Kidney–targeted drug delivery systems

Kidney-targeted drug delivery systems represent a promising technology to improve drug efficacy and safety in the treatment of renal diseases. In this review, we summarize the strategies that have been employed to develop kidney-targeted drug delivery systems. We also describe how macromolecular carriers and prodrugs play crucial roles in targeting drugs to particular target cells in the kidney. New technologies render it possible to create renal targeting conjugates and other delivery systems including nanoparticles and liposomes present promising strategies to achieve the goal of targeting drugs to the kidney.KEY WORDS: Kidney-targeted, Prodrug, Macromolecular carrier, Nanoparticles, Liposomes     

Prodrugs for transdermal drug delivery – trends and challenges

Prodrugs continue to attract significant interest in the transdermal drug delivery field. These moieties can confer favorable physicochemical properties on transdermal drug delivery candidates. Alkyl chain lengthening, pegylation are some of the strategies used for prodrug synthesis. It is usually important to optimize partition coefficient, water and oil solubilities of drugs. In this review, progress made in the field of prodrugs for percutaneous penetration is highlighted and the challenges discussed.     

Current trends in antithyroid drug treatment of Graves’ disease

Introduction: Graves’ hyperthyroidism is associated with significant morbidity and mortality risk. The thionamides, methimazole, its pro-drug derivative carbimazole, and propylthiouracil, remain a cornerstone of management. Yet despite decades of use, optimal strategies for maximising treatment response and curtailing adverse effect risk remains uncertain.

Areas covered: We reviewed the current literature on the evidence based medical management of Graves’ disease. Specifically, we evaluated current approaches to the use of thionamides, adjunctive therapies, and potential novel agents for controlling Graves’ hyperthyroidism.

Expert opinion: Primary medical therapy is successful in less than 50% of cases and so careful selection of patients for medical treatment based on a combination of pathological and pragmatic considerations is essential. Carbimazole or methimazole is the treatment of choice in the non-pregnant population driven by its more favourable pharmacokinetic and adverse effect profile over propylthiouracil. In pregnancy the choice of treatment is less straightforward and an approach that minimises undue fetal exposure to all thionamides should be adopted. Additional data is needed on the value of adjunctive therapies including potassium perchlorate, iodides, glucocorticoids, lithium, and cholestyramine. Novel agents directed against pathogenetic targets including TSH receptor blocking monoclonal antibodies and small molecule antagonists may hold promise for the future.     

Can cell systems biology rescue drug discovery?

The focus of innovation in current drug discovery is on new targets, yet compound efficacy and safety in biological models of disease - not target selection - are the criteria that determine which drug candidates enter the clinic. We consider a biology-driven approach to drug discovery that involves screening compounds by automated response profiling in disease models based on complex human-cell systems. Drug discovery through cell systems biology could significantly reduce the time and cost of new drug development.     

What does systems biology mean for drug development?

