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.     

In-silico simulations of advanced drug delivery systems: What will the future offer?

This commentary enlarges on some of the topics addressed in the Position Paper “Towards more effective advanced drug delivery systems” by Crommelin and Florence (2013). Inter alia, the role of mathematical modeling and computer-assisted device design is briefly addressed in the Position Paper. This emerging and particularly promising field is considered in more depth in this commentary. In fact, in-silico simulations have become of fundamental importance in numerous scientific and related domains, allowing for a better understanding of various phenomena and for facilitated device design. The development of novel prototypes of space shuttles, nuclear power plants and automobiles are just a few examples. In-silico simulations are nowadays also well established in the field of pharmacokinetics/pharmacodynamics (PK/PD) and have become an integral part of the discovery and development process of novel drug products. Since Takeru Higuchi published his seminal equation in 1961 the use of mathematical models for the analysis and optimization of drug delivery systems in vitro has also become more and more popular. However, applying in-silico simulations for facilitated optimization of advanced drug delivery systems is not yet common practice. One of the reasons is the gap between in vitro and in vivo (PK/PD) simulations. In the future it can be expected that this gap will be closed and that computer assisted device design will play a central role in the research on, and development of advanced drug delivery systems.     

Future of the transdermal drug delivery market – have we barely touched the surface?

ABSTRACT

Introduction: Transdermal drug delivery is the movement of drugs across the skin for absorption into the systemic circulation. Transfer of the drug can occur via passive or active means; passive transdermal products do not disrupt the stratum corneum to facilitate delivery whereas active technologies do. Due to the very specific physicochemical properties necessary for successful passive transdermal drug delivery, this sector of the pharmaceutical industry is relatively small. There are many well-documented benefits of this delivery route however, and as a result there is great interest in increasing the number of therapeutic substances that can be delivered transdermally.

Areas Covered: This review discusses the various transdermal products that are currently/have been marketed, and the paths that led to their success, or lack of. Both passive and active transdermal technologies are considered with the advantages and limitations of each highlighted. In addition to marketed products, technologies that are in the investigative stages by various pharmaceutical companies are reviewed.

Expert Opinion: Passive transdermal drug delivery has made limited progress in recent years, however with the ongoing intense research into active technologies, there is great potential for growth within the transdermal delivery market. A number of active technologies have already been translated into marketed products, with other platforms including microneedles, rapidly progressing towards commercialisation.     

Advances in drug delivery: is triple therapy the future for the treatment of chronic obstructive pulmonary disease?

Introduction: Current therapies for chronic obstructive pulmonary disease (COPD) focus on the improvement of clinical symptoms via the use of bronchodilators: β₂-adrenoreceptor agonists and muscarinic (M3) acetycholine receptor antagonists. The combination of inhaled corticosteroids (ICSs) and long-acting β₂ agonists (LABAs), or LABAs and anticholinergics has become an efficient alternative to single therapies. These combinations consist of a LABA and an ICS together with an anticholinergic, such as ipratropium or tiotropium.

Areas covered: This review summarizes the latest thinking and findings on the usefulness of triple therapy in the treatment and management of COPD. Drawing on commercial, clinical, scientific and intellectual property data and publications, it aims to provide an overview to understand the efficacy and need for COPD triple therapy. The reader will gain an in-depth view of the triple therapy approach in managing COPD, existing molecules in the market or in development as well as new chemical entities. Clinical evidence in support of triple therapy, formulations and products are also discussed.

Expert opinion: There is limited documented clinical evidence for the use of triple therapy in COPD, reflected in the lack of commercial activity in the field. The future for the management of COPD may lie with triple therapy, but may equally rest on a better understanding of the disease and subsequent development of new chemical entities, such as dimer molecules, longer-acting β-agonists and antimuscarinics.     

