Biomedical microelectromechanical systems (BioMEMS): Revolution in drug delivery and analytical techniques

Advancement in microelectromechanical system has facilitated the microfabrication of polymeric substrates and the development of the novel class of controlled drug delivery devices. These vehicles have specifically tailored three dimensional physical and chemical features which together, provide the capacity to target cell, stimulate unidirectional controlled release of therapeutics and augment permeation across the barriers. Apart from drug delivery devices microfabrication technology’s offer exciting prospects to generate biomimetic gastrointestinal tract models. BioMEMS are capable of analysing biochemical liquid sample like solution of metabolites, macromolecules, proteins, nucleic acid, cells and viruses. This review summarized multidisciplinary application of biomedical microelectromechanical systems in drug delivery and its potential in analytical procedures.     

Hard and soft micromachining for BioMEMS: review of techniques and examples of applications in microfluidics and drug delivery

Recent development in microfabrication (micromachining, microelectromechanical systems, MEMS) permits the integration of hard and soft structures, and enables the design of controllable microfluidic systems, which may be applied to drug delivery. In this paper, we present a tutorial review of both classical "hard" and more recent "soft" micromachining techniques. We then provide examples where these techniques are combined to produce hydrogel-based microfluidic control systems. The most complex of these systems utilizes a very small hydrogel based on phenylboronic acid to control the flow of an insulin solution in response to changes in glucose concentration.     

Organogels in drug delivery

In the last decade, interest in physical organogels has grown rapidly with the discovery and synthesis of a very large number of diverse molecules, which can gel organic solvents at low concentrations. The gelator molecules immobilise large volumes of liquid following their self-assembly into a variety of aggregates such as rods, tubules, fibres and platelets. The many interesting properties of these gels, such as their thermoreversibility, have led to much excitement over their industrial applications. However, only a few organogels are currently being studied as drug/vaccine delivery vehicles as most of the existing organogels are composed of pharmaceutically unacceptable organic liquids and/or unacceptable/untested gelators. In this paper a brief overview of organogels is presented, followed by a more in-depth review of the gels that have been investigated for drug and/or vaccine delivery. These include microemulsion-based gels and lecithin gels (studied for transdermal delivery), sorbitan monostearate organogels and amphiphilogels (studied as vaccine adjuvants and for oral and transdermal drug delivery, respectively), gels composed of alanine derivatives (investigated as in situ forming gels) and Eudragit organogels (studied as a matrix for suppositories). Finally, pluronic lecithin organogels, descendents of lecithin gels but which are not really organogels, are briefly discussed for their interesting history, their root and the wide interest in these systems.     

Nanobiotechnology in drug delivery

Nanotechnology is a novel branch of science that deals with the characterization, creation, and utilization of materials, devices, and systems at the nanometer scale. Advances in nanotechnology are spurring a revolution in science, engineering and therapeutics, particularly in drug delivery. Targeted delivery of therapeutic molecules is the most desirable feature of an effective drug therapy. Conventional chemotherapy faces major drawbacks such as poor specificity of the drug, increased adverse effects, and reduced therapeutic efficacy. Application of nanotechnology in drug delivery systems has provided new avenues for engineering materials with molecular precision. This aids in fabricating nanoscale delivery devices that combine diagnostic and therapeutic actions for immediate administration of therapy. Nanotechnology can generate a library of sophisticated drug delivery systems that integrate molecular recognition and site-specific delivery of the therapeutic agents. It formulates therapeutic agents in biocompatible nanomaterials such as nanoparticles, nanocapsules, liposomes, and micelles. This review focuses on some of the nano-sized systems used in drug delivery and discusses the potential applications of nanotechnology in the delivery of macromolecular therapeutic agents.     

Nanosuspensions in drug delivery

A surprisingly large proportion of new drug candidates emerging from drug discovery programmes are water insoluble, and therefore poorly bioavailable, leading to abandoned development efforts. These so-called 'brickdust' candidates can now be rescued by formulating them into crystalline nanosuspensions. In the process of overcoming issues involving solubility, additional pharmacokinetic benefits of the drugs so formulated have come to be appreciated. As such, insolubility issues of the past have provoked a paradigm change, which now offers novel solutions for innovative drugs of the future.     

Organogels in drug delivery

In the last decade, interest in physical organogels has grown rapidly with the discovery and synthesis of a very large number of diverse molecules, which can gel organic solvents at low concentrations. The gelator molecules immobilise large volumes of liquid following their self-assembly into a variety of aggregates such as rods, tubules, fibres and platelets. The many interesting properties of these gels, such as their thermoreversibility, have led to much excitement over their industrial applications. However, only a few organogels are currently being studied as drug/vaccine delivery vehicles as most of the existing organogels are composed of pharmaceutically unacceptable organic liquids and/or unacceptable/untested gelators. In this paper a brief overview of organogels is presented, followed by a more in-depth review of the gels that have been investigated for drug and/or vaccine delivery. These include microemulsion-based gels and lecithin gels (studied for transdermal delivery), sorbitan monostearate organogels and amphiphilogels (studied as vaccine adjuvants and for oral and transdermal drug delivery, respectively), gels composed of alanine derivatives (investigated as in situ forming gels) and Eudragit organogels (studied as a matrix for suppositories). Finally, pluronic lecithin organogels, descendents of lecithin gels but which are not really organogels, are briefly discussed for their interesting history, their root and the wide interest in these systems.     

