Oral delivery of proteins and peptides: Challenges,status quo and future perspectives

Proteins and peptides (PPs) have gradually become more attractive therapeutic molecules than small molecular drugs due to their high selectivity and efficacy, but fewer side effects. Owing to the poor stability and limited permeability through gastrointestinal (GI) tract and epithelia, the therapeutic PPs are usually administered by parenteral route. Given the big demand for oral administration in clinical use, a variety of researches focused on developing new technologies to overcome GI barriers of PPs, such as enteric coating, enzyme inhibitors, permeation enhancers, nanoparticles, as well as intestinal microdevices. Some new technologies have been developed under clinical trials and even on the market. This review summarizes the history, the physiological barriers and the overcoming approaches, current clinical and preclinical technologies, and future prospects of oral delivery of PPs.     

“Vital in today's time”: Evaluation of a disaster table-top exercise for pharmacists and pharmacy staff

BackgroundWhile the importance of pharmacists’ involvement in disaster management is becoming increasingly recognised in the literature, there remains little research on methods for preparing pharmacists and pharmacy staff for disasters.Objective(s): To investigate the use of a table-top disaster exercise to improve disaster awareness and preparedness for pharmacists and pharmacy staff attending The Society of Hospital Pharmacists of Australia (SHPA) Medicine Management conference 2019.MethodsA table-top disaster exercise was developed by the research team and presented as a workshop at the SHPA's annual conference in 2019. The workshop presented attendees with the hypothetical ‘Cyclone Oma’ that was tracking across the fictional state of ‘New Cardiff’. Each workshop table was assigned a different hospital and was required to respond to Cyclone Oma as the scenario evolved. Workshop attendees were invited to complete a pre- and post-survey assessing their perceptions of disaster management and preparedness for pharmacists and pharmacy staff.ResultsThe pre- and post-workshop survey was completed by 41 out of the 47 attendees. Participants’ assessments of their understanding of disaster management activities increased after attending the workshop (p< 0.001). Most participants felt the workshop improved their understanding of their role in a disaster (87.8%, 36/41) and allowed them to identify their strengths and weaknesses in disaster management (90.2%, 37/41). The workshop was well received with 92.7% (38/41) of participants stating they would like further continuing professional development opportunities in disaster management.ConclusionsThis is the first disaster table-top exercise in Australia targeted specifically at the pharmacy workforce to be conducted and evaluated. The exercise improved understanding of disaster management and was well received by the participants. This research calls for further education and training opportunities in disaster management targeted at the pharmacy workforce.     

Physician-pharmacist collaboration on chronic non-cancer pain management during the opioid crisis: A qualitative interview study

BackgroundManagement of chronic non-cancer pain is complex, requiring clinicians to balance pain management with the risk of opioid abuse. The role of ambulatory care pharmacists in chronic pain management is well-established, but little research has explored the feasibility of building collaboration on chronic pain and opioid management between physicians and community pharmacists.ObjectiveTo explore physician and pharmacist perspectives on the opioid crisis and the possibility of physician and community pharmacist collaborations to manage chronic non-cancer pain in the context of the opioid crisis.MethodsSemi-structured interviews were performed with a snowball convenience sample 15 physicians and 25 pharmacists in North Carolina between November 2016 and April 2017. Transcribed data were analyzed using applied thematic analysis, and resulting codes were organized into themes and domains which emerged from analysis.ResultsBoth physicians and pharmacists described current care deficiencies and steps needed to mitigate opioid abuse and diversion. Physicians discussed the need for additional supports and resources for chronic pain management and regarded positively the role of the community pharmacist in chronic pain management and mitigating opioid abuse. Pharmacists identified cost as the major barrier to implementing new services, and expressed willingness to participate in new chronic pain and opioid interventions.ConclusionWithin the study sample, strong interest exists for collaboration between physicians and community pharmacists. This highlights a potential opportunity to expand care for patients with chronic non-cancer pain.     

A review of existing strategies for designing long-acting parenteral formulations: Focus on underlying mechanisms,and future perspectives

The need for long-term treatments of chronic diseases has motivated the widespread development of long-acting parenteral formulations (LAPFs) with the aim of improving drug pharmacokinetics and therapeutic efficacy. LAPFs have been proven to extend the half-life of therapeutics, as well as to improve patient adherence; consequently, this enhances the outcome of therapy positively. Over past decades, considerable progress has been made in designing effective LAPFs in both preclinical and clinical settings. Here we review the latest advances of LAPFs in preclinical and clinical stages, focusing on the strategies and underlying mechanisms for achieving long acting. Existing strategies are classified into manipulation of in vivo clearance and manipulation of drug release from delivery systems, respectively. And the current challenges and prospects of each strategy are discussed. In addition, we also briefly discuss the design principles of LAPFs and provide future perspectives of the rational design of more effective LAPFs for their further clinical translation.     

