Glass Microneedles: A Case Study for Regulatory Approval Using a Quality by Design Approach.

In this paper, a roadmap is provided for the regulatory approval of one of the exciting and dynamic drug delivery fields, microneedles, by using a Quality by Design approach to pharmaceutical product development. In this regard, a quality target product profile (QTPP) and the critical quality attributes (CQA) of microneedles are identified. A case study of the recently patented method of fabricating glass microneedles entirely from a therapeutic agent, thus eliminating the requirement for additional excipients is discussed. The glass microneedle, ArrayPatch, is a propriety wearable device with platform potential consisting of an array of sharp, but painless, dissolvable microneedles manufactured with 100% drug. The microneedles penetrate the skin on application and dissolve to deliver a locally effective dose. The in vitro characterization of the microneedle CQAs under WHO-guided stability conditions will be described to assess the manufacturing readiness of ArrayPatch.  A live technical video is also provided, presenting a unique procedure of jugular vein cannulation through the ear vein of a pig animal model to study the in vivo pharmacokinetics of ArrayPatch compared to standard-of-care marketed products.

Dissolving microneedles: Applications and growing therapeutic potential.

Microneedles are a rapidly developing method for the transdermal delivery of therapeutic compounds. All types of microneedles, whether solid, hollow, coated, or dissolving function by penetrating the stratum corneum layer of the skin producing a microchannel through which therapeutic agents may be delivered. To date, coated and hollow microneedles have been the most successful, despite suffering from issues such as poor drug loading capabilities and blocked pores. Dissolving microneedles, on the other hand, have superior drug loading as well as other positive attributes that make it an ideal delivery system, including simple methods of fabrication and disposal, and abundantly available materials. Indeed, dissolvable microneedles can even be fabricated entirely from the therapeutic agent itself thus eliminating the requirement for additional excipients. This focused review presents the recent developments and trends of dissolving microneedles as well as potential future directions. The advantages, and disadvantages of dissolving microneedles as well as fabrication materials and methods are discussed. The potential applications of dissolving microneedles as a drug delivery system in different therapeutic areas in both research literature and clinical trials is highlighted. Applications including the delivery of cosmetics, vaccine delivery, diagnosis and monitoring, cancer, pain and inflammation, diabetes, hair and scalp disorders and inflammatory skin diseases are presented. The current trends observed in the microneedle landscape with particular emphasis on contemporary clinical trials and commercial successes as well as barriers impeding microneedle development and commercialisation are also discussed.

Investigating microcrystalline cellulose crystallinity using Raman spectroscopy.

Microcrystalline cellulose (MCC) is a semi-crystalline material with inherent variable crystallinity due to raw material source and variable manufacturing conditions. MCC crystallinity variability can result in downstream process variability. The aim of this study was to develop models to determine MCC crystallinity index (%CI) from Raman spectra of 30 commercial batches using Raman probes with spot sizes of 100 µm (MR probe) and 6 mm (PhAT probe). A principal component analysis model separated Raman spectra of the same samples captured using the different probes. The %CI was determined using a previously reported univariate model based on the ratio of the peaks at 380 and 1096 cm-1. The univariate model was adjusted for each probe. The %CI was also predicted from spectral data from each probe using partial least squares regression models (where Raman spectra and univariate %CI were the dependent and independent variables, respectively). Both models showed adequate predictive power. For these models a general reference amorphous spectrum was proposed for each instrument. The development of the PLS model substantially reduced the analysis time as it eliminates the need for spectral deconvolution. A web application containing all the models was developed. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10570-021-04093-1.

In Silico, In Vitro, and In Vivo Evaluation of Precipitation Inhibitors in Supersaturated Lipid-Based Formulations of Venetoclax.