The complexity and flexibility of cellular architectures is increasingly recognized by impressive progress on the side of molecular analytics, i.e. proteomics, genomics and metabolomics. One of the messages from systems biology is that the number of molecular species in cellular networks is orders of magnitude bigger than anticipated by genomic analysis, in particular by fast posttranslational modifications of proteins. The requirements to manage external signals, integrate spatiotemporal signal transduction inside an organism and at the same time optimizing networks of biochemical and chemical reactions result in chemically extremely fine tuned molecular entities. Chemical side reactions of enzymatic activity, like e.g. random oxidative damage of proteins by free radicals during aging constantly introduce epigenetic alterations of protein targets. These events gradually and on an individual stochastic scale, keep modifying activities of these targets, and their affinities and selectivities towards biological and pharmacological ligands. One further message is that many of the key reactions in living systems are essentially based on interactions of low affinities and even low selectivities. This principle is responsible for the enormous flexibility and redundancy of cellular circuitries. So, in complex disorders like cancer or neurodegenerative diseases, which are rooted in relatively subtle and multimodal dysfunction of important physiologic pathways, drug discovery programs based on the concept of high affinity/high specificity compounds ("one-target, one-disease"), which still dominate the pharmaceutical industry increasingly turn out to be unsuccessful. Despite improvements in rational drug design and high throughput screening methods, the number of novel, single-target drugs fell much behind expectations during the past decade and the treatment of "complex diseases" remains a most pressing medical need. Currently a change of paradigm can be observed with regard to a new focus on agents that modulate multiple targets simultaneously. Targeting cellular function as a system rather than on the level of the single protein molecule significantly increases the size of the drugable proteome and is expected to introduce novel classes of multi-target drugs with fewer adverse effects and toxicity. Multiple target approaches have recently been used to design medications against atherosclerosis, cancer, depression, psychosis and neurodegenerative diseases. A focussed approach towards "systemic" drugs will certainly require the development of novel computational and mathematical concepts for appropriate modelling of complex data and extraction of "screenable" information from biological systems essentially ruled by deterministic chaotic processes on a background of individual stochasticity.     

Role of polymer–drug conjugates in organ-specific delivery systems

Polymers have been utilized to deliver the drug to targeted site in controlled manner, achieving the high-therapeutic efficacy. Polymeric drug conjugates having variable ligands as attachments have been proved to be biodegradable, stimuli sensitive and targeted systems. Numerous polymeric drug conjugates having linkers degraded by acidity or intracellular enzymes or sensitive to over expressed groups of diseased organ/tissue have been synthesized during last decade to develop targeted delivery systems. Most of these organs have number of receptors attached with different cells such as Kupffer cells of liver have mannose-binding receptors while hepatocytes have asialoglycoprotein receptors on their surface which mainly bind with the galactose derivatives. Such ligands can be used for achieving high targeting and intracellular delivery of the drug. This review presents detailed aspects of receptors found in different cells of specific organ and ligands with binding efficiency to these specific receptors. This review highlights the need of further studies on organ-specific polymer–drug conjugates by providing detailed account of polymeric conjugates synthesized till date having organ-specific targeting.     

Edoxaban drug–drug interactions with ketoconazole,erythromycin, and cyclosporine

AimsEdoxaban, a novel factor Xa inhibitor, is a substrate of cytochrome P450 3 A4 (CYP3A4) and the efflux transporter P‐glycoprotein (P‐gp). Three edoxaban drug–drug interaction studies examined the effects of P‐gp inhibitors with varying degrees of CYP3A4 inhibition.MethodsIn each study, healthy subjects received a single oral dose of 60 mg edoxaban with or without an oral dual P‐gp/CYP3A4 inhibitor as follows: ketoconazole 400 mg once daily for 7 days, edoxaban on day 4; erythromycin 500 mg four times daily for 8 days, edoxaban on day 7; or single dose of cyclosporine 500 mg with edoxaban. Serial plasma samples were obtained for pharmacokinetics and pharmacodynamics. Safety was assessed throughout the study.ResultsCoadministration of ketoconazole, erythromycin, or cyclosporine increased edoxaban total exposure by 87%, 85%, and 73%, respectively, and the peak concentration by 89%, 68%, and 74%, respectively, compared with edoxaban alone. The half‐life did not change appreciably. Exposure of M4, the major active edoxaban metabolite, was consistent when edoxaban was administered alone or with ketoconazole and erythromycin. With cyclosporine, M4 total exposure increased by 6.9‐fold and peak exposure by 8.7‐fold, suggesting an additional interaction. Pharmacodynamic effects were reflective of increased edoxaban exposure. No clinically significant adverse events were observed.ConclusionsAdministration of dual inhibitors of P‐gp and CYP3A4 increased edoxaban exposure by less than two‐fold. This effect appears to be primarily due to inhibition of P‐gp. The impact of CYP3A4 inhibition appears to be less pronounced, and its contribution to total clearance appears limited in healthy subjects.     

