Rapid Assessment of Homogeneity and Stability of Amorphous Solid Dispersions by Atomic Force Microscopy—From Bench to Batch

Purpose

To verify the robustness and fundamental value of Atomic Force Microscopy (AFM) and AFM-based assays to rapidly examine the molecular homogeneity and physical stability of amorphous solid dispersions on Hot-Melt-Extrudates.

Methods

Amorphous solid dispersions were prepared with a Hot-Melt Extruder (HME) and profiled by Raman Microscopy and AFM following a sequential analytical routine (Multi-Scale-Imaging-of-Miscibiliy (MIMix)). Extrudates were analyzed before and after incubation at elevated temperature and humidity. The data were compared with published results as collected on miniaturized melt models. The value of molecular phase separation rates for long term stability prediction was assessed.

Results

Data recorded on the extrudates are consistent with those published, and they can be compared side by side. Such direct data comparisons allow the identification of possible sources of extrudate heterogeneities. The surface roughness analysis of fracture-exposed interfaces is a novel quantitative way to trace on the nanometer scale the efficiencies of differently conducted HME-processes. Molecular phase separation rates are shown to be relevant for long term stability predictions.

Conclusions

The AFM-based assessment of API:excipient combinations is a robust method to rapidly identify miscible and stable solid dispersions in a routine manner. It provides a novel analytical tool for the optimization of HME processes.     

Particle uptake by Peyer’s patches: a pathway for drug and vaccine delivery

Particle uptake by Peyer’s patches offers the possibility of tailoring vaccines that can be delivered orally. However, particle uptake by the follicle-associated epithelium in the gastrointestinal tract depends on several different factors that are the physicochemical properties of the particles, the physiopathological state of the animal, the analytical method used to evaluate the uptake and finally the experimental model. These parameters do not allow a clear idea about the optimal conditions to target the Peyer’s patches. The goal of this review is to clarify the role of each factor in this uptake.     

Characterization of formaldehyde’s genotoxic mode of action by gene expression analysis in TK6 cells

Gene expression analysis has been established as a tool for the characterization of genotoxic mechanisms of chemical mutagens. It has been suggested that expression analysis is capable of distinguishing compounds that cause DNA damage from those that interfere with mitotic spindle function. Formaldehyde (FA) is known to be a DNA-reactive substance which mainly induces chromosomal damage in cultured mammalian cells. However, there has been concern that FA might also induce leukemia-specific aneuploidies, although recent cytogenetic studies excluded a relevant aneugenic potential of FA. We now investigated whether gene expression profiling can be used as a molecular tool to further characterize FA’s genotoxic mode of action and to differentiate between clastogenic and aneugenic activity. TK6 cells were exposed to FA for 4 and 24 h, and changes in gene expression were analyzed using a whole-genome human microarray. Results were compared to the expression profiles of two DNA-damaging clastogens (methyl methanesulfonate and ethyl methanesulfonate) and two aneugens (colcemid and vincristine). The genotoxic activity of FA, MMS and EMS under these conditions was confirmed by comet assay experiments. The gene expression profiles indicated that clastogens and aneugens induce discriminable gene expression patterns. Exposure of TK6 cells to FA led to a discrete gene expression pattern, and all toxicogenomics analyses revealed a closer relationship of FA with clastogens than with aneugens.     

On the Links Between Elastic Constants and Effective Elastic Behavior of Pharmaceutical Compacts: Importance of Poisson’s Ratio and Use of Bulk Modulus

The elastic properties of pharmaceutical powders and compacts are of great interest to understand the complex phenomena that occur during and after the tableting process. The elastic recovery after compression is known to be linked with adverse phenomena such as capping or delamination of tablets. Classically, the elastic behavior is modeled using linear elasticity and is characterized using only Young's modulus (E), often by using a value extrapolated at zero porosity. In this work, four pharmaceutical products were studied. The elastic behavior of compacts obtained using a large range of applied pressure was characterized. First, it was found more suitable to use apparent elastic moduli than extrapolations at zero porosity. Then, the results indicate that there was not always a good correlation between the values of Young's modulus and the actual elastic recovery of the compacts. Poisson’s ratio (v), which differs from one product to another and is porosity-dependent, must be taken into account. Finally, the bulk modulus (K), which combines E and v, was shown to be well correlated with the elastic recovery of the compacts and can be considered as a relevant parameter to characterize the elastic behavior of pharmaceutical compacts.     

