Can preclinical drug development help to predict adverse events in clinical trials?

The development of novel therapeutics is associated with high rates of attrition, with unexpected adverse events being a major cause of failure. Serious adverse events have led to organ failure, cancer development and deaths that were not expected outcomes in clinical trials. These life-threatening events were not identified during therapeutic development due to the lack of preclinical safety tests that faithfully represented human physiology. We highlight the successful application of several novel technologies, including high-throughput screening, organs-on-chips, microbiome-containing drug-testing platforms and humanised mouse models, for mechanistic studies and prediction of toxicity. We propose the incorporation of similar preclinical tests into future drug development to reduce the likelihood of hazardous therapeutics entering later-stage clinical trials.

Wireless sensor networks for pharmaceutical lyophilization: Quantification of local gas pressure and temperature in primary drying.

Wireless sensor networks have become prolific in a wide range of industrial processes and offer several key advantages over their wired counterparts in terms of positioning flexibility, modularity, interconnectivity, and data routing. We demonstrate their utility in pharmaceutical lyophilization by developing a series of wireless devices to measure spatial variations in gas pressure and temperature during primary drying. The influence of shelf temperature, chamber pressure, excipient concentration, and dryer configuration are explored for various representative cycles using a laboratory-scale pharmaceutical lyophilizer. Pressure and temperature variations across the shelf for these cases are shown to vary up to 1.2 Pa and 10 °C, respectively. Experimental measurements are supported by computational fluid dynamics simulations to reveal the mechanisms driving the vapor flow. The measurements and simulation data are then combined to estimate the shelf-wise sublimation rate in the inverse sense to within a deviation of 3% based on comparison with gravimetric data. We then apply the sublimation rate profile to obtain the vial heat transfer coefficient and product mass transfer resistance for a 5% w/v mannitol formulation. Finally, these parameters are applied to a one-dimensional quasi-steady heat transfer model to predict the evolution of the product temperature over the course of primary drying. Thermocouple measurements of product temperature are compared directly to the simulated data and demonstrate accuracy comparable to existing published one-dimensional models.

Patient-Derived Organoids as a Model for Cancer Drug Discovery.

In the search for the ideal model of tumours, the use of three-dimensional in vitro models is advancing rapidly. These are intended to mimic the in vivo properties of the tumours which affect cancer development, progression and drug sensitivity, and take into account cell-cell interactions, adhesion and invasiveness. Importantly, it is hoped that successful recapitulation of the structure and function of the tissue will predict patient response, permitting the development of personalized therapy in a timely manner applicable to the clinic. Furthermore, the use of co-culture systems will allow the role of the tumour microenvironment and tissue-tissue interactions to be taken into account and should lead to more accurate predictions of tumour development and responses to drugs. In this review, the relative merits and limitations of patient-derived organoids will be discussed compared to other in vitro and ex vivo cancer models. We will focus on their use as models for drug testing and personalized therapy and how these may be improved. Developments in technology will also be considered, including the use of microfluidics, 3D bioprinting, cryopreservation and circulating tumour cell-derived organoids. These have the potential to enhance the consistency, accessibility and availability of these models.

Pharmaceutical Technology Innovation Strategy Based on the Function of Blood Transport Proteins as DDS Carriers for the Treatment of Intractable Disorders and Cancer.

Blood transport proteins are biogenic molecules with unique and interesting inherent characteristics that make up living organisms. As the utilization of their inherent characteristics can be a groundbreaking strategy to resolve and improve several clinical problems, attempts have been made to develop pharmaceutical and biomedical preparations based on blood transport proteins for the treatment and diagnosis of disorders. Among various blood transport proteins, we focus on the immense potential of hemoglobin and albumin to serve as carriers of biomedical gases (oxygen and carbon monoxide) and anticancer agents (low-molecular compounds and antisense oligodeoxynucleotides), respectively, for the development of innovative drug delivery systems (DDS) to treat intractable disorders and solid cancers. In this review, I introduce the pharmaceutical technology, strategies, and application of DDS carriers that have been designed on the basis of the structure and function of hemoglobin and albumin. In addition, the prospect of using hemoglobin and albumin as materials for DDS carriers is discussed.