Community pharmacists and communication in the time of COVID-19: Applying the health belief model

The emergence of the novel coronavirus disease (COVID-19) pandemic presents an unprecedented health communications challenge. Healthcare providers should reinforce behaviors that limit the spread of the pandemic, including social distancing and remaining in the home whenever possible. Formal communications toolkits may not be prepared in a timely fashion. Community pharmacists can reinforce mitigation behaviors by applying the health belief model (HBM). This commentary provides an overview of the HBM and offers suggestions on how community pharmacists can use it as a guide to patient communication in these uncertain contexts.     

Drug shortages in hospitals: Actors’ perspectives

BackgroundDespite an increasing focus on drug shortages, no standardized global definition of a drug shortage seems to exist. This raises the question of whether healthcare actors are discussing the same phenomenon, which may influence their actions when managing, solving and preventing drug shortages. Further, the literature reports a lack of national contingency plans for managing drug shortages in hospitals.ObjectiveTo explore national-level communication, decision-making and collaboration on drug shortage management carried out in Denmark by secondary healthcare actors.MethodsSeven semi-structured interviews were conducted with actor representatives from Amgros, the procurement department of the hospital pharmacy in the Capital Region of Denmark, two medicine suppliers, two pharmaceutical wholesalers and distributors, and the Danish Medicines Agency. Data was analyzed using a social constructivist approach.ResultsNo common definition of a drug shortage exists among the actors, but referential definitions related to “contract” and delivered “as expected” were identified. Additionally, actors initiate drug shortage procedures differently, and, as efforts are minimally coordinated, the work procedures are often needlessly duplicated. Further, discrepancies in available drug shortage information arise, as information is distributed through different electronic systems, unavailable to all actors. Besides, Amgros (a national organization responsible for tendering and procuring medicines in hospitals) and the procurement department of the hospital pharmacy in the Capital Region of Denmark make joint decisions regarding the choice of alternative drugs. However, the study found that actors had diverse collaborative relationships, especially those with the Danish Medicines Agency, and that these were limited to contact regarding medicine regulations and unlicensed medicine.ConclusionThe study provided insight into national-level communication, decision-making and collaboration on drug shortage management by different actors in hospitals. This knowledge is useful in the development of a national contingency plan for drug shortage management.     

Pure drug nano-assemblies: A facile carrier-free nanoplatform for efficient cancer therapy

Nanoparticulate drug delivery systems (Nano-DDSs) have emerged as possible solution to the obstacles of anticancer drug delivery. However, the clinical outcomes and translation are restricted by several drawbacks, such as low drug loading, premature drug leakage and carrier-related toxicity. Recently, pure drug nano-assemblies (PDNAs), fabricated by the self-assembly or co-assembly of pure drug molecules, have attracted considerable attention. Their facile and reproducible preparation technique helps to remove the bottleneck of nanomedicines including quality control, scale-up production and clinical translation. Acting as both carriers and cargos, the carrier-free PDNAs have an ultra-high or even 100% drug loading. In addition, combination therapies based on PDNAs could possibly address the most intractable problems in cancer treatment, such as tumor metastasis and drug resistance. In the present review, the latest development of PDNAs for cancer treatment is overviewed. First, PDNAs are classified according to the composition of drug molecules, and the assembly mechanisms are discussed. Furthermore, the co-delivery of PDNAs for combination therapies is summarized, with special focus on the improvement of therapeutic outcomes. Finally, future prospects and challenges of PDNAs for efficient cancer therapy are spotlighted.     

Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives

Since accelerated metabolism produces much higher levels of reactive oxygen species (ROS) in cancer cells compared to ROS levels found in normal cells, human MutT homolog 1 (MTH1), which sanitizes oxidized nucleotide pools, was recently demonstrated to be crucial for the survival of cancer cells, but not required for the proliferation of normal cells. Therefore, dozens of MTH1 inhibitors have been developed with the aim of suppressing cancer growth by accumulating oxidative damage in cancer cells. While several inhibitors were indeed confirmed to be effective, some inhibitors failed to kill cancer cells, complicating MTH1 as a viable target for cancer eradication. In this review, we summarize the current status of developing MTH1 inhibitors as drug candidates, classify the MTH1 inhibitors based on their structures, and offer our perspectives toward the therapeutic potential against cancer through the targeting of MTH1.     

