Pulsatile drug release control using hydrogels.

Current research in the field of drug delivery devices, by which pulsed and/or pulsatile release is achieved, has been intensified. In this article several types of drug delivery systems using hydrogels are discussed that showed pulsed and/or pulsatile drug delivery characteristics. As is frequently found in the living body, many vital functions are regulated by pulsed or transient release of bioactive substances at a specific site and time. Thus it is important to develop new drug delivery devices to achieve pulsed delivery of a certain amount of drugs in order to mimic the function of the living systems, while minimizing undesired side effects. Special attention has been given to the thermally responsive poly(N-isopropylacrylamide) and its derivative hydrogels. Thermal stimuli-regulated pulsed drug release is established through the design of drug delivery devices, hydrogels, and micelles. Development of modified alginate gel beads with pulsed drug delivery characteristic is also described in this article.     

Drug delivery from ordered mesoporous matrices

Research interest in silica-based ordered mesoporous materials (SMMs) as drug delivery systems has grown drastically in the last few years owing to the great versatility and stability of these mesoporous matrices. This review aims to resume the work carried out in this area so far and the possible applications in biomedical technologies. The different SMMs can be designed and tailored using different chemical strategies according to the drug and clinical necessity. The available channels of SMMs that can be used to store drugs can be opened and closed by different systems, in the so-called stimuli-responsive release devices. These systems could improve the therapeutic efficacy compared with conventional sustained release systems. SMMs offer such a great versatility that can be used both for oral and for local drug delivery, with huge possible applications in different clinical areas.     

Chronopharmaceutics: as a clinically relevant drug delivery system

Current research in the field of drug delivery devices, by which pulsatile release is achieved, has been intensified. In this article, an attempt has been made to discuss several types of drug delivery systems that show pulsatile drug delivery characteristics. As found frequently in the living body, many vital functions are regulated by pulsed or transient release of bioactive substances at a specific site and time. Thus it is important to develop new drug delivery devices to achieve pulsed delivery of a certain amount of drugs in order to mimic the function of the living systems, while minimizing undesired side-effects. Pulsatile delivery, which is meant as the liberation of drugs following programmed lag phases, has drawn increasing interest, especially in view of emerging chronotherapeutic approaches. This review article is an attempt to discuss various design strategies, chiefly including reservoir, capsular, and osmotic formulations, and drug delivery systems which cause the pulsed or triggered release of bioactive compounds induced due to certain stimuli like thermal, electrical, and magnetic.     

Mesoporous silica formulation strategies for drug dissolution enhancement: a review

Introduction: Silica materials, in particular mesoporous silicas, have demonstrated excellent properties to enhance the oral bioavailability of poorly water-soluble drugs. Current research in this area is focused on investigating the kinetic profile of drug release from these carriers and manufacturing approaches to scale-up production for commercial manufacture.

Areas covered: This review provides an overview of different methods utilized to load drugs onto mesoporous silica carriers. The influence of silica properties and silica pore architecture on drug loading and release are discussed. The kinetics of drug release from mesoporous silica systems is examined and the manufacturability and stability of these formulations are reviewed. Finally, the future prospects of mesoporous silica drug delivery systems are considered.

Expert opinion: Substantial progress has been made in the characterization and development of mesoporous drug delivery systems for drug dissolution enhancement. However, more research is required to fully understand the drug release kinetic profile from mesoporous silica materials. Incomplete drug release from the carrier and the possibility of drug re-adsorption onto the silica surface need to be investigated. Issues to be addressed include the manufacturability and regulation status of formulation approaches employing mesoporous silica to enhance drug dissolution. While more research is needed to support the move of this technology from the bench to a commercial medicinal product, it is a realistic prospect for the near future.     

Application of mesoporous silicon dioxide and silicate in oral amorphous drug delivery systems

Aqueous solubility of an active pharmaceutical ingredient is an important consideration to ensure successful drug development. Mesoporous materials have been investigated as an amorphous drug delivery system owing to their nanosized capillaries and large surface areas. The complex interactions of crystalline compounds with mesoporous media and their implication in drug delivery are not well understood. Molecules interacting with porous media behave very differently than those in bulk phase. Their altered dynamics and thermodynamics play an important role in the properties and product performance of the amorphous system. In this review, application of mesoporous silicon dioxide and silicates in drug amorphization is the main focus. First, as background, the nature of gas-porous media interactions is summarized. The synthesis of various types of mesoporous silica, which are used by many investigators in this field, is described. Second, the behavior of molecules confined in mesopores is compared with those in bulk, crystalline phase. The molecular dynamics of compounds due to confinement, analyzed using various techniques, and their consequences in drug delivery are discussed. Finally, the preparation and performance of drug delivery systems using mesoporous silica are examined.     