The concept of using precipitation inhibitors (PIs) to sustain supersaturation is well established for amorphous formulations but less in the case of lipid-based formulations (LBF). This study applied a systematic in silico-in vitro-in vivo approach to assess the merits of incorporating PIs in supersaturated LBFs (sLBF) using the model drug venetoclax. sLBFs containing hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), PVP-co-vinyl acetate (PVP/VA), Pluronic F108, and Eudragit EPO were assessed in silico calculating a drug-excipient mixing enthalpy, in vitro using a PI solvent shift test, and finally, bioavailability was assessed in vivo in landrace pigs. The estimation of pure interaction enthalpies of the drug and the excipient was deemed useful in determining the most promising PIs for venetoclax. The sLBF alone (i.e., no PI present) displayed a high initial drug concentration in the aqueous phase during in vitro screening. sLBF with Pluronic F108 displayed the highest venetoclax concentration in the aqueous phase and sLBF with Eudragit EPO the lowest. In vivo, the sLBF alone showed the highest bioavailability of 26.3 ± 14.2%. Interestingly, a trend toward a decreasing bioavailability was observed for sLBF containing PIs, with PVP/VA being significantly lower compared to sLBF alone. In conclusion, the ability of a sLBF to generate supersaturated concentrations of venetoclax in vitro was translated into increased absorption in vivo. While in silico and in vitro PI screening suggested benefits in terms of prolonged supersaturation, the addition of a PI did not increase in vivo bioavailability. The findings of this study are of particular relevance to pre-clinical drug development, where the high in vivo exposure of venetoclax was achieved using a sLBF approach, and despite the perceived risk of drug precipitation from a sLBF, including a PI may not be merited in all cases.

Ethics Reporting Practices in Aging Research From the Arab Region.

Objectives: This study aims to assess the extent of ethics reporting practices in aging research from Arab countries. Methods: A systematic scoping review of research on aging in 22 Arab countries from seven databases (1994-2013) identified 637 publications warranting institutional ethical approval and 612 publications warranting informed consent. We used multivariable regression analysis to examine variations by time, place, and study characteristics. Results: Only 36.6% of articles reported approval from a Research Ethics Committee and 38.7% reported informed consent. Reporting of ethical research practices increased significantly over time and as research collaborations and journal impact factor increased, and when sampling frame included institutionalized participants. In contrast, failure to report ethical research practices was significantly more common in non-English articles and those that did not report a funding source. Discussion: Despite gains across time, reporting of ethical research practices remains suboptimal in the Arab region. Further guidelines and capacity building are needed.

Silver Citrate Nanoparticles Inhibit PMA-Induced TNFα Expression via Deactivation of NF-κB Activity in Human Cancer Cell-Lines, MCF-7.

BACKGROUND: The nuclear factor kappa-B (NF-κB) is a major transcription factor responsible for the production of numerous inflammatory mediators, including the tumor necrosis factor (TNFα), which has a lethal association with cancer's onset. The silver nanoparticles (AgNPs) are widely used in cancer treatment and several other biomedical applications. OBJECTIVE: The study aimed to determine the effects of silver citrate nanoparticles (AgNPs-CIT) on NF-κB activation together with TNFα mRNA/protein expressions in the phorbol myristate acetate (PMA)-stimulated MCF-7 human breast cancer cell-lines. METHODS: The AgNPs-CIT were synthesized by the reduction method, and the prepared AgNPs-CIT were characterized for their shape, absorption in UV-VIS electromagnetic radiations, size distribution, ζ-potential, and antioxidant activity. The MCF-7 cell-lines were pretreated with AgNPs-CIT and stimulated with PMA. The TNFα mRNA expressions were determined by real-time PCR, whereas the protein production was determined by the ELISA. The NF-κB activity was distinctly observed by highly-specific DNA-based ELISA, and by NF-κB-specific inhibitor, Bay 11-7082. RESULTS: The prepared AgNPs-CIT were spherical and have an absorption wavelength range of 381-452 nm wherein the particles size ranged between 19.2±0.1 to 220.77±0.12 nm with the charge range -9.99±0.8 to -34.63±0.1 mV. The prepared AgNPs-CIT showed comparative antioxidant activity at >40% inhibitions level of the DPPH radicals. The AgNPs-CIT were found to be non-toxic to MCF-7 cell-lines and inhibited PMA-induced activation of the NF-κBp65, and also the mRNA/protein expression of TNFα. CONCLUSION: This is the first report that showed AgNPs-CIT inhibited TNFα expression via deactivation of the NF-κB signaling event in stimulated breast cancer cells. The results have important implications for the development of novel therapeutic strategies for the prevention/treatment of cancers and/or inflammatory disorders.

Application of percolation threshold to disintegration and dissolution of ibuprofen tablets with different microcrystalline cellulose grades.