Automated compounding technology and workflow solutions for the preparation of chemotherapy: a systematic review.

OBJECTIVES: The current systematic review (SR) was undertaken to summarise the published literature reporting the clinical and economic value of automation for chemotherapy preparation management to include compounding workflow software and robotic compounding systems. METHODS: Literature searches were conducted in MEDLINE, Embase and the Cochrane Library on 16 November 2017 to identify publications investigating chemotherapy compounding workflow software solutions used in a hospital pharmacy for the preparation of chemotherapy. RESULTS: 5175 publications were screened by title and abstract and 18 of 72 full publications screened were included. Grey literature searching identified an additional seven publications. The SR identified 25 publications relating to commercial technologies for compounding (Robotic compounding systems: APOTECAchemo (n=12), CytoCare (n=5) and RIVA (n=1); Workflow software: Cato (n=6) and Diana (n=1)). The studies demonstrate that compounding technologies improved accuracy in dose preparations and reduced dose errors compared with manual compounding. Comparable levels of contamination were reported for technologies compared with manual compounding. The compounding technologies were associated with reductions in annual costs compared with manual compounding, but the impact on compounding times was not consistent and was dependent on the type of compounding technology. CONCLUSIONS: The published evidence suggests that the implementation of chemotherapy compounding automation solutions may reduce compounding errors and reduce costs; however, this is highly variable depending on the form of automation. In addition, the available evidence is heterogeneous, sparse and inconsistently reported. A key finding from the current SR is a 'call to action' to encourage pharmacists to publish data following implementation of chemotherapy compounding technologies in their hospital, which would allow for evidence-based recommendations on the benefits of chemotherapy compounding technologies.

Systematic analysis of molecular mechanism of resveratrol for treating pulmonary hypertension based on network pharmacology technology.

Resveratrol is a polyphenolic antioxidant derived from plant products such as grapes. Previous studies explored the effects of resveratrol on pulmonary hypertension (PH). However, systematic research on the exact mechanism of action of resveratrol is still lacking; in particular, our knowledge on the molecule-gene interaction is limited. In this study, systematic pharmacology and bioinformatic approaches were employed to identify the potential targets of resveratrol for treating PH. Furthermore, core genes were identified by constructing a protein-protein interaction network and by conducting topology analyses. The results showed that the effect of resveratrol may be closely associated with targets such as AKT serine/threonine kinase 1 (AKT1), mitogen-activated protein kinase 3 (MAPK3), Sirtuin-1 (SIRT1) and proto-oncogene tyrosine-protein kinase Src (SRC), as well as biological processes such as cell proliferation, inflammatory response, and redox balance. The present study systematically elucidates the mechanisms by which resveratrol alleviates PH and provides a new perspective on drug research for this disease.

Harnessing the therapeutic potential of anticancer drugs through amorphous solid dispersions.

The treatment of cancer is still a major challenge. But tremendous progress in anticancer drug discovery and development has occurred in the last few decades. However, this progress has resulted in few effective oncology products due to challenges associated with anticancer drug delivery. Oral administration is the most preferred route for anticancer drug delivery, but the majority of anticancer drugs currently in product pipelines and the majority of those that have been commercially approved have inherently poor water solubility, and this cannot be mitigated without compromising their potency and stability. The poor water solubility of anticancer drugs, in conjunction with other factors, leads to suboptimal pharmacokinetic performance. Thus, these drugs have limited efficacy and safety when administered orally. The amorphous solid dispersion (ASD) is a promising formulation technology that primarily enhances the aqueous solubility of poorly water-soluble drugs. In this review, we discuss the challenges associated with the oral administration of anticancer drugs and the use of ASD technology in alleviating these challenges. We emphasize the ability of ASDs to improve not only the pharmacokinetics of poorly water-soluble anticancer drugs, but also their efficacy and safety. The goal of this paper is to rationalize the application of ASD technology in the formulation of anticancer drugs, thereby creating superior oncology products that lead to improved therapeutic outcomes.

