emerged as a novel oral dosage form with a potential to deliver a wide range of drug candidates to paediatric and geriatric patients. Compression of excipients offers a costeffective and translatable methodology for the manufacture of ODTs. Though, technical challenges prevail such as difficulty to achieve suitable tablet mechanical strength while ensuring rapid disintegration in the mouth, poor compressibility of preferred ODT diluent Dmannitol, and limited use for modified drug-release. The work investigates excipients’ functionality in ODTs and proposes new methodologies for enhancing material characteristics via process and particle engineering. It also aims to expand ODT applications for modified drug-release. Preformulation and formulation studies employed a plethora of techniques/tests including AFM, SEM, DSC, XRD, TGA, HSM, FTIR, hardness, disintegration time, friability, stress/strain and Heckel analysis. Tableting of D-mannitol and cellulosic excipients utilised various compression forces, material concentrations and grades. Engineered D-mannitol particles were made by spray drying mannitol with pore former NH4HCO3. Coated microparticles of model API omeprazole were prepared using water-based film forming polymers. The results of nanoscopic investigations elucidated the compression profiles of ODT excipients. Strong densification of MCC (Py is 625 MPa) occurs due to conglomeration of physicomechanical factors whereas D-mannitol fragments under pressure leading to poor compacts. Addition of cellulosic excipients (L-HPC and HPMC) and granular mannitol to powder mannitol was required to mechanically strengthen the dosage form (hardness >60 N, friability <1%) and to maintain rapid disintegration (<30 sec). Similarly, functionality was integrated into D-mannitol by fabrication of porous, yet, resilient particles which resulted in upto 150% increase in the hardness of compacts. The formulated particles provided resistance to fracture under pressure due to inherent elasticity while promoted tablet disintegration (50-77% reduction in disintegration time) due to porous nature. Additionally, coated microparticles provided an ODT-appropriate modified-release coating strategy by preventing drug (omeprazole) release.

A pragmatic approach for engineering porous mannitol and mechanistic evaluation of particle performance

The importance of mannitol has increased recently as an emerging diluent for orodispersible dosage forms. The study aims to prepare spray dried mannitol retaining high porosity and mechanical strength for the development of orally disintegrating tablets (ODTs). Aqueous feed of d-mannitol (10% w/v) comprising ammonium bicarbonate, NH4HCO3 (5% w/v) as pore former was spray dried at inlet temperature of 110-170°C. Compacts were prepared at 151MPa and characterized for porosity, hardness and disintegration time. Particle morphology and drying mechanisms were studied using thermal (HSM, DSC and TGA) and polymorphic (XRD) methods. Tablet porosity increased from 0.20±0.002 for pure mannitol to 0.53±0.03 using fabricated porous mannitol. Disintegration time dropped by 50-77% from 135±5.29s for pure mannitol to 75.33±2.52-31.67±1.53s for mannitol 110-170°C. Hardness increased by 150% at 110°C (258.67±28.89N) and 30% at 150°C (152.70±10.58N) compared to pure mannitol tablets (104.17±1.70N). Increasing inlet temperature resulted in reducing tablet hardness due to generation of 'micro-sponge'-like particles exhibiting significant elastic recovery. Impact of mannitol polymorphism on plasticity/elasticity cannot be ruled out as a mixture of α and β polymorphs formed upon spray drying.

A new inverse DEA method for merging banks

This study suggests a novel application of Inverse Data Envelopment Analysis (InvDEA) in strategic decision making about mergers and acquisitions in banking. The conventional DEA assesses the efficiency of banks based on the information gathered about the quantities of inputs used to realize the observed level of outputs produced. The decision maker of a banking unit willing to merge/acquire another banking unit needs to decide about the inputs and/or outputs level if an efficiency target for the new banking unit is set. In this paper, a new InvDEA-based approach is developed to suggest the required level of the inputs and outputs for the merged bank to reach a predetermined efficiency target. This study illustrates the novelty of the proposed approach through the case of a bank considering merging with or acquiring one of its competitors to synergize and realize higher level of efficiency. A real data set of 42 banking units in Gulf Corporation Council countries is used to show the practicality of the proposed approach.