The study presented was conducted to determine whether a percolation threshold value, previously determined for ibuprofen/microcrystalline cellulose (MCC) blends using percolation theory and compression data (Queiroz et al., 2019), could translate to tablet disintegration and dissolution data. The influence of MCC grade (air stream dried versus spray dried) on tablet disintegration and dissolution was also investigated. Complementary to conventional disintegration and dissolution testing, Raman imaging determined drug distribution within tablets, and in-line particle video microscopy (PVM) and focused-beam reflectance measurement (FBRM) monitored tablet disintegration. Tablets were prepared containing 0-30% w/w ibuprofen. Raman imaging confirmed the percolation threshold by quantifying the number and equivalent circular diameters of ibuprofen domains on tablet surfaces. Across the percolation threshold, a step change in dissolution behaviour occurred, and tablets containing air stream dried MCC showed slower disintegration rates compared to tablets containing spray dried MCC. Dissolution measurements confirmed experimentally a percolation threshold in agreement with that determined using percolation theory and compression data. An increase in drug domains, due to cluster formation, and less efficient tablet disintegration contributed to slower ibuprofen dissolution above the percolation threshold. Slower dissolution was measured for tablets containing air stream dried compared to spray dried MCC.

Somatostatin receptors as a new active targeting sites for nanoparticles.

The delivery of nanoparticles through receptor-mediated cell interactions has nowadays a major attention in the area of drug targeting applications. This specific kind of targeting is mediated by localized receptors impeded into the target site with subsequent drugs internalization. Hence, this type of interaction would diminish side effects and enhance drug delivery efficacy to the target site. Somatostatin receptors (SSTRs) are one type of G protein-coupled receptors, which could be active targeted for various purposes. There are five SSTRs types (SSTR1-5) which are localized at various organs in the body and spread into different tissues. SSTRs could be considered as a promising target to various nanoparticles which is facilitated when nanoparticles are modified through specific ligand or coating to allow better binding. This review discusses the exploration of SSTRs for active targeting of nanoparticles with certain emphasize on their interaction at the cellular level.

Enalapril maleate orally disintegrating tablets: tableting and in vivo evaluation in hypertensive rats.

The aim of this study was to develop orally disintegrating tablets (ODTs) for enalapril maleate (EnM) to facilitate its administration to the elderly or other patients having dysphagia. Compatibility between EnM and various excipients was studied using differential scanning calorimetry. ODTs of EnM were prepared by direct compression of EnM mixtures with various superdisintegrants. The tablets were evaluated for physical properties including drug content, hardness, friability, disintegration time, wetting time, and drug release. The antihypertensive effect of the optimum EnM ODTs was evaluated in vivo in hypertensive rats and compared with commercial EnM formulation. EnM ODTs had satisfactory results in terms of drug content and friability. Tablet wetting and disintegration were fast and dependent on the used superdisintegrant where croscarmellose showed the fastest wetting and disintegration time of ∼7 s. EnM release from the tablets was rapid where complete release was obtained in 10-15 min. Selected EnM ODTs rapidly and efficiently reduced the rat's blood pressure to its normal value within 1 h, compared with 4 h for EnM commercial formulation. These results confirm that EnM ODTs could find application in the management of hypertension in the elderly or other patients having dysphagia.

Taste Masking Approaches for Medicines.

Undesirable taste is an important problem for patient compliance. Several oral pharmaceuticals and bulking agents have disagreeable and bitter-tasting components. The Bitter taste characteristics found in such systems have been eliminated or minimized by the development of numerous formulations with improved performance and acceptability especially in children and elderly patient. This review is mainly concerned with the bitter-masking techniques published in peer-reviewed journals and will shed light on different methods of masking undesirable taste of the drugs, and their pharmaceutical applications. Hence, nearly no reference will be made to the techniques published as patent applications.

Enhanced skin deposition and delivery of voriconazole using ethosomal preparations.

Despite its broad-spectrum antifungal properties, voriconazole has many side effects when administered systemically. The aim of this work was to develop an ethosomal topical delivery system for voriconazole and test its potential to enhance the antifungal properties and skin delivery of the drug. Voriconazole was encapsulated into various ethosomal preparations and the effect of phospholipid and ethanol concentrations on the ethosomes properties were evaluated. The ethosomes were evaluated for drug encapsulation efficiency, particle size and morphology and antifungal efficacy. Drug permeability and deposition were tested in rat abdominal skin. Drug encapsulation efficiency of up to 46% was obtained and it increased with increasing the phospholipid concentration, whereas the opposite effect was observed for the ethanol concentration. The ethosomes had a size of 420-600 nm and negative zeta potential. The particle size of the ethosomes increased by increasing their ethanol content. The ethosomes achieved similar inhibition zones against Aspergillus flavus at a 2-fold lower drug concentration compared with drug solution in dimethyl sulfoxide. The ex vivo drug permeability through rat abdominal skin was ∼6-fold higher for the ethosomes compared with the drug hydroalcoholic solution. Similarly, the amount of drug deposited in the skin was higher for the ethosomes and was dependent on the ethanol concentration of the ethosomes. These results confirm that voriconazole ethosomal preparations are promising topical delivery systems that can enhance the drug antifungal efficacy and improve its skin delivery.