Nonionic surfactant vesicular systems for effective drug delivery—an overview

Vesicular systems are a novel means of drug delivery that can enhance bioavailability of encapsulated drug and provide therapeutic activity in a controlled manner for a prolonged period of time. Liposomes were the first such system but they suffer from a number of drawbacks including high cost and lack of stability at various pHs. Niosomes are a nonionic surfactant vesicular system, which can be easily and reliably made in the laboratory. Many factors affect noisome formation such as the method of manufacture, nature of surfactant and encapsulated drug, temperature at which the lipids are hydrated and the critical packing parameter. This review describes all aspects of niosomes including their different compositions, the various methods of preparation, the effect of changing manufacturing parameters, methods of characterization, factors that affect their stability, their use by various routes of administration, their therapeutic applications and the most important patents. The review also provides detailed information of the various types of niosomes that provide effective drug delivery.     

Classification of stimuli–responsive polymers as anticancer drug delivery systems

Abstract

Although several anticancer drugs have been introduced as chemotherapeutic agents, the effective treatment of cancer remains a challenge. Major limitations in the application of anticancer drugs include their nonspecificity, wide biodistribution, short half-life, low concentration in tumor tissue and systemic toxicity. Drug delivery to the tumor site has become feasible in recent years, and recent advances in the development of new drug delivery systems for controlled drug release in tumor tissues with reduced side effects show great promise. In this field, the use of biodegradable polymers as drug carriers has attracted the most attention. However, drug release is still difficult to control even when a polymeric drug carrier is used. The design of pharmaceutical polymers that respond to external stimuli (known as stimuli–responsive polymers) such as temperature, pH, electric or magnetic field, enzymes, ultrasound waves, etc. appears to be a successful approach. In these systems, drug release is triggered by different stimuli. The purpose of this review is to summarize different types of polymeric drug carriers and stimuli, in addition to the combination use of stimuli in order to achieve a better controlled drug release, and it discusses their potential strengths and applications. A survey of the recent literature on various stimuli–responsive drug delivery systems is also provided and perspectives on possible future developments in controlled drug release at tumor site have been discussed.     

Transgenic probiotica as drug delivery systems: the golden bullet?

Functional human proteins are constitutively produced in genetically modified bacteria that survive on human mucosal surfaces, to the benefit of the host. The successful Phase I clinical trial with IL-10-producing Lactococcus lactis for Crohn's disease has opened new avenues for the use of transgenic bacteria as delivery vehicles. The major advantage of this novel strategy is the avoidance of systemic side effects associated with conventional therapies. This methodology opens up an alternative method for local delivery of therapeutic proteins to various mucosal tissues.     

Providing an earlier warning of emerging drug trends: the føre var system

In 2002 the Bergen Clinics Foundation established Føre Var, a citywide ‘earlier warning’ system geared towards the identification, monitoring and reporting of drug and alcohol trends in the city of Bergen, Norway, on a six-monthly basis. The primary goal for the system was the dissemination of earlier, more reliable information on new and emerging trends to enable timely and more effective interventions by policy makers and practitioners in the drug and alcohol field. The Føre Var system triangulates and cross-references a wide range of statistical and quantitative data including seizures data, treatment figures, alcohol sales and a school survey, with information from a number of ‘leading edge’ or sensitive data sources, including Internet sites, youth and local media, cultural mapping and key informants. Data is collected from sources every six months, analysed for identifiable patterns and trends and disseminated widely. This paper details the system's developmental stages and methodologies, in addition to summarizing results from the first three Føre Var reports. In conclusion, the strengths and weaknesses of the model, its replicability as well as the potential advantages of a city-level network are discussed.     