Present status of Catharanthus roseus monoterpenoid indole alkaloids engineering in homo- and hetero-logous systems.

Catharanthus roseus synthesizes one of the most structurally, chemically and biologically active phytomolecules monoterpenoids indole alkaloids (MIAs) with having a wide range of pharmaceutical activities. Being the sole source of antineoplastic MIAs vinblastine and vincristine C. roseus has become one of the most valued plant. The low in planta availability of these MIAs and unavailability of alternative chemical synthesis system has enhanced their demand and equally let to the exorbitant market cost. To bridge this gap alternative production systems have been investigated using MIAs metabolic engineering (ME) in the homologous and heterologous systems. The availability of improved recombinant technologies along with genomics and metabolomics tools has opened the door of tremendous new potentials of ME. To encash these potentials of ME for MIAs pathway, efforts were made by expressing constitutive structure biosynthesis enzymes, transporters, and transcription factors of C. roseus MIAs biosynthesis in both homologous and heterologous systems. Here we review the knowledge of C. roseus MIAs pathway metabolic engineering in homologous and heterologous systems, gained in the past 35 years of C. roseus research.

Benchtop systems for in vivo molecular screening of labeled compounds, as a tool to speed up drug research.

BACKGROUND: For every new drug, >10,000 candidate molecules are tested for ~15 years. This is the daily mission of thousands research teams worldwide. It is well proven that small animal imaging speeds up this work, increases accuracy and decreases costs. However, commercial imaging systems have high purchase cost, require high service contracts, special facilities and trained staff. Thus, they are affordable to only few large research centres and not to the majority of small and medium research teams internationally. There are two main reasons that urge the addressing of this problem at large scale now: Firstly, small animal imaging started in 2000 and quickly research community and pharma industry understood its value, which opened preclinical imaging market (>2.5 Bil $). Continuous evolution in medicine and biology clearly shows the need to speed up research using new tools. Asian countries rapidly invest funds in drug research, enlarging existing market. Secondly, until recently such systems were based on complicated electronics and expensive components. Evolution in detector technology, electronics, software and 3D printing, made feasible the development of benchtop imaging systems, with attractive end user price. MATERIALS AND METHODS: Being an active partner of numerous international and national projects, we tried to identify the main requirements that an imaging system should have, in order to become a screening tool for daily use. Thus, we recently developed a new generation of affordable, but high-performance imaging systems, which can fulfil the daily needs of all research labs activated in preclinical research. Our technology covers the field of SPECT (Single Photon Emission Computed Tomography) and PET (Positron Emission Tomography) imaging, while an optical and x-ray imaging system is under development. The systems are based on well tested technology, including pixeliated scintillators, Position Sensitive Photomultipliers, programmable ADCs (Analog to Digital Converters) and FPGAs (Field Programmable Gate Arrays) and are connected with a standard laptop through USB and Ethernet connection. The systems are named "eyes-series" and have been already tested for fast screening of small animals injected with labeled compounds including peptides, antibodies and nanoparticles. Besides their performance, they are offered at a fraction of the cost of the commercial ones, comparable to standard lab equipment such as HPLC, gamma counter etc, opening new prospects in preclinical research. The first system is called "γ-eye™" and it is a dedicated system for imaging photons (γ-rays) which are emitted from radiolabelled biomolecules (2D-SPECT). The second system is called "ß-eye™" and detects positrons (ß-rays) from similar biomolecules (2D-PET). They both have dimensions which are 35x35x30cm and weight which is less that 30kgr. The spatial resolution of both systems is <2mm and their energy resolution <20%. Their sensitivity allows real time imaging for the first second post injection, while images are shown in real time during acquisition. They allow recording of fast frames, down to 1min, thus it is possible to perform fast kinetic studies. Finally, they are both provided along with a laptop that has preinstalled the required software, named "VISUAL-eyes". RESULTS: The technical specifications and performance evaluation of our technology will be presented. Different applications including oncology, regenerative medicine, nanomedicine and lung imaging will be given. Finally, the results of the comparison against high performance systems and a typical workflow for optimizing throughput will be demonstrated.