Engagement experiences of Hispanic Generation 1.5 English language learners at a Massachusetts community college

Hispanic Generation 1.5 students are foreign-born, U.S. high school graduates who are socialized in the English dominant K-12 school system while still maintaining the native language and culture at home (Allison, 2006; Blumenthal, 2002; Harklau, Siegal, & Losey, 1999; Rumbault & Ima, 1988). When transitioning from high school to college, these students sometimes assess into ESL courses based on their English language abilities, and because of this ESL placement, Hispanic Generation 1.5 students might have different engagement experiences than their mainstream peers. Engagement is a critical factor in student success and long-term retention because students’ positive and negative engagement experiences affect their membership and sense of belonging at the institution. The purpose of this study was to describe the engagement and membership experiences of Hispanic Generation 1.5 students’ at a Massachusetts community college. This study employed naturalistic inquiry within an embedded descriptive case study design that included three units of analysis: the students’ engagement experiences in (a) ESL courses, (b) developmental courses, and (c) mainstream courses. The main source of data was in-depth interviews with Hispanic Generation 1.5 students at Commonwealth of Massachusetts Community College. Criterion sampling was used to select the interview participants, ensuring that all participants were native Spanish speakers and were taking or had taken at least one ESL course at the institution. The study findings show that these Hispanic Generation 1.5 students at the college did not perceive peer engagement as critical to academic success. Most times the participants avoided peer engagement outside of the classroom, especially with fellow Hispanic students, who they felt would deter them from their English language development and general academic work. Engagement with ESL faculty and ESL academic support staff played the most critical role in the participants’ sense of belonging and success, and students who were required to engage with faculty and academic support staff outside of the classroom were the most satisfied with their educational experiences. While the participants were all disappointed with some aspect of their ESL placement, they valued the ESL engagement experiences more than the engagement experiences while completing developmental and credit coursework.

A influência da relevância social no viés de grupo

Behaviors found in every culture, general human tendencies, are knew in Evolutionary Psychology as evolved psychological mechanisms. Those behaviors date back the Environment of Evolutionary Adaptedness, and a well know example of such behavior is the group bias (or intergroup bias). This bias consists of recognizing members of your own group and favor them, while disregarding or even harming outsiders. This behavior was and still is extensively studies, among the most important conclusions about this phenomenon is the Minimal Groups Paradigm, in which it was discovered that the group bias could trigger even when the groupings were done in following very arbitrary criteria. In the current study, our goal was to test if the participants, when playing an economic game, would behave in a similar fashion under a minimal group situation and real groups, with social meaning. With this in mind we made two experimental conditions, a Low Social Meaning one (LSM) where the groups were represented by letters (H, B, O and Y) in which participants would be ramdomly assorted to each group; and the High Social Meaning condition (HSM) in which religion was used as a group marker, containing the two most dominating religious groups in Brazil, catholic and evangelic, another group containing all the other affiliations e the fourth and last group representing atheists and agnostics. The ratio of donations in-group/out-group was roughly the same across both conditions. However, the amount of wafers donated to ingroup was significantly bigger in the HSM condition. By verifying which aspects of the individual best predicted the observed group bias, we discovered that the in-group Entitativity perception as well as the Group Identification were the most relevant variables, however, only in the HSM condition. Simultaneously, by verifying the generosity, biased or not, we observed that the agreeableness personality factor was the only variable able to predict it, and only in the LSM condition. We conclude that our generosity, or the lack of it, is for most part defined by our personality, the Agreeableness factor in particular. But this very generosity can be biased by the social meaning of the involved groups and that, if the social meaning is big enough, even people who, thanks to their personality, normally wouldn’t show generosity, are able to do so when the receiver is an in-group member.

Le Facce del Coating

Studio degli elementi frontali, posteriori e di collegamento di una macchina per il coating continuo di prodotti farmaceutici.