Is ward round participation by clinical pharmacists a valuable use of time and money? A time and motion study

BackgroundWhile the benefits of multidisciplinary ward round (WR) participation by clinical pharmacists have been demonstrated, it can be time-consuming. No previous studies have compared the specific benefits of WR participation and other clinical activities.ObjectivesTo assess the clinical impact of different clinical pharmacist activities and analyse patterns of practice based on WR involvement and timing and significance of clinical interventions.MethodsIn a prospective, observational time and motion study, clinical pharmacists servicing 6 unmatched specialty areas in a major quaternary public hospital were observed and their activities documented. Pharmacists' self-recorded interventions underwent expert panel assessment for significance and potential cost savings. Workflows and interventions were analysed for the 4 pharmacists involved in WRs (‘WR pharmacists’) during their time ‘on’ and ‘off’ rounds and for 2 pharmacists not involved in WRs (‘non-WR pharmacists’) using chi-square analyses.ResultsDuring 170 h of observation, 267 clinical interventions (53.9% minor, 40.1% moderate, 6.0% major) were recorded. WR pharmacists spent 24.3% of their time on rounds, and 64.8% of interventions were made during this time (intervention rates: 4.5/hour on WR vs. 0.8/hour off WR vs. 1.3/hour for non-WR pharmacists). Differences in WR and non-WR pharmacists’ workflows were observed, although there was no difference in time spent on clinical/patient-centred activities (p = 0.70). WR involvement was associated with significantly quicker interventions (p < 0.001). All major interventions were made by WR pharmacists; 80% were made on rounds. Major interventions were estimated to have decreased lengths of stay, intensive care requirements and procedure costs.ConclusionsClinical pharmacists focussed on patient-centred activities, regardless of WR involvement. Notwithstanding differences in the WR and non-WR specialty areas, WR participation was associated with more significant and timely interventions and potential cost savings. Coupled with the subjective benefits of WR participation observed, these findings support the potential value of clinical pharmacist WR participation.     

Gene therapy for neurodegenerative disorders: advances,insights and prospects

Gene therapy is rapidly emerging as a powerful therapeutic strategy for a wide range of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Some early clinical trials have failed to achieve satisfactory therapeutic effects. Efforts to enhance effectiveness are now concentrating on three major fields: identification of new vectors, novel therapeutic targets, and reliable of delivery routes for transgenes. These approaches are being assessed closely in preclinical and clinical trials, which may ultimately provide powerful treatments for patients. Here, we discuss advances and challenges of gene therapy for neurodegenerative disorders, highlighting promising technologies, targets, and future prospects.     

Evolution of blood–brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies

Blood–brain barrier (BBB) strictly controls matter exchange between blood and brain, and severely limits brain penetration of systemically administered drugs, resulting in ineffective drug therapy of brain diseases. However, during the onset and progression of brain diseases, BBB alterations evolve inevitably. In this review, we focus on nanoscale brain-targeting drug delivery strategies designed based on BBB evolutions and related applications in various brain diseases including Alzheimer's disease, Parkinson's disease, epilepsy, stroke, traumatic brain injury and brain tumor. The advances on optimization of small molecules for BBB crossing and non-systemic administration routes (e.g., intranasal treatment) for BBB bypassing are not included in this review.     

In vitro and in vivo correlation for lipid-based formulations: Current status and future perspectives

Lipid-based formulations (LBFs) have demonstrated a great potential in enhancing the oral absorption of poorly water-soluble drugs. However, construction of in vitro and in vivo correlations (IVIVCs) for LBFs is quite challenging, owing to a complex in vivo processing of these formulations. In this paper, we start with a brief introduction on the gastrointestinal digestion of lipid/LBFs and its relation to enhanced oral drug absorption; based on the concept of IVIVCs, the current status of in vitro models to establish IVIVCs for LBFs is reviewed, while future perspectives in this field are discussed. In vitro tests, which facilitate the understanding and prediction of the in vivo performance of solid dosage forms, frequently fail to mimic the in vivo processing of LBFs, leading to inconsistent results. In vitro digestion models, which more closely simulate gastrointestinal physiology, are a more promising option. Despite some successes in IVIVC modeling, the accuracy and consistency of these models are yet to be validated, particularly for human data. A reliable IVIVC model can not only reduce the risk, time, and cost of formulation development but can also contribute to the formulation design and optimization, thus promoting the clinical translation of LBFs.     