Three ‘D’s: Design approach,dimensional printing,and drug delivery systems as promising tools in healthcare applications

The development of pharmaceutical drug products is required for the treatment of disease, which has resulted in an increasing number of approvals by regulatory agencies across the globe. To establish a hassle-free manufacturing process, the systematic use of a quality-by-design (QbD) approach combined with process analytical technology (PAT) and printing techniques can revolutionize healthcare applications. Printing technology has been emerged in various dimensions, such as 3D, 4D, and 5D printing, with respect to their production capabilities, durability, and accuracy of pharmaceutical manufacturing, which can efficiently deliver novel patient-centric healthcare products with holistic characteristics. In this review, we provide current trends in pharmaceutical product development using a design approach and high-quality printing techniques.     

‘Smart’ nanoparticles as drug delivery systems for applications in tumor therapy

Introduction: In the therapy of clinical diseases such as cancer, it is important to deliver drugs directly to tumor sites in order to maximize local drug concentration and reduce side effects. This objective may be realized by using ‘smart’ nanoparticles (NPs) as drug delivery systems, because they enable dramatic conformational changes in response to specific physical/chemical stimuli from the diseased cells for targeted and controlled drug release.

Areas covered: In this review, we first briefly summarize the characteristics of ‘smart’ NPs as drug delivery systems in medical therapy, and then discuss their targeting transport, transmembrane and endosomal escape behaviors. Lastly, we focus on the applications of ‘smart’ NPs as drug delivery systems for tumor therapy.

Expert opinion: Biodegradable ‘smart’ NPs have the potential to achieve maximum efficacy and drug availability at the desired sites, and reduce the harmful side effects for healthy tissues in tumor therapy. It is necessary to select appropriate NPs and modify their characteristics according to treatment strategies of tumor therapy.     

Searching for new cardiovascular drugs: towards improved systems for drug screening?

Introduction: The pharmaceutical industry urgently needs new ways of profiling the safety and efficacy of new cardiovascular (CV) drugs and more effectively transitioning these compounds through the stages of CV drug screening. This article reviews new technologies and methodological innovations and assesses whether these frameworks offer improved solutions to the problems facing the contemporary CV drug development.

Areas covered: The article comprises literature derived from a systematic search (from 2000 onwards) using the US patent office and ESP@CENET search engines as well as through multiple Boolean terms. The article focuses on patents relating to technologies and resources and categorises the patents according to their niche in the CV drug screening landscape.

Expert opinion: The CV drug pipeline is stalling due to the inability of many contemporary drug screening frameworks to discriminate between safe, efficacious therapy and hazardous off-target effect. Given the current limitations of drug screening frameworks, there is little scope for expanding the CV drug portfolio with newer, safer drugs with improved mechanisms of action. New screening modalities are urgently needed. Searches reveal that there are few examples of truly new technologies and systems in the patent literature. This apparent failure to revamp facets of the CV drug screening process can only perpetuate the inability of current platforms to improve the CV drug pipeline. Consequently, with few exceptions, there is stagnation in pre-clinical assay design that limits the pharmaceutical industry's ability to search for new drugs in new and more effective ways.     

Pectin-coated chitosan–LDH bionanocomposite beads as potential systems for colon-targeted drug delivery

This work introduces results on a new drug delivery system (DDS) based on the use of chitosan/layered double hydroxide (LDH) biohybrid beads coated with pectin for controlled release in the treatment of colon diseases. Thus, the 5-aminosalicylic acid (5ASA), the most used non-steroid-anti-inflammatory drug (NSAID) in the treatment of ulcerative colitis and Crohn's disease, was chosen as model drug aiming to a controlled and selective delivery in the colon. The pure 5ASA drug and the hybrid material prepared by intercalation in a layered double hydroxide of Mg₂Al using the co-precipitation method, were incorporated in a chitosan matrix in order to profit from its mucoadhesiveness. These compounds processed as beads were further treated with the polysaccharide pectin to create a protective coating that ensures the stability of both chitosan and layered double hydroxide at the acid pH of the gastric fluid. The resulting composite beads presenting the pectin coating are stable to water swelling and procure a controlled release of the drug along their passage through the simulated gastrointestinal tract in in vitro experiments, due to their resistance to pH changes. Based on these results, the pectin@chitosan/LDH-5ASA bionanocomposite beads could be proposed as promising candidates for the colon-targeted delivery of 5ASA, with the aim of acting only in the focus of the disease and minimizing side effects.     