Can nasal drug delivery bypass the blood-brain barrier?: questioning the direct transport theory

The connection between the nasal cavity and the CNS by the olfactory neurones has been investigated extensively during the last decades with regard to its feasibility to serve as a direct drug transport route to the CSF and brain. This drug transport route has gained much interest as it may circumvent the blood-brain barrier (BBB), which prevents some drugs from entering the brain. Approximately 100 published papers mainly reporting animal experiments were reviewed to evaluate whether the experimental design used and the results generated provided adequate pharmacokinetic information to assess whether the investigated drug was transported directly from the olfactory area to the CNS. In the analysis the large anatomical differences between the olfactory areas of animals and humans and the experimental conditions used were evaluated. The aim of this paper was to establish the actual evidence for the feasibility of this direct transport route in humans. Twelve papers presented a sound experimental design to study direct nose to CNS transport of drugs based on the authors' criteria. Of these, only two studies in rats were able to provide results that can be seen as an indication for direct transport from the nose to the CNS. No pharmacokinetic evidence could be found to support a claim that nasal administration of drugs in humans will result in an enhanced delivery to their target sites in the brain compared with intravenous administration of the same drug under similar dosage conditions.     

Advances in drug delivery: Is triple therapy the future for the treatment of chronic obstructive pulmonary disease?

INTRODUCTION: Current therapies for chronic obstructive pulmonary disease (COPD) focus on the improvement of clinical symptoms via the use of bronchodilators: β(2)-adrenoreceptor agonists and muscarinic (M3) acetylcholine receptor antagonists. The combination of inhaled corticosteroids (ICSs) and long-acting β(2) agonists (LABAs), or LABAs and anticholinergics has become an efficient alternative to single therapies. These combinations consist of a LABA and an ICS together with an anticholinergic, such as ipratropium or tiotropium. AREAS COVERED: This review summarizes the latest thinking and findings on the usefulness of triple therapy in the treatment and management of COPD. Drawing on commercial, clinical, scientific and intellectual property data and publications, it aims to provide an overview to understand the efficacy and need for COPD triple therapy. The reader will gain an in-depth view of the triple therapy approach in managing COPD, existing molecules in the market or in development as well as new chemical entities. Clinical evidence in support of triple therapy, formulations and products are also discussed. EXPERT OPINION: There is limited documented clinical evidence for the use of triple therapy in COPD, reflected in the lack of commercial activity in the field. The future for the management of COPD may lie with triple therapy, but may equally rest on a better understanding of the disease and subsequent development of new chemical entities, such as dimer molecules, longer-acting β-agonists and antimuscarinics.     

The feasibility of oral targeted drug delivery: Gut immune to particulates?

Targeted drug delivery is constantly updated with a better understanding of the physiological and pathological features of various diseases. Depending on high safety, good compliance and many other undeniable advantages, attempts have been undertaken to complete an intravenous-to-oral conversion of targeted drug delivery. However, oral delivery of particulates to systemic circulation is highly challenging due to the biochemical aggressivity and immune exclusion in the gut that restrain absorptio...     

Squalamine: a polyvalent drug of the future?

The purpose of this mini-review is to summarize and highlight the different advances in our understanding of the antimicrobial and antiangiogenic activity of squalamine, a cationic steroid isolated in 1993 from the dogfish shark Squalus Acanthias. Indeed, squalamine has shown to be useful for the treatment of important diseases such as cancers (lung, ovarian, brain and others), age-related macular degeneration (AMD) and the control of body weight in man. All these results led to a question: could we consider squalamine as a polyvalent drug of the future?     

Polymer-cysteamine conjugates: new mucoadhesive excipients for drug delivery?