Receptor-mediated targeted drug delivery systems for treatment of inflammatory bowel disease: Opportunities and emerging strategies

Inflammatory bowel disease (IBD) is a chronic intestinal disease with painful clinical manifestations and high risks of cancerization. With no curative therapy for IBD at present, the development of effective therapeutics is highly advocated. Drug delivery systems have been extensively studied to transmit therapeutics to inflamed colon sites through the enhanced permeability and retention (EPR) effect caused by the inflammation. However, the drug still could not achieve effective concentration value that merely utilized on EPR effect and display better therapeutic efficacy in the inflamed region because of nontargeted drug release. Substantial researches have shown that some specific receptors and cell adhesion molecules highly expresses on the surface of colonic endothelial and/or immune cells when IBD occurs, ligand-modified drug delivery systems targeting such receptors and cell adhesion molecules can specifically deliver drug into inflamed sites and obtain great curative effects. This review introduces the overexpressed receptors and cell adhesion molecules in inflamed colon sites and retrospects the drug delivery systems functionalized by related ligands. Finally, challenges and future directions in this field are presented to advance the development of the receptor-mediated targeted drug delivery systems for the therapy of IBD.     

Coamorphous System of Florfenicol-Oxymatrine for Improving the Solubility and Dissolution Rate of Florfenicol: Preparation,Characterization and Molecular Dynamics Simulation

Coamorphous system has proved to be an effective approach to improve the solubility of BCSⅡ drugs. Florfenicol (FF) is a widely used veterinary antibiotic but has poor aqueous solubility. Therefore, the coamorphous system of florfenicol and oxymatrine (OMT) formulated at 1:1 and 1:2 M ratios were prepared by using solvent evaporation, followed by a series of characterization in terms of PXRD, DSC, FTIR and Raman spectroscopy. It was found that FF and OMT are miscible according to Hansen solubility parameters. The molecular electrostatic potential (MEP) and radial distribution function (RDF) analysis demonstrated the possible hydrogen bond interaction in coamorphous system, which was confirmed by FTIR and Raman spectra. The coamorphous FF-OMT (1:1) maintained stability for 60 days at 25 °C/0% RH and 30 days at 40 °C/75% RH, which may be attributed to better molecular miscibility of FF and OMT and the strong hydrogen bond of O–H (FF)?O–N (OMT) and N–H (FF)?O–N (OMT). In addition, the apparent solubility and permeability, dissolution and intrinsic dissolution rate (IDR) of the acquired coamorphous solids were obviously increased compared with crystalline FF. In conclusion, a drug-drug coamorphous formulation can be applied to improve the solubility and dissolution of crystalline FF.     

Effects of valproate,an HDAC inhibitor,on the expression of folate carriers and folate metabolism-related genes in the placenta of rats

Valproate (VPA), an antiepileptic drug, is known to inhibit histone deacetylases (HDACs). Exposure to VPA during pregnancy increases several fetal risks. The maintenance of folate level during pregnancy is essential for adequate fetal development, and the placenta plays a critical role in supplying nutrients to the fetus. The aim of this study was to elucidate the effects of VPA on the gene expression of folate carriers and metabolizing enzymes in the rat placenta at both mid and late gestation periods. Pregnant rats were orally administered VPA on a single day or 4 days (repeated administration). Gene expression of folate carriers (Folr1, Slc19a1, Slc46a1) and metabolizing enzymes (Cth, Mtr, Mtrr, Mthfr, Dhfr) was assessed in the placenta on gestational day (GD) 13 or GD20. In the control rats, the expression of Folr1, Slc46a1, Cth, and Mthfr tended to be upregulated, whereas that of Mtrr and Dhfr was downregulated during gestation; the expression of Slc19a1 and Mtr did not change. Repeated VPA administration reduced the placental expression of Folr1and Mtr on GD20 and increased the expression of Dhfr on GD13 compared with the control. These findings indicate that administration of VPA alters the placental gene expression of folate carriers and metabolism-related enzymes.     

Targeting regulated cell death (RCD) with small-molecule compounds in cancer therapy: A revisited review of apoptosis,autophagy-dependent cell death and necroptosis

Evasion of regulated cell death (RCD), mainly referring to apoptosis, autophagy-dependent cell death, necroptosis, and other subroutines, is one of the well-established hallmarks of cancer cells. Accumulating evidence has revealed several small-molecule compounds that target different subroutines of RCD in cancer therapy. In this review, we summarize key pathways of apoptosis, autophagy-dependent cell death and necroptosis in cancer, and describe small-molecule compounds that target these pathways and have potential as therapeutics. These inspiring findings light the way towards the discovery of more ‘magic bullets’ that could work individually or cooperatively to target precisely the three RCD subroutines and so improve cancer treatment.     