Cyclodextrins in drug delivery

Cyclodextrins are a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. Cyclodextrin molecules are relatively large with a number of hydrogen donors and acceptors and, thus, in general they do not permeate lipophilic membranes. In the pharmaceutical industry cyclodextrins have mainly been used as complexing agents to increase aqueous solubility of poorly soluble drugs, and to increase their bioavailability and stability. Studies in both humans and animals have shown that cyclodextrins can be used to improve drug delivery from almost any type of drug formulation. However, the addition of cyclodextrins to existing formulations without further optimisation will seldom result in acceptable outcome. Currently there are ~ 30 different pharmaceutical products worldwide containing drug/cyclodextrin complexes on the market.     

Cyclodextrins in drug delivery

Cyclodextrins are a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. Cyclodextrin molecules are relatively large with a number of hydrogen donors and acceptors and, thus, in general they do not permeate lipophilic membranes. In the pharmaceutical industry cyclodextrins have mainly been used as complexing agents to increase aqueous solubility of poorly soluble drugs, and to increase their bioavailability and stability. Studies in both humans and animals have shown that cyclodextrins can be used to improve drug delivery from almost any type of drug formulation. However, the addition of cyclodextrins to existing formulations without further optimisation will seldom result in acceptable outcome. Currently there are approximately 30 different pharmaceutical products worldwide containing drug/cyclodextrin complexes on the market.     

Nanoparticles in drug delivery

Alkylcyanoacrylates can be polymerized in acidified aqueous media by a process of anionic polymerization. The small particles produced tend to be monodisperse and have sizes in the range of 20 to 3000 nm depending upon the polymerization conditions and the presence of additives in the form of surfactants and other stabilizers. The polyalkylcyanoacrylate nanoparticles so produced have been studied in recent years as a possible means of targeting drugs to specific sites in the body, with particular emphasis in cancer chemotherapy. The small colloidal carriers are biodegradable and drug substances can be incorporated normally by a process of surface adsorption. The review by Davis and others considers the formulation of nanoparticles, the important physicochemical variables such as pH, monomer concentration, added stabilizers, ionic strengths, etc., as well as the characteristics of the particle so created in terms of surface charge, particle size, and molecular weight. Monodisperse particles in the range of 20 to 3000 nm can be obtained. In addition, by the use of stabilizers such as dextran and its derivatives, which can be incorporated into the nanoparticle surface by a process of polymer grafting, it is possible to make nanoparticles with interesting surface characteristics and different surface charges (sign). The stability of nanoparticles in vitro and their biodegradation in vivo are examined, and the possible formation of toxic products such as formaldehyde is highlighted. Alternative biodegradable acrylates are mentioned. Drugs can be incorporated into nanoparticles by either direct incorporation during the polymerization process or adsorption to preformed nanoparticles. The efficiency of the incorporation and the release characteristics of model compounds as well as anticancer drugs are discussed. Methods for examining these processes, including the determination of adsorption and desorption, kinetics, and isotherms, are mentioned. Selectivity in drug targeting can, in theory, be achieved by the attachment of some form of homing device, normally a monoclonal antibody or a lectin. Work in vitro and in vivo, where nanoparticles have been coated with monoclonal antibodies, is described. Finally, methods for the labeling of nanoparticles with gamma-emitting radionuclides are presented, and results obtained in animal species are given.     

Self-emulsifying drug delivery systems in oral (poly)peptide drug delivery

Introduction: Oral administration of most therapeutic peptides and proteins is mainly restricted due to the enzymatic and absorption membrane barrier of the GI tract. In order to overcome these barriers, various technologies have been explored. Among them, self-emulsifying drug delivery systems (SEDDS) received considerable attention as potential carriers to facilitate oral peptide and protein delivery in recent years.

Areas covered: This review article intends to summarize physiological barriers which limit the bioavailability of orally administrated peptide and protein drugs. Furthermore, the potential of SEDDS to protect incorporated peptides and proteins towards peptidases and proteases and to penetrate the mucus layer is reviewed. Their permeation-enhancing properties and their ability to release the drug in a controlled way are described. Moreover, this review covers the results of in vivo studies providing evidence for this promising approach.

Expert opinion: As SEDDS can: i) provide a protective effect towards a presystemic metabolism; ii) efficiently permeate the intestinal mucus gel layer in order to reach the absorption membrane; and iii) be produced in a very simple and cost-effective manner, they are a promising tool for oral peptide and protein drug delivery.     