Sincronización de la ovulación y el ciclo inducido por el efecto "macho" mediante la administración de progesterona por vía intravaginal en cabras en período de anestro estacional

Algunos de los métodos alternativos a los tratamientos hormonales clásicos utilizando progestágenos y eCG, para la inducción y sincronización del celo y la ovulación, unido a la inseminación artificial (IA) a tiempo fijo en ganado caprino, están basados como el IMA.PRO2® en el estímulo por la presencia de los machos (efecto macho) y la sincronización de la ovulación inducida mediante prostaglandina F2α o sus análogos. En estos métodos, la administración de una dosis baja de progesterona o progestágenos durante un breve periodo de tiempo en el momento de la introducción de los machos, es un método efectivo para evitar la presencia de cuerpos lúteos de mala calidad que generan ciclos cortos, consiguiendo un primer ciclo inducido de adecuada función luteal. En el método IMA-PRO2® en el momento de la introducción de los machos se administran 25 mg de progesterona por vía intramuscular en vehículo oleoso, con buenos resultados de fertilidad después de la administración de cloprostenol y la IA sistemática, sin embargo las directivas europeas han marcado nuevas restricciones a la administración de esteroides en animales de producción, que en el caso de la progesterona o progestágenos sólo son permitidas por vía intravaginal. Se diseñaron cuatro experimentos con el fin de desarrollar una administración de progesterona por vía intravaginal, utilizable en la práctica a nivel de campo y con una eficacia similar en términos de fertilidad, en el conjunto del método IMA-PRO2®...

The Relationship Between Cadwaladerite Al(OH)2Cl∙4H2O and Lesukite Al2(OH)5Cl∙2H2O as Investigated by SEM, PXRD, FTIR and Raman Spectroscopy

Cadwaladerite (Al(OH)2Cl∙4H2O) collected from Cerro Pintados, Chile described by Gordon in 1941 is designated as “doubtful” by the IMA. Material collected from the same locality in 2015 resembling the description of cadwaladerite gave a powder XRD pattern similar to lesukite (Al2(OH)5Cl∙2H2O). However, Gordon provided no X-ray data for his material from Cerro Pintados. In order to determine whether cadwaladerite and lesukite are the same mineral species, measurements were made on a suite of samples from various localities. A portion of the material collected by Gordon in 1941 was also obtained from the Mineralogical Museum of Harvard University. Type material of lesukite from a fumarolic environment at the Tolbachik Fissure in Kamchatka, Russia was obtained as well as lesukite from the Maria Mine, Chile (Arica Province) and a previously undescribed locality for lesukite (Barranaca del Sulfato, Mejillones Peninsula, Antofagasta Province). All samples are yellow to yellow-orange in colour and all exhibit small cubic crystals (up to 50µm), even Gordon’s cadwaladerite which was thought to be amorphous. The Chilean samples are all associated with halite and sometimes with anhydrite. These five samples were studied by SEM, FTIR, powder XRD, and Raman spectroscopy. A ratio of Al:Cl less than or equal to 1.3:1 was observed for all the samples, including measurements made on lesukite from the Russian locality Vergasova et al. studied in 1997, and determined to have a 2:1 ratio. SEM-EDS analyses also show all samples to have minor iron substitution, as well as copper substitution in two samples. FTIR spectra are very similar for all samples. Raman spectroscopy done on both samples collected in Cerro Pintados and the Russian lesukite gave similar spectra. Powder XRD analyses on all samples showed spectra identified to be lesukite, including Gordon’s cadwaladerite. Crystal cell parameters calculated from powder XRD ranged from 19.778Å to 19.878Å. Results using modern instrumental techniques confirm Gordon’s cadwaladerite, collected in 1939 and described in 1941, and lesukite are the same mineral species.

Sellar Spine Associated with Endocrine and Neuro-Ophthalmological Manifestations

A case of sellar spine, associated with neuro-ophthalmological and endocrine abnormalities, is reported. The case described is a rare malformation, of which the authors found only six cases in the literature.