Innovation in Chemistry,Manufacturing, and Controls—A Regulatory Perspective From Industry

This review describes the landscape of novel modalities such as cell and gene therapies, viruses, other novel biologics, oligomers, and emerging technologies, including modern analytics. We summarize the regulatory history and recent landmark developments in some major markets and examine specific chemistry, manufacturing, and controls (CMC) challenges, including suggestions for exploration of potential science-based approaches in support of regulatory strategy development from an industry perspective. In addition, we evaluate the economic factors contributing to patient access to innovation and discuss the impact of regulation. There is a desperate need for a consistent form of regulation where global approaches to regulatory strategies can be harmonized, and specific CMC challenges can be dealt with using the appropriate science and risk-based tools. Although these tools are well described in current guidance documents, the specifics of applicability to complex novel modalities can still result in differing regulatory advice and outcomes. The future goals for efficiently regulating innovative modalities and technologies could be aided by more regulatory harmonization, regulatory education, and industry cooperation through consortia, enabling industry to supply key information to regulators in a transparent yet well-defined manner, and utilizing mutually understood risk-benefit analyses to produce drugs with appropriate safety, efficacy, and quality characteristics.     

An update on oral drug delivery via intestinal lymphatic transport

Orally administered drug entities have to survive the harsh gastrointestinal environment, penetrate the enteric epithelia and circumvent hepatic metabolism before reaching the systemic circulation. Whereas the gastrointestinal stability can be well maintained by taking proper measures, hepatic metabolism presents as a formidable barrier to drugs suffering from first-pass metabolism. The pharmaceutical academia and industries are seeking alternative pathways for drug transport to circumvent problems associated with the portal pathway. Intestinal lymphatic transport is emerging as a promising pathway to this end. In this review, we intend to provide an updated overview on the rationale, strategies, factors and applications involved in intestinal lymphatic transport. There are mainly two pathways for peroral lymphatic transport—the chylomicron and the microfold cell pathways. The underlying mechanisms are being unraveled gradually and nowadays witness increasing research input and applications.     

A homogenous nanoporous pulmonary drug delivery system based on metal-organic frameworks with fine aerosolization performance and good compatibility

Pulmonary drug delivery has attracted increasing attention in biomedicine, and porous particles can effectively enhance the aerosolization performance and bioavailability of drugs. However, the existing methods for preparing porous particles using porogens have several drawbacks, such as the inhomogeneous and uncontrollable pores, drug leakage, and high risk of fragmentation. In this study, a series of cyclodextrin-based metal-organic framework (CD-MOF) particles containing homogenous nanopores were delicately engineered without porogens. Compared with commercial inhalation carrier, CD-MOF showed excellent aerosolization performance because of the homogenous nanoporous structure. The great biocompatibility of CD-MOF in pulmonary delivery was also confirmed by a series of experiments, including cytotoxicity assay, hemolysis ratio test, lung function evaluation, in vivo lung injury markers measurement, and histological analysis. The results of ex vivo fluorescence imaging showed the high deposition rate of CD-MOF in lungs. Therefore, all results demonstrated that CD-MOF was a promising carrier for pulmonary drug delivery. This study may throw light on the nanoporous particles for effective pulmonary administration.     

Clinical and economic impact of medication reconciliation by designated ward pharmacists in a hospitalist-managed acute medical unit

BackgroundMinimizing unintended medication errors after admission is a common goal for clinical pharmacists and hospitalists.ObjectiveWe assessed the clinical and economic impact of a medication reconciliation service in a model of designated ward pharmacists working in a hospitalist-managed acute medical unit as part of a multidisciplinary team.MethodsIn this retrospective observational study, we compared pharmacist intervention records before and after the implementation of a medication reconciliation service by designated pharmacists. The frequency and type of intervention were assessed and their clinical impact was estimated according to the length of hospital stay and 30-day readmission rate. A cost analysis was performed using the average hourly salary of a pharmacist, cost of interventions (time spent on interventions), and cost avoidance (avoided costs generated by interventions).ResultsAfter the implementation of the medication reconciliation service, the frequency of pharmacist interventions increased from 3.9% to 22.1% (p < 0.001). Intervention types were also more diverse than those before the implementation. The most common interventions included identifying medication discrepancies between pre-admission and hospitalization (22.7%) and potentially inappropriate medication use in the elderly (13.1%). The median length of hospital stay decreased from 9.6 to 8.9 days (p = 0.024); the 30-day readmission rate declined significantly from 7.8% to 4.8% (p = 0.046). Over two-thirds of interventions accepted by hospitalists were considered clinically significant or greater in severity. The cost difference between avoided cost and cost of interventions was 9838.58 USD in total or 1967.72 USD per month.ConclusionsThe implementation of a designated pharmacist-led medication reconciliation service had a positive clinical and economic impact in our hospitalist unit.