In the present study, the features of two new thiolated polymers--the so-called thiomers--were investigated. Mediated by a carbodiimide cysteamine was covalently attached to sodium carboxymethylcellulose (Na-CMC) and neutralised polycarbophil (Na-PCP). Depending on the weight-ratio polymer to cysteamine during the coupling reaction, the resulting CMC-cysteamine conjugate and PCP-cysteamine conjugate showed in maximum 43 +/- 15 and 138 +/- 22 micromole thiol groups per g polymer (mean +/- S.D.; n=3), respectively, which were used for further characterisation. Tensile studies carried out with the CMC-cysteamine conjugate on freshly excised porcine intestinal mucosa displayed no significantly (P<0.01) improved mucoadhesion, whereas, the mucoadhesive properties of the PCP-cysteamine conjugate were increased 2.5-fold compared with the unmodified polymer. The swelling behaviour of the CMC-cysteamine conjugate was uninfluenced by the covalent attachment of the sulfhydryl compound. In contrast the swelling behaviour of the PCP-cysteamine conjugate was improved significantly (P<0.01) versus unmodified PCP. Furthermore, in aqueous solutions the disintegration time of tablets based on the CMC- and PCP-cysteamine conjugates was prolonged 1.5 and 3.2-fold, respectively, in comparison to tablets containing the corresponding unmodified polymers. According to these results, especially the PCP-cysteamine conjugate represents a promising new pharmaceutical excipient for various drug delivery systems.     

Newer insights into the drug delivery approaches of α-glucosidase inhibitors

INTRODUCTION: α-Glucosidase inhibitors (AGIs) are an important category of oral antidiabetic agents being extensively exploited for the effective management of type 2 diabetes and associated disorders. These drugs significantly reduce the postprandial rise in glycemic and plasma insulin levels both in nondiabetics and in type 2 diabetic patients. Currently only three drugs belonging to this category, viz, acarbose, miglitol and voglibose are in the market. The major limitations associated with the administration of AGIs are the stringent repetitive dosing schedule at specified time intervals, along with a high incidence of gastrointestinal disturbances that mainly include flatulence, abdominal distension, borborygmus and diarrhea. All these factors tend to decrease patient compliance. AREAS COVERED: This review focuses on the various formulation approaches being targeted for the effective delivery of AGIs, viz, unit matrix systems, bioadhesive pellets, hydrogels and lipid-based granules. EXPERT OPINION: It is concluded that development of a successful controlled-release delivery system for these drugs will obviate the need of repeated administration, which in turn will improve patient compliance.     

Intravitreal drug delivery in retinal disease: are we out of our depth?

Introduction: With the ever-increasing global burden of retinal disease, there is an urgent need to vastly improve formulation strategies that enhance posterior eye delivery of therapeutics. Despite intravitreal administration having demonstrated notable superiority over other routes in enhancing retinal drug availability, there still exist various significant physical/biochemical barriers preventing optimal drug delivery into the retina. A further complication lies with an inability to reliably translate laboratory-based retinal models into a clinical setting. Several formulation approaches have recently been evaluated to improve intravitreal therapeutic outcomes, and our aim in this review is to highlight strategies that hold the most promise.

Areas covered: We discuss the complex barriers faced by the intravitreal route and examine how formulation strategies including implants, nanoparticulate carriers, viral vectors and sonotherapy have been utilized to attain both sustained delivery and enhanced penetration through to the retina. We conclude by highlighting the advances and limitations of current in vitro, ex vivo and in vivo retinal models in use by researchers globally.

Expert opinion: Various nanoparticle compositions have demonstrated the ability to overcome the retinal barriers successfully; however, their utility is limited to the laboratory setting. Optimization of these formulations and the development of more robust experimental retinal models are necessary to translate success in the laboratory into clinically efficacious outcomes.     

Is the oral route possible for peptide and protein drug delivery?

Oral delivery of peptides and proteins remains an attractive alternative to parenteral delivery and has challenged various attempts at delivery development. Incorporation of new tools into the delivery systems that can raise membrane permeability of macromolecules is essential to attain high oral bioavailability that is acceptable in clinical applications. In developing oral protein delivery systems with high bioavailability, three practical approaches might be most helpful: (1) modification of the physicochemical properties of macromolecules; (2) addition of novel function to macromolecules; or (3) use of improved delivery carriers. Clearly, it is essential that these approaches maintain the biological activity of the proteins.