Geographical variation of Indian Russell’s viper venom and neutralization of its coagulopathy by polyvalent antivenom

Abstract

Indian Russell’s viper venoms of four different geographical locations were found to vary in composition, coagulopathy and phospholipase A₂ (PLA₂) activity. Venom from Kerala showed highest procoagulant activity followed by Tamil Nadu, West Bengal and Karnataka whereas PLA₂ activity was highest in venom from West Bengal. The commercial polyvalent antivenom differentially neutralized the aforesaid activities of the crude venoms. Antivenomics study showed the presence of non-immunodepleted and partially immunodepleted proteins in the crude venoms. Thus, Indian Russell’s viper venom from different region varies in composition and accentuates the need to design regiospecific antivenoms to confront the problem of envenomation more effectively.     

Fluoroquinolone-associated tendon-rupture: a summary of reports in the Food and Drug Administration’s adverse event reporting system

Objective: To review and summarize reports of tendon rupture associated with each fluoroquinolone (FQ) currently marketed in the United States (US), as reported to the FDA’s Adverse Event Reporting System (FAERS).

Methods: FAERS data were reviewed for reports of tendon rupture associated with each FQ from their respective approval date through September 2012. Disproportional reporting signal detection was estimated using empirical Bayes geometric mean (EBGM) with 95% confidence intervals (CI).

Results: There were 2495 FAERs reports of tendon rupture associated with currently approved FQs. Most FAERS reports were associated with levofloxacin (n = 1555) followed by ciprofloxacin (n = 606) and moxifloxacin (n = 230). Signal detection results for FQs were as follows: levofloxacin (EBGM = 55.2, 95% CI = 52.3 – 58.0), ciprofloxacin (EBGM = 20.0, 95% CI = 18.2 – 21.6), moxifloxacin (EBGM = 13.3, 95% CI = 11.7 – 15.1), norfloxacin (EBGM = 9.6, 95% CI = 6.5 – 13.5), ofloxacin (EBGM = 8.2, 95%CI = 6.3 – 10.2) and gemifloxacin (EBGM = 1.9, 95% CI = 0.7 – 4.5). The mean age of affected individuals was 59.6 ± 5.1 years. Corticosteroids were administered concomitantly with FQs in 21.2% of cases.

Conclusion: As noted in boxed warnings, FQ use is associated with increased tendon rupture risk. Risk factors for FQ associated tendon rupture include use in the elderly, and in patients with concomitant corticosteroids. Further monitoring may be needed due to antibiotic overuse and marketing of newer FQs.     

PKC-Mediated Potentiation of Morphine Analgesia by St. John’s Wort in Rodents and Humans

Our purpose was to combine the use of morphine with clinically available inhibitors of protein kinase C (PKC), finally potentiating morphine analgesia in humans. Thermal tests were performed in rodents and humans previously administered with acute or chronic morphine combined or not with increasing doses of the PKC-blocker St. John’s Wort (SJW) or its main component hypericin. Phosphorylation of the γ subunit of PKC enzyme was assayed by western blotting in the periaqueductal grey matter (PAG) from rodents co-administered with morphine and hypericin and was prevented in rodent PAG by SJW or hypericin co-administration with morphine, inducing a potentiation of morphine analgesia in thermal pain. The score of pain assessment in healthy volunteers were decreased by 40% when morphine was co-administered with SJW at a dose largely below those used to obtain an antidepressant or analgesic effect in both rodents and humans. The SJW/hypericin potentiating effect lasted in time and preserved morphine analgesia in tolerant mice. Our findings indicate that, in clinical practice, SJW could reduce the dose of morphine obtaining the same analgesic effect. Therefore, SJW and one of its main components, hypericin, appear ideal to potentiate morphine-induced analgesia.     

Drug policing assemblages: Repressive drug policies and the zonal banning of drug users in Denmark’s club land

BackgroundZonal banning of disorderly and intoxicated young people has moved to centre stage in debates about nightlife governance. Whereas existing research has primarily focused on the use of zonal banning orders to address problems of alcohol-related harm and disorder, this article highlights how zonal banning is also used to target drug-using clubbers in Denmark.MethodsBased on ethnographic observations and interviews with nightlife control agents in two Danish cities, the article aims to provide new insights into how the enforcement of national drug policies on drug-using clubbers, is shaped by plural nightlife policing complexes.ResultsThe paper demonstrates how the policing of drug-using clubbers is a growing priority for both police and private security agents. The article also demonstrates how the enforcement of zonal bans on drug-using clubbers involves complex collaborative relations between police, venue owners and private security agents.ConclusionThe paper argues that a third-party policing perspective combined with assemblage theory is useful for highlighting how the enforcement of national drug policies and nightlife banning systems is shaped by their embeddedness in local ‘drug policing assemblages’ characterized by inter-agency relation-building, the creative combination of public and private (legal) resources and internal power struggles. It also provides evidence of how drug policing assemblages give rise to many different, and often surprising, forms of jurisdiction involving divergent performances of spaces-, objects- and authorities of governance.     