The role of plant expression platforms in biopharmaceutical development: possibilities for the future.

Introduction: Plant-made vaccines have been in the pipeline for nearly thirty years. Generated stably in transgenic plants or transiently using virus expression systems, pharmaceuticals have been developed to address global pandemics as well as several emerging One Health Diseases.Areas covered: This review describes the generation of plant-made vaccines to address some of the world's most growing health concerns, including both infectious and non-communicable diseases, such as cancer. The review provides an overview of the research taking place in this field over the past three to five years. The PubMed database was searched under the topic of plant-made vaccine between the periods of 2014 and 2019.Expert opinion: While vaccines and other biologics have been shown to be cheap safe and efficacious, they have not yet entered the marketplace largely due to regulatory constraints. The lack of an appropriate regulatory structure to guide plant-made vaccines through to commercial development has stalled efforts to provide life-saving medicines to low- and middle-income families. In my opinion, it is paramount that regulatory hurdles are mitigated to address emerging infectious diseases such as Ebola and Zika in a timely manner.

Recent Advances in Polymeric Implants.

Implantable drug delivery systems, such as drug pumps and polymeric drug depots, have emerged as means of providing predetermined drug release profiles at the desired site of action. While initial implants aimed at providing an enduring drug supply, developments in polymer chemistry and pharmaceutical technology and the growing need for refined drug delivery patterns have prompted the design of sophisticated drug delivery implants such as on-demand drug-eluting implants and personalized 3D printed implants. The types of cargo loaded into these implants range from small drug molecules to hormones and even therapeutic cells. This review will shed light upon recent advances in materials and composites used for polymeric implant fabrication, highlight select approaches employed in polymeric implant fabrication, feature medical applications where polymeric implants have a significant impact, and report recent advances made in these areas.

[Supramolecular Pharmaceutical Sciences: A Novel Concept for Future Pharmaceutical Sciences].

Supramolecular chemistry is a useful and important domain for understanding pharmaceutical sciences, since various physiological reactions (e.g., protein association) and drug activities (e.g., the substrate/receptor reaction) are based on supramolecular chemistry. Biological components, such as DNA and cells, are also supermolecules. However, supramolecular chemistry to date has not been a major domain in the field of pharmaceutical study. In this article, we propose a new concept in pharmaceutical sciences termed "supramolecular pharmaceutical sciences" which combines pharmaceutical sciences and supramolecular chemistry. "Supramolecular pharmaceutical sciences" could encompass strictly controlled molecular arrangement, stimulus responsible molecular motion, new functions beyond those of existing molecules, more accurate drug design, new active pharmaceutical ingredients, new perspectives for the investigation of the drug mechanisms, and novel pharmaceutical technologies. Moreover, pharmaceutical sciences are useful for supramolecular chemistry, because biological reactions are very accurate reactions, making this a win-win relationship. Thus, supramolecular pharmaceutical sciences could be useful for developing new methods, hypotheses, ideas, materials, mechanisms, and strategies in the realm of pharmaceutical science.

Lipid-polymer hybrid nanocarrier-mediated cancer therapeutics: current status and future directions.

The new generation of nanoparticles (NPs) encompass attributes of lipids and polymers and are referred to as 'lipid-polymer hybrid nanoparticles' (LPHNPs). LPHNPs have helped shed light on the mechanisms involved in targeted and non-specific drug delivery. Research has also highlighted the opportunities and challenges faced by the use of nanomedicine as personalized therapies in oncology. Here, we review the development of LPHNPs as cancer therapeutics, focusing on the methods deployed for enhancing the targeting efficiency and applications of LPHNPs.

Modern iron replacement therapy: clinical and pathophysiological insights.

Iron deficiency, with or without anemia, is extremely frequent worldwide, representing a major public health problem. Iron replacement therapy dates back to the seventeenth century, and has progressed relatively slowly until recently. Both oral and intravenous traditional iron formulations are known to be far from ideal, mainly because of tolerability and safety issues, respectively. At the beginning of this century, the discovery of hepcidin/ferroportin axis has represented a turning point in the knowledge of the pathophysiology of iron metabolism disorders, ushering a new era. In the meantime, advances in the pharmaceutical technologies are producing newer iron formulations aimed at minimizing the problems inherent with traditional approaches. The pharmacokinetic of oral and parenteral iron is substantially different, and diversities have become even clearer in light of the hepcidin master role in regulating systemic iron homeostasis. Here we review how iron therapy is changing because of such important advances in both pathophysiology and pharmacology.