Changes of Soluble CD40 Ligand in the Progression of Acute Myocardial Infarction Associate to Endothelial Nitric Oxide Synthase Polymorphisms and Vascular Endothelial Growth Factor But Not to Platelet CD62P Expression

Reported in vitro data implicated soluble CD40 ligand (sCD40L) in endothelial dysfunction and angiogenesis. However, whether sCD40L could exert that influence in endothelial dysfunction and angiogenesis after injury in acute myocardial infarction (AMI) patients remains unclear. In the present study, we evaluated the association of sCD40L with markers of platelet activation, endothelial, and vascular function during a recovery period early after AMI. To achieve this goal, the time changes of soluble, platelet-bound, and microparticle-bound CD40L levels over 1 month were assessed in AMI patients and correlated with endothelial nitric oxide synthase (eNOS) polymorphisms, vascular endothelial growth factor (VEGF) concentrations, and platelet expression of P-selectin (CD62P). The association of soluble form, platelet-bound, and microparticle-bound CD40L with CD62P expression on platelets, a marker of platelet activation, was also assessed to evaluate the role of CD40L in the thrombosis, whereas the association with eNOS and VEGF was to evaluate the role of CD40L in vascular dysfunction. This work shows for the first time that time changes of sCD40L over 1 month after myocardial infarct onset were associated with G894T eNOS polymorphism and with the VEGF concentrations, but not to the platelet CD62P expression. These results indicate that, in terms of AMI pathophysiology, the sCD40L cannot be consider just as being involved in thrombosis and inflammation but also as having a relevant role in vascular and endothelial dysfunction.

Safety Assessment Tool for Construction Zone Work Phasing Plans, 2016

The Highway Safety Manual (HSM) is the compilation of national safety research that provides quantitative methods for analyzing highway safety. The HSM presents crash modification functions related to freeway work zone characteristics such as work zone duration and length. These crash modification functions were based on freeway work zones with high traffic volumes in California. When the HSM-referenced model was calibrated for Missouri, the value was 3.78, which is not ideal since it is significantly larger than 1. Therefore, new models were developed in this study using Missouri data to capture geographical, driver behavior, and other factors in the Midwest. Also, new models for expressway and rural two-lane work zones that barely were studied in the literature were developed. A large sample of 20,837 freeway, 8,993 expressway, and 64,476 rural two-lane work zones in Missouri was analyzed to derive 15 work zone crash prediction models. The most appropriate samples of 1,546 freeway, 1,189 expressway, and 6,095 rural two-lane work zones longer than 0.1 mile and with a duration of greater than 10 days were used to make eight, four, and three models, respectively. A challenging question for practitioners is always how to use crash prediction models to make the best estimation of work zone crash count. To solve this problem, a user-friendly software tool was developed in a spreadsheet format to predict work zone crashes based on work zone characteristics. This software selects the best model, estimates the work zone crashes by severity, and converts them to monetary values using standard crash estimates. This study also included a survey of departments of transportation (DOTs), Federal Highway Administration (FHWA) representatives, and contractors to assess the current state of the practice regarding work zone safety. The survey results indicate that many agencies look at work zone safety informally using engineering judgment. Respondents indicated that they would like a tool that could help them to balance work zone safety across projects by looking at crashes and user costs.

Understanding COPD: A Vision on Phenotypes, Comorbidities and Treatment Approach

Chronic Obstructive Pulmonary Disease (COPD) phenotypes have become increasingly recognized as important for grouping patients with similar presentation and/or behavior, within the heterogeneity of the disease. The primary aim of identifying phenotypes is to provide patients with the best health care possible, tailoring the therapeutic approach to each patient. However, the identification of specific phenotypes has been hindered by several factors such as which specific attributes are relevant, which discriminant features should be used for assigning patients to specific phenotypes, and how relevant are they to the therapeutic approach, prognostic and clinical outcome. Moreover, the definition of phenotype is still not consensual. Comorbidities, risk factors, modifiable risk factors and disease severity, although not phenotypes, have impact across all COPD phenotypes. Although there are some identified phenotypes that are fairly consensual, many others have been proposed, but currently lack validation. The on-going debate about which instruments and tests should be used in the identification and definition of phenotypes has contributed to this uncertainty. In this paper, the authors review present knowledge regarding COPD phenotyping, discuss the role of phenotypes and comorbidities on the severity of COPD, propose new phenotypes and suggest a phenotype-based pharmacological therapeutic approach. The authors conclude that a patient-tailored treatment approach, which takes into account each patient's specific attributes and specificities, should be pursued.