The use of national reimbursement reports to support formulary decisions of the hospital’s Drug and Therapeutics Committee: a comparative analysis

International Journal of Clinical Pharmacy - Background New therapies that do not reach patients in need, have not achieved their goal. Drug and Therapeutics Committees in hospitals ensure access...     

Knowledge and pharmacological management of Alzheimer’s disease by managing community pharmacists: a nationwide study

Background Managing community pharmacists can play a leading role in supporting community dwelling individuals with Alzheimer’s disease and their caregivers. Objective The main purpose of this study was to assess knowledge of managing community pharmacists towards Alzheimer’s disease and its pharmacological management. Setting Community pharmacies in the Maltese islands. Method A nationwide survey was conducted with full-time managing community pharmacists in possession of a tertiary education degree in pharmacy studies. The level of knowledge was investigated using the Alzheimer’s Disease Knowledge Scale and the Alzheimer’s Disease Pharmacotherapy Measure. Participants were also asked to rate a number of statements related to disease management. Results Maltese managing community pharmacists (57 % response rate) had inadequate knowledge on risk factors, caregiving issues and pharmacological management of Alzheimer’s disease. Age and number of years working in a community pharmacy setting were found to be negatively correlated with increased knowledge. Conclusion The findings highlight the need of providing training and continued educational support to managing community pharmacists in order to provide quality advice to individuals with dementia and their caregivers in the community.     

Young women’s narratives on sex in the context of heavy alcohol use: Friendships,gender norms and the sociality of consent

BackgroundAlthough young women’s friendships remain understudied in drinking contexts, some researchers have pointed to how young women can make use of each other to manage sexual advances when drinking. In this paper, we explore how young women make use of friends to negotiate their sexual boundaries, and construct the meaning of sexual experiences in a context of heavy alcohol use.MethodsThe data stems from a large scale research project at the Centre for Alcohol and Drug Research, Aarhus University, which included 140 interviews with young Danes between the ages of 18–25. In the present study, we primarily use narratives from 33 in-depth interviews with young women, who recall their personal sexual experiences with men in the context of heavy alcohol use.ResultsWe find that these young women make meaning of their sexual experiences in relation to friends through a negotiation of their emotional response as well as dominant gender norms. We argue that friends may serve to prevent sexual regret and offer support in instances where young women feel regret after engaging in sex when drinking heavily. However, we also argue that friends may encourage a more humorous approach in recounting sexual encounters in the context of heavy alcohol use, which may contradict their initial feelings of the encounter and gloss over issues of sexual consent.ConclusionWith this article we point to how young women's ability to negotiate the meaning of their sexual experiences as well as that of sexual consent more generally, are interlinked with prevalent gender norms that play out in the context of friendships. The young women in our study narrated friends as more central to negotiations of sexual boundaries than sexual partners when in a context of heavy alcohol use.On this basis, we develop the term ‘social consent’, which we suggest that future studies and preventive efforts should take into account in order to challenge the gender norms that can serve to normalize sexual violence in drinking contexts.     

Improvement of Memory in Mice and Increase of Hippocampal Excitability in Rats by Ginsenoside Rg1’s Metabolites Ginsenoside Rh1 and Protopanaxatriol

Ginsenoside Rg1 has been reported to improve cognitive function in many memory-impaired animal models. However, little is known about the bioactivity of its metabolites in the central nervous system in vivo. In the present study, we employed the step through test and electrophysiological approach to investigate the effects of ginsenoside Rg1’s primary metabolite ginsenoside Rh1 and end metabolite protopanaxatriol (Ppt) on learning and memory as well as hippocampal excitability. The behavioral study showed that both ginsenoside Rh1 and Ppt significantly ameliorated memory-impaired models induced by scopolamine in mice. Consistently, the electrophysiological work revealed that ginsenoside Rh1 and Ppt as well as their precursor ginsenoside Rg1 all increased hippocampal excitability in the dentate gyrus of anesthetized rats. These results demonstrated that both ginsenoside Rh1 and Ppt had similar but more potent actions than ginsenoside Rg1 in improving memory and hippocampal excitability, suggesting the role of ginsenoside’s sugar moieties in biological activities is not as necessary as traditionally considered.     