Incidence and determinants of severity of unintentional injuries among students of private schools in Dubai: a cross-sectional study.

A cross-sectional study was performed on a student population in grades 7-12 in 10 private schools in Dubai in the academic year 2012/13. The study was in two phases. The first was used to estimate incidence rate of injuries, where the total injuries that took place in the schools in 2012 was divided by the total student population in the studied schools in the same year multiplied by 1000. The second was to study the determinants of severity through randomly selecting 1000 cases of injuries. A self-administered questionnaire was given to the participants after obtaining verbal consent. Sociodemographic characteristics showed that most (74.2%) of the students in this study were male and about half (57.3%) were aged 12-14 years. The incidence rate of injuries was 297.7/1000, and most of the injuries (88.9%) were mild. Poor school safety was blamed for most of the injuries, and falls were the most frequent type of injury.

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.

Ethics in times of conflict: some reflections on Syria, in the backdrop of Iraq.

Ethical challenges facing research and reporting from conflict-affected zones are well known; among them is the difficulty of finding reliable information; the tendency to take sides and define actors as either good or evil; the precarious security situation of residents and the ever-changing scenarios on the ground. We observed, however, that these challenges go unacknowledged in research and reporting on health state and on the health system from the conflict in Iraq and Syria, with the lines between science and journalistic reporting routinely blurred in the literature. What should be the restraining factor of academic research against prejudiced reporting on injury, death and the healthcare system has mostly failed in the Syrian conflict. Even social media, with its promise of 'independent' and 'citizens' voice', can be skewed, with much of the output in the Syria crisis coming from one side only, largely due to access issues. While researchers in conflict-affected zones, such as Syria, may need to take a position on one side or another when reporting, death, destruction and disease, it is important that they admit to the challenges of accessing unbiased data, the near impossibility of obtaining representative samples and the risk of the contamination of evidence, clinical or otherwise. The example of the Syrian and Iraqi conflicts (as context) indicates a need to reassess research ethics in conflict zones and their implications for policy.

Public health challenges in the political economy of conflict: the case of Syria.

Recent uprisings in the Arab world and a full-scale war in Syria are widely viewed as popular demand for political voice against repressive regimes. However, growing economic inequalities and serious economic dysfunction played a role as trigger for conflict than is commonly accepted. Tunisia, Egypt and Syria all implemented policies of liberalization over the past two decades, leading to the worsening of living standards for the majority. The various forms of liberalization played a significant role in embedding social division and discontent whose outcomes affected other countries of the region with the onset of market reforms in nascent welfare states. Egypt, for example, was viewed by the World Bank as an economic 'best performer', despite regular riots over food prices, job losses and land expropriation for tourism. Tunisia was praised by donors just prior to the uprising (in 2010), for 'weathering well' the global economic downturn through 'sound macroeconomic management'. In Syria, the market economy made its mark over the 90s, but macroeconomic adjustment policies were implemented in a bilateral agreement with the European Union and approved by the International Monetary Fund in 2003. The economic stabilization programme that followed had limited concern for social impacts such as jobs losses, price rises and national debt, which ultimately caused immense hardship for the population at large, acting as a trigger for the initial uprising in 2011, prior to its transformation into a fully blown conflict. This article focuses on reforms implemented in the health sector and sets these in the context of the current political economy of Syria. It suggests that a protective approach to public health services during and in the aftermath of conflict may increase the possibilities of reconstruction and reconciliation between warring sides.

Lipidic dispersion to reduce food dependent oral bioavailability of fenofibrate: In vitro, in vivo and in silico assessments.