Site-specific drug delivery systems. III. Nasal drug delivery

The nasal cavity has a large surface and a rich blood supplied mucosa. Drugs absorbed by blood vessels pass directly into the systemic circulation, thereby avoiding first-pass metabolism. Numbers of factors limit the intranasal absorption of drugs, especially peptide and protein drugs. These factors are the epithelial and mucus barrier, the rapid mucociliar clearance and the enzymatic activity. Increasing the residence time of the drug formulation in the nasal cavity and a period of contact with nasal mucosa, may improve drug absorption. Approaches to increase the residence time of drug formulations in the nasal cavity usually involve the use of microspheres, liposomes and bioadhesive gels.     

Pulsed drug delivery

Modern drug delivery aims to develop drug delivery systems that are able to meet specific therapeutic requirements. Whereas sustained drug release aims to maintain a constant drug level within the body, pulsed drug delivery intends to release the drug rapidly within a short period of time, as a result of a biological or external trigger, after a specific lag time. This editorial highlights some of the recent advances in new concepts for pulsed drug delivery and proposes some future strategies.     

Erythrocyte-based drug delivery

The use of a physiological carrier to deliver therapeutics throughout the body to both improve their efficacy while minimising inevitable adverse side effects, is an extremely fascinating perspective. The behaviour of erythrocytes as a delivery system for several classes of molecules (i.e., proteins, including enzymes and peptides, therapeutic agents in the form of nucleotide analogues, glucocorticoid analogues) has been studied extensively as they possess several properties, which make them unique and useful carriers. Furthermore, the possibility of using carrier erythrocytes for selective drug targeting to differentiated macrophages increases the opportunities to treat intracellular pathogens and to develop new drugs. Finally, the availability of an apparatus that permits the encapsulation of drugs into autologous erythrocytes has made this technology available in many clinical settings and co-mpetitive with other drug delivery systems.     

Ocular drug delivery

Drug delivery to the eye is hampered by anatomical factors, including the corneal epithelium, the blood-aqueous barrier and the blood-retinal barrier. This review aims to outline the major routes of ocular drug delivery, including systemic, topical, periocular and intravitreal. The pharmacokinetics, the disadvantages and the clinical relevance of these drug delivery routes have been emphasised. Recent advances in surgical techniques, therapeutic approaches and material sciences have produced exciting new therapies for ocular diseases. The role of ophthalmic drug formulation in targeting the desired ocular tissue and enhancing drug delivery by the chosen route whilst minimising side effects is also discussed.     

Colon drug delivery

Oral drug delivery to the colon has attracted significant attention during the past 20 years. Colon targeting is recognised to have several therapeutic advantages, such as the oral delivery of drugs that are destroyed by the stomach acid and/or metabolised by pancreatic enzymes. Sustained colonic release of drugs can be useful in the treatment of nocturnal asthma, angina and arthritis. Local treatment of colonic pathologies, such as ulcerative colitis, colorectal cancer and Crohn's disease, is more effective with the delivery of drugs to the affected area. Likewise, colonic delivery of vermicides and colonic diagnostic agents requires smaller doses. This article aims to provide an insight into the design and manufacturing considerations, and an evaluation of colonic drug delivery systems in order to understand why there are still few delivery technologies that have reached the market, despite intensive research in this field. For this purpose, various approaches to colon-specific drug delivery are discussed.     

Intranasal drug delivery

In recent years the nasal route has received a great deal of attention as a convenient and reliable method for the systemic administration of drugs. Although this route is currently being marketed for the systemic administration of several drugs, it has only recently been studied. This chapter deals with animal techniques to study nasal absorption and the effect of physico-chemical and biopharmaceutical properties of drugs on the rate and extent of absorption. It also discusses factors affecting peptide absorption and methods to improve the nasal bioavailability of peptides. In the last part of the chapter the utility of the nasal route for the delivery of drugs to the brain is discussed.     

Ultrasound-directed drug delivery

It has been proven, that the cellular uptake of drugs and genes is increased, when the region of interest is under ultrasound insonification, and even more when a contrast agent is present. This increased uptake has been attributed to the formation of transient porosities in the cell membrane, which are big enough for the transport of drugs into the cell (sonoporation). Owing to this technique, new ultrasound contrast agents that incorporate a therapeutic compound have become of interest. Combining ultrasound contrast agents with therapeutic substances, such a chemotherapeutics and virus vectors, may lead to a simple and economic method to instantly cure upon diagnosis, using conventional ultrasound scanners. There are two hypotheses for explaining the sonoporation phenomenon, the first being microbubble oscillations near a cell membrane, the second being microbubble jetting through the cell membrane. Based on modeling, high-speed photography, and recent cellular uptake measurements, it is concluded that microbubble jetting behavior is less likely to be the dominant sonoporation mechanism. Ultrasound-directed drug delivery using microbubbles is a promising method that has great potential in the treatment of malignant disorders.