Drug safety testing,disposals and dealing in an English field: Exploring the operational and behavioural outcomes of the UK’s first onsite ‘drug checking’ service

BackgroundIn a year when UK drug-related deaths and festival drug-related deaths reached their highest on record, a pilot festival drug safety testing service was introduced with the aim of reducing drug-related harm. This paper describes the operational and behavioural outcomes of this pilot and explores the relationship between drug use, supply and policing within festival grounds.MethodsChemists in a temporary laboratory analysed 247 substances submitted by the public to a free, confidential testing service across four days at a UK festival in July 2016. Test results were returned to service users embedded in 230 healthcare consultations delivered to approximately 900 festival-goers (one in five drug using festival-goers) that included harm reduction advice and the opportunity to use a disposal service for further substances of concern. Consultation data were collected at point of care, matched with test results, coded and analysed using SPSSResultsTest results revealed that one in five substances was not as sold or acquired. One in five service users utilised the disposal service for further substances of concern in their possession and another one in six moderated their consumption. Two thirds of those whose sample was missold disposed of further substances, compared with under one in ten whose sample was as sold. Service users who acquired substances onsite at the festival were more than twice as likely to have been missold them as those acquired offsite, were nearly twice as likely to use the disposal service and were on average two years younger. Women were more likely to be using the drug for the first time and more likely to use the disposal service. Test results were shared with emergency services; alerts issued across site and an unanticipated feedback loop occurred to some drug suppliers.ConclusionThis pilot suggests that festival-goers engage productively with onsite drug safety testing services when given the opportunity, such services can access harder-to-reach and new user groups and can play a part in reducing drug-related harm by identifying and informing service users, emergency services and offsite drug using communities about substances of concern. Disposals to the testing service for onward police destruction provide an externally corroborated measure of impact, reducing harm to the individual and others by removing such substances from site. Evidence of differential dealing onsite and its potential negative consequences has implications for future research and policing.     

Public’s perception and satisfaction on the roles and services provided by pharmacists – Cross sectional survey in Sultanate of Oman

Background and objectives: An important factor that will help in advancement of the pharmacy services in any country would be to understand the public needs, expectation and satisfaction. There are limited published studies conducted in Sultanate of Oman regarding the perception and satisfaction of public on the role and services provided by pharmacists. The present study was conducted to assess the perception and satisfaction of general public in Sultanate of Oman on the roles, and services received from the pharmacists. Methods: The survey was conducted among public in the Governorates of A’Dahera and Muscat in Oman during 2013. The questionnaire had items to assess two aspects: perception on the roles and responsibilities of pharmacists and satisfaction on the services provided. The responses to the questions marked in a five point Likert scale were assessed using a scoring scheme. Accordingly, the median perception, and satisfaction score and median total score for the participants were estimated. The median scores of the participants were related with the demographics of the participants and frequency of visit to pharmacy. Results: A total of 390 completed questionnaires were obtained. The median total score of the participants based on all the questions was 79 (Inter Quartile Range (IQR), 12) which represents a moderate score. The median perception and satisfaction scores were 44 (IQR 5) and 34 (IQR 7) which represent a good and moderate score, respectively. Perception of the participants differed based on employment status, frequency of visit to pharmacy and governorate represented by participants while satisfaction was influenced by educational qualification and frequency of visit to pharmacy. Conclusions: Public had a good perception regarding the roles of the pharmacists while they were only moderately satisfied with the services provided. Steps have to be taken to improve the services and relationship of pharmacists, and thereby improve the satisfaction of the customers. An extended study in a broader population involving more governorates will provide an enhanced representation regarding this important aspect.     