Novel formulations that overcome the solubility limitations of poorly water soluble drugs (PWSD) are becoming ever more critical to a drug development process inundated with these compounds. There is a clear need for developing bio-enabling formulation approaches to improve oral bioavailability for PWSD, but also to establish a range of predictive in vitro and in silico biopharmaceutics based tools for guiding formulation design and forecasting in vivo effects. The dual aim of this study was to examine the potential for a novel lipid based formulation, termed a lipidic dispersion, to enhance fasted state oral bioavailability of fenofibrate, while also assessing the predictive ability of biorelevant in vitro and in silico testing. Formulation as a lipidic dispersion improved both dissolution and solubilisation of fenofibrate through a combination of altered solid state characteristics and incorporation of solubilising lipidic excipients. These changes resulted in an increased rate of absorption and increased maximal plasma concentrations compared to a commercial, micronised product (Lipantil® Micro) in a pig model. Combination of biorelevant in vitro measurements with in silico physiologically based pharmacokinetic (PBPK) modelling resulted in an accurate prediction of formulation performance and forecasts a reduction in food effects on fenofibrate bioavailability through maximising its fasted state dissolution.

Comparison of in vitro tests at various levels of complexity for the prediction of in vivo performance of lipid-based formulations: case studies with fenofibrate.

The objectives of this study were to characterise three prototype fenofibrate lipid-based formulations using a range of in vitro tests with differing levels of complexity and to assess the extent to which these methods provide additional insight into in vivo findings. Three self-emulsifying drug delivery systems (SEDDS) were prepared: a long chain (LC) Type IIIA SEDDS, a medium chain (MC) Type IIIA SEDDS, and a Type IIIB/IV SEDDS containing surfactants only (SO). Dilution, dispersion and digestion tests were performed to assess solubilisation and precipitation behaviour in vitro. Focussed beam reflectance measurements and solid state characterisation of the precipitate was conducted. Oral bioavailability was evaluated in landrace pigs. Dilution and dispersion testing revealed that all three formulations were similar in terms of maintaining fenofibrate in a solubilised state on dispersion in biorelevant media. During in vitro digestion, the Type IIIA formulations displayed limited drug precipitation (<5%), whereas the Type IIIB/IV formulation displayed extensive drug precipitation (~70% dose). Solid state analysis confirmed that precipitated fenofibrate was crystalline. The oral bioavailability was similar for the three lipid formulations (65-72%). In summary, the use of LC versus MC triglycerides in Type IIIA SEDDS had no impact on the bioavailability of fenofibrate. The extensive precipitation observed with the Type IIIB/IV formulation during in vitro digestion did not adversely impact fenofibrate bioavailability in vivo, relative to the Type IIIA formulations. These results were predicted suitably using in vitro dilution and dispersion testing, whereas the in vitro digestion method failed to predict the outcome of the in vivo study.

A novel lipid-based solid dispersion for enhancing oral bioavailability of Lycopene--in vivo evaluation using a pig model.

Lycopene is a potent anti-oxidant, which has been widely reported for its potential benefits at reducing the risks of certain types of cancer e.g. prostate cancer. The oral bioavailability of this highly lipophilic carotenoid is low and highly influenced by the extent of intestinal lymphatic uptake. The aim of this study was to develop an optimised formulation, which allows for efficient absorption following oral administration. A self-emulsifying drug delivery system (SEDDS) and solid dispersion of Lycopene were developed initially. Subsequently, a novel lipid based solid dispersion (LBSD) was designed. Processing via a solid dispersion approach was found to alter the solid state characteristics of Lycopene, as determined by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The bioavailability of Lycopene was significantly increased after oral administration of LBSD to fasted pigs, relative to the commercial product (Lycovit(®)). A clear distinction in terms of Cmax and AUC was observed between Lycovit(®) and LBSD. In conclusion, a novel LBSD formulation was developed to enhance the oral bioavailability of the model lipophilic compound, Lycopene, by enhancing dissolution in the gastrointestinal tract and promoting intestinal lymphatic uptake utilising digestible lipid excipients.

Reforms and emerging noncommunicable disease: some challenges facing a conflict-ridden country--the case of the Syrian Arab Republic.

The past year witnessed considerable turbulence in the Arab world-in this case, Syria, a lower middle-income country with a record of a strong public health infrastructure. This paper explores the current challenges facing its health system from reforms, civil strife and international sanctions all of which we argue have serious implications for population health. The health sector in Syria was little known, and until recently, it was well integrated to provide preventive and specialized care when needed. Regionally, it was one of the few countries ready and capable of addressing the challenges of demographic and epidemiologic transition with a long-standing emphasis on primary care and prevention, unlike most countries of the region. This context has changed dramatically through the recent implementation of reforms and the current civil war. Changes to financing, management and the delivery of health service placed access to services in jeopardy, but now, these are compounded by the destruction from an intractable and violent conflict and international sanctions. This paper explores some of the combined effects of reforms, conflict and sanctions on population health.