Searching for new cardiovascular drugs: towards improved systems for drug screening?

Introduction: The pharmaceutical industry urgently needs new ways of profiling the safety and efficacy of new cardiovascular (CV) drugs and more effectively transitioning these compounds through the stages of CV drug screening. This article reviews new technologies and methodological innovations and assesses whether these frameworks offer improved solutions to the problems facing the contemporary CV drug development. Areas covered: The article comprises literature derived from a systematic search (from 2000 onwards) using the US patent office and ESP@CENET search engines as well as through multiple Boolean terms. The article focuses on patents relating to technologies and resources and categorises the patents according to their niche in the CV drug screening landscape. Expert opinion: The CV drug pipeline is stalling due to the inability of many contemporary drug screening frameworks to discriminate between safe, efficacious therapy and hazardous off-target effect. Given the current limitations of drug screening frameworks, there is little scope for expanding the CV drug portfolio with newer, safer drugs with improved mechanisms of action. New screening modalities are urgently needed. Searches reveal that there are few examples of truly new technologies and systems in the patent literature. This apparent failure to revamp facets of the CV drug screening process can only perpetuate the inability of current platforms to improve the CV drug pipeline. Consequently, with few exceptions, there is stagnation in pre-clinical assay design that limits the pharmaceutical industry's ability to search for new drugs in new and more effective ways.     

Polymorphism of miconazole during preparation of solid systems of the drug and β-cyclodextrins

Kneading and coevaporate procedures were used in an endeavour to prepare cyclodextrin inclusion complexes of the antimycotic drug miconazole. Crystalline miconazole was present in the preparations containing β-cyclodextrin. A kneading product of miconazole and hydroxypropyl-β-cyclodextrin, molar ratio 1:2, was amorphous. It might be a genuine inclusion complex or more probably a mixture of amorphous miconazole and amorphous hydroxypropyl-β-cyclodextrin. The antimycotic effect of the amorphous kneading product was tested against a strain of Candida albicans in a fluid medium. The product had a fungicidal effect whereas a physical mixture of miconazole and hydroxypropyl-β-cyclodextrin only inhibited the growth of the fungus. The kneading product had an effect which was similar to the effect of the water-soluble miconazole nitrate salt.It was observed during the study that commercially available miconazole from different manufacturers contained at least two different crystal forms of the drug.     

In situ gel systems as ‘smart’ carriers for sustained ocular drug delivery

Introduction: In situ gel systems refer to a class of novel delivery vehicles, composed of natural, semisynthetic or synthetic polymers, which present the unique property of sol–gel conversion on receipt of biological stimulus.

Areas covered: The present review summarizes the latest developments in in situ gel technology, with regard to ophthalmic drug delivery. Starting with the mechanism of ocular absorption, the review expands on the fabrication of various polymeric in situ gel systems, made up of two or more polymers presenting multi-stimuli sensitivity, coupled with other interesting features, such as bio-adhesion, enhanced penetration or sustained release. Various key issues and challenges in this area have been addressed and critically analyzed.

Expert opinion: The advent of in situ gel systems has inaugurated a new transom for ‘smart’ ocular delivery. By virtue of possessing stimuli-responsive phase transition properties, these systems can easily be administered into the eye, similar to normal eye drops. Their unique gelling properties endow them with special features, such as prolonged retention at the site of administration, followed by sustained drug release. Despite the superiority of these systems as compared with conventional ophthalmic formulations, further investigations are necessary to address the toxicity issues, so as to minimize regulatory hurdles during commercialization.     

Merging drug companies, submerging creativity?

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