Variability in PXR-mediated induction of CYP3A4 by commercial preparations and dry extracts of St. John’s wort

St. John’s wort (SJW, Hypericum perforatum) is a well-tolerated herbal medicine widely used for the treatment of mild and moderate depressions. In the last 5 years, SJW has been implicated in drug interactions, which are largely mediated by the induction of the drug metabolizing enzymes, especially CYP3A4. There is still some controversy regarding the exact mechanism of induction and the identity of the SJW constituents involved. We investigated in LS174T cells the induction of CYP3A4 by ten SJW extracts, six commercial preparations, and the purified SJW constituent hyperforin. The content of hyperforin among the commercial preparations of SJW varied 62-fold (range 0.49–30.57 mg/dose). The CYP3A4 induction was mediated by PXR, but not by CAR. The magnitude of the induction correlated statistically significantly with the content of hyperforin in commercial SJW preparations (R = 0.87, p = 0.004) and in dry extracts (R = 0.65, p = 0.03), but not with their content of flavonoids or hypericin. Most of the CYP3A4 induction response occurred in the hyperforin range encountered in the blood of patients treated with SJW preparations. A temperature-induced decrease in the hyperforin content of a selected dry SJW extract abolished the induction of CYP3A4. In conclusion, commercial SJW preparations still exhibit an enormous variability in CYP3A4 induction, which is mediated by hyperforin and PXR. SJW preparations with lower hyperforin content should reduce the frequency of clinical interactions involving this herbal drug. This work was partly funded by the Deutsche Forschungsgemeinschaft (DFG) grant WO505/2-2.     

Fabrication of Hierarchical Polymeric Thin Films by Spin Coating Toward Production of Amorphous Solid Dispersion for Buccal Drug Delivery System: Preparation,Characterization, and In Vitro Release Investigations

The landscape of thin films is continuously evolving as an attractive self-administration mean to drive patient compliance. This work reports incorporation of drugs into various polymeric compositions using spin coating technology to screen amorphous solid dispersion film formation for buccal applications. Polarized light microscopy and differential scanning calorimetry were used for characterization. Physical stability was assessed after films storage at 0% RH/25°C for 6 months. Chlorpheniramine maleate, theophylline, and famotidine were used as model drugs and mixed with Opadry amb II^® or Kollicoat IR^®. Acryl-EZE II^® or Zein was also used as surface (design I) or surface and base polymers (design II). Of all the drug-Opadry combinations, only chlorpheniramine was amorphously dispersed up to 25% (w/w). In contrast, Kollicoat IR^® resulted in amorphous dispersions of all the tested drugs, suggesting that it has a better solubilization capacity. Drugs prepared in design II achieved higher in vitro release compared to respective design I, indicating that lower content of Acryl-EZE II^® or Zein can decrease drug release over 3 h. It has been also revealed that Zein could improve physical stability of the aged theophylline solid-dispersed films. Release kinetics of model drugs were satisfactory when described by first-order kinetics, facilitated through anomalous transport of both diffusion and polymer swelling.     

It’s what’s inside that counts: egg contaminant concentrations are influenced by estimates of egg density,egg volume,and fresh egg mass

In egg contaminant studies, it is necessary to calculate egg contaminant concentrations on a fresh wet weight basis and this requires accurate estimates of egg density and egg volume. We show that the inclusion or exclusion of the eggshell can influence egg contaminant concentrations, and we provide estimates of egg density (both with and without the eggshell) and egg-shape coefficients (used to estimate egg volume from egg morphometrics) for American avocet (Recurvirostra americana), black-necked stilt (Himantopus mexicanus), and Forster’s tern (Sterna forsteri). Egg densities (g/cm³) estimated for whole eggs (1.056 ± 0.003) were higher than egg densities estimated for egg contents (1.024 ± 0.001), and were 1.059 ± 0.001 and 1.025 ± 0.001 for avocets, 1.056 ± 0.001 and 1.023 ± 0.001 for stilts, and 1.053 ± 0.002 and 1.025 ± 0.002 for terns. The egg-shape coefficients for egg volume (K _v ) and egg mass (K _w ) also differed depending on whether the eggshell was included (K _v  = 0.491 ± 0.001; K _w  = 0.518 ± 0.001) or excluded (K _v  = 0.493 ± 0.001; K _w  = 0.505 ± 0.001), and varied among species. Although egg contaminant concentrations are rarely meant to include the eggshell, we show that the typical inclusion of the eggshell in egg density and egg volume estimates results in egg contaminant concentrations being underestimated by 6–13 %. Our results demonstrate that the inclusion of the eggshell significantly influences estimates of egg density, egg volume, and fresh egg mass, which leads to egg contaminant concentrations that are biased low. We suggest that egg contaminant concentrations be calculated on a fresh wet weight basis using only internal egg-content densities, volumes, and masses appropriate for the species. For the three waterbirds in our study, these corrected coefficients are 1.024 ± 0.001 for egg density, 0.493 ± 0.001 for K _v , and 0.505 ± 0.001 for K _w .