External Validation of the ProACS Score for Risk Stratification of Patients with Acute Coronary Syndromes

INTRODUCTION: The ProACS risk score is an early and simple risk stratification score developed for all-cause in-hospital mortality in acute coronary syndromes (ACS) from a Portuguese nationwide ACS registry. Our center only recently participated in the registry and was not included in the cohort used for developing the score. Our objective was to perform an external validation of this risk score for short- and long-term follow-up. METHODS: Consecutive patients admitted to our center with ACS were included. Demographic and admission characteristics, as well as treatment and outcome data were collected. The ProACS risk score variables are age (≥72 years), systolic blood pressure (≤116 mmHg), Killip class (2/3 or 4) and ST-segment elevation. We calculated ProACS, Global Registry of Acute Coronary Events (GRACE) and Canada Acute Coronary Syndrome risk score (C-ACS) risk scores for each patient. RESULTS: A total of 3170 patients were included, with a mean age of 64±13 years, 62% with ST-segment elevation myocardial infarction. All-cause in-hospital mortality was 5.7% and 10.3% at one-year follow-up. The ProACS risk score showed good discriminative ability for all considered outcomes (area under the receiver operating characteristic curve >0.75) and a good fit, similar to C-ACS, but lower than the GRACE risk score and slightly lower than in the original development cohort. The ProACS risk score provided good differentiation between patients at low, intermediate and high mortality risk in both short- and long-term follow-up (p<0.001 for all comparisons). CONCLUSIONS: The ProACS score is valid in external cohorts for risk stratification for ACS. It can be applied very early, at the first medical contact, but should subsequently be complemented by the GRACE risk score.

Use of CPAP to Reduce Arterial Stiffness in Moderate-to-Severe Obstructive Sleep Apnoea, Without Excessive Daytime Sleepiness (STIFFSLEEP): an Observational Cohort Study Protocol

INTRODUCTION: Sleepiness is a cardinal symptom in obstructive sleep apnoea (OSA) but most patients have unspecific symptoms. Arterial stiffness, evaluated by pulse wave velocity (PWV), is related to atherosclerosis and cardiovascular (CV) risk. Arterial stiffness was reported to be higher in patients with OSA, improving after treatment with continuous positive airway pressure (CPAP). This study aims to assess whether the same effect occurs in patients with OSA and without sleepiness. METHODS AND ANALYSIS: This observational study assesses the CV effect of CPAP therapy on a cohort of patients with moderate-to-severe OSA; the effect on the subcohorts of sleepy and non-sleepy patients will be compared. A systematic and consecutive sample of patients advised CPAP therapy will be recruited from a single outpatient sleep clinic (Centro Hospitalar de Lisboa Central-CHLC, Portugal). Eligible patients are male, younger than 65 years, with confirmed moderate-to-severe OSA and apnoea-hypopnea index (AHI) above 15/hour. Other sleep disorders, diabetes or any CV disease other than hypertension are exclusion criteria. Clinical evaluation at baseline includes Epworth Sleepiness Scale (ESS), and sleepiness is defined as ESS above 10. OSA will be confirmed by polygraphic study (cardiorespiratory, level 3). Participants are advised to undertake an assessment of carotid-femoral PWV (cf-PWV) and 24 hours evaluation of ambulatory blood pressure monitoring (ABPM), at baseline and after 4 months of CPAP therapy. Compliance and effectiveness of CPAP will be assessed. The main outcome is the variation of cf-PWV over time.