Partnership for productive development of biosimilar products: perspectives of access to biological products in the Brazilian market / Parceria para o desenvolvimento produtivo com produtos biossimilares: perspectivas de acesso a produtos biológicos no mercado brasileiro

ABSTRACT The manufacturing process for biological products is complex, expensive and critical to the final product, with an impact on their efficacy and safety. They have been increasingly used to treat several diseases, and account for approximately 50% of the yearly budget for the Brazilian public health system. As the patents of biological products expire, several biosimilars are developed. However, there are concerns regarding their efficacy and safety; therefore, the regulatory agencies establish rules to approve and monitor these products. In Brazil, partnership programs between national government-owned companies and private technology holders have been implemented, aiming at knowledge sharing, capacity-building and technological transfer. Such partnerships locally promote manufacturing of these strategic drugs at reduced costs to the public health system. These agreements offer mutual advantages to both the government and patent holders: for the former, a biotechnological development flow is established and enables potential cost reduction and self-sufficient production; whereas for the latter, exclusive sales of the product are ensured during technological transfer, for a fixed period.

RESUMO O processo de manufatura de produtos biológicos é complexo, oneroso e crítico para o produto final, com impacto em sua eficácia e segurança. Seu uso está sendo cada vez mais ampliado no tratamento de diversas doenças, e cerca de 50% do orçamento anual do sistema de saúde público brasileiro é consumido por tais produtos. Com o término da proteção de patentes de produtos biológicos diversos, estão sendo desenvolvidos os biossimilares. Porém, há preocupações relacionadas com sua eficácia e segurança, fazendo com que os órgãos reguladores criem regulamentações para sua aprovação e monitoramento. No Brasil, estão sendo implantados programas de parceria entre laboratórios públicos nacionais e laboratórios detentores de tecnologia, objetivando a obtenção de conhecimento, capacitação profissional e transferência desta tecnologia. Tais parcerias visam à produção local destes medicamentos estratégicos a um custo reduzido para o Sistema Único de Saúde. Os acordos oferecem vantagens mútuas para o governo e o laboratório detentor da patente do produto biológico: ao primeiro, estabelece-se um fluxo de desenvolvimento biotecnológico, que possibilita potencial redução de custos e autossuficiência na produção, enquanto ao segundo garante-se a exclusividade da venda do produto durante a transferência da tecnologia por um prazo estabelecido.

Transcription factor decoy technology: A therapeutic update.

Targeting transcription factors represents one possibility to interfere with a known activated regulatory pathway that promotes disease. Double-stranded transcription factor decoy (TFD) oligodeoxynucleotides (ODN) are therapeutic drug candidates, which are able to specifically target and neutralize key transcription factors involved in the pathogenesis of a given disease. These short double-stranded TFD molecules mimic the consensus DNA binding site of a specific transcription factor in the promoter region of its target genes. Therefore, it is possible to exploit this nucleic acid-based drug class for the treatment of diseases caused by aberrant expression of such target genes the products of which are involved in disease initiation and progression. This research update focuses firstly on the mechanism of action of TFD molecules. Long-term effects of such ODNs depend on their stability and the efficiency by which they are delivered to the target tissue and taken up by their target cells. Hence structural modifications like e.g., single-stranded TFD molecules hybridising to itself to form an intramolecular hairpin molecule or circular ODNs assuming a dumbbell configuration, intended to enhance both stability and efficacy, are addressed. Also specific drug delivery methods like ultrasound-targeted microbubble destruction with TFD ODN-coated microbubbles or adeno-associated viral (AAV) vectors for tissue-specific transduction and long-term TFD molecule expression in non-dividing cells will be discussed. Finally, current therapeutic applications of TFD ODN will be summarized.