The potential of calcium silicate hydrate as a carrier of ibuprofen

Calcium silicate nanostructured materials are promising drug carriers owing to their excellent biocompatibility, good bioactivity and high drug-loading capacity. In recent years, studies have been carried out on the synthesis of calcium silicate hydrate (CSH) nanostructured materials with desirable sizes and morphologies and their applications in drug delivery, where very interesting results and important insights have been documented. This editorial is not intended to offer a comprehensive review on the research on CSH nanostructured materials as drug carriers; rather, it presents representative examples: i) mesoporous microspheres; ii) ultrathin nanosheets; iii) iron oxide/CSH core/shell nanocomposites; and iv) CSH/block copolymer nanocomposites, and important results obtained in the study of CSH drug delivery systems for ibuprofen (IBU) as a model drug. These results show that the nanostructured CSH materials with specially designed architectures as IBU carriers have ultrahigh drug-loading capacity and sustainable drug release properties; thus, they are promising drug carriers for IBU. In addition, a new drug release kinetics has been found in the nanostructured CSH drug delivery systems. Most recently, new insight has been gained by tracking the behavior of these drug delivery systems on the molecular level using synchrotron-based X-ray spectroscopy.     

Functionalized mesoporous silica particles for application in drug delivery system

In these years, ordered mesoporous silica materials have shown promising applications in drug delivery system as drug carriers. These carriers with stable mesoporous structure, large surface area, good biocompatibility and tailored size of mesopores exhibit significant property of higher drug loading. However, silica-based mesoporous materials cannot control the release of the loaded drug without modifications. In this paper, we review the recent research work discussing functionalization of mesoporous materials by various components and methods for application in drug delivery systems. All the examples show that these functionalized mesoporous silica-based systems have great potential for a variety of drug delivery applications, specifically in the fields of the drug targeted and controlled delivery systems.     

Stimuli-responsive molecularly imprinted polymers for drug delivery: a review

Molecular imprinting is an efficient technique for introducing regions with a highly specific molecular arrangement into a polymeric matrix. The first example of a molecularly imprinted polymer (MIP) was reported half a century ago; however, the use of molecular imprinting has become a well established practical tool only in the last decade. Recently, MIPs are widely used, for example, in chromatographic applications or enzyme antibody mimics. MIPs have also been used in biological applications such as drug delivery systems (DDS), and they have also been successfully applied as excipients in controlled delivery systems. Their huge potential could bring about intelligent drug release; this refers to the release, in a predictable way, of therapeutic agents in response to specific environmental stimuli (the presence of another molecule, pH changes, temperature, etc.). This review is focused on particular intelligent devices of this type that exhibit selective recognition (traps for toxic molecules) and release (of drugs in order to prolong the duration of pharmacological action) in response to specific stimuli. The "stimuli-responsive molecularly imprinted polymers" reviewed in this paper are expected to contribute significantly to the exploration and development of new generations of intelligent and self-regulated drug delivery systems.     

Drug delivery from the oral cavity: focus on a novel mechatronic delivery device

Dental drug delivery systems have been used for a long time, in particular for the local therapy of diseases affecting the oral cavity. Research today concentrates on the design of formulations to increase their retention time. Even today, however, prosthetic devices incorporating drug delivery are rarely used. Mainly, they are focused on prophylaxis and the release of antibacterial agents. However, as buccal delivery, because of its undeniable advantages, has become popular for systemic drug delivery, and prolonged well-controlled release has been identified as beneficial, especially for chronic diseases, a new class of delivery systems is evolving: highly miniaturized computerized delivery systems, integrated into a dental appliance. Dental delivery systems today are used in two ways: the main application is the local treatment of diseases affecting the oral cavity itself like periodontitis or fungal infections. The second is for systemic drug delivery.     

The pH-controlled dual-drug release from mesoporous bioactive glass/polypeptide graft copolymer nanomicelle composites

Dual-drug delivery systems are investigated for combined therapy with drugs having distinct therapeutic effects. However, the majority of current dual-drug delivery systems are designed for simultaneous release of two different drugs; the release of each individual drug cannot be controlled. In this study, we have demonstrated a novel dual-drug delivery system based on mesoporous bioactive glass/polypeptide graft copolymer nanomicelle composites. Water-soluble gentamicin and fat-soluble naproxen were used as model drugs in the study of this system. A pH-controlled release of individual drugs was achieved by the predominant release of gentamicin from mesoporous bioactive glass in an acid environment and fast release of naproxen in an alkaline environment from polypeptide nanomicelles. Our results suggest that the mesoporous bioactive glass/PBLG-g-PEG nanomicelle composites can be used as a dual-drug delivery system, and that the individual drug release can be controlled by the pH of the surrounding environment.     

Multiphase flow microfluidics for the production of single or multiple emulsions for drug delivery

Considerable effort has been directed towards developing novel drug delivery systems. Microfluidics, capable of generating monodisperse single and multiple emulsion droplets, executing precise control and operations on these droplets, is a powerful tool for fabricating complex systems (microparticles, microcapsules, microgels) with uniform size, narrow size distribution and desired properties, which have great potential in drug delivery applications. This review presents an overview of the state-of-the-art multiphase flow microfluidics for the production of single emulsions or multiple emulsions for drug delivery. The review starts with a brief introduction of the approaches for making single and multiple emulsions, followed by presentation of some potential drug delivery systems (microparticles, microcapsules and microgels) fabricated in microfluidic devices using single or multiple emulsions as templates. The design principles, manufacturing processes and properties of these drug delivery systems are also discussed and compared. Furthermore, drug encapsulation and drug release (including passive and active controlled release) are provided and compared highlighting some key findings and insights. Finally, site-targeting delivery using multiphase flow microfluidics is also briefly introduced.     

PLGA微球的修饰及其应用

微球作为新型的药物载体系统已广泛用于临床研究,高分子化合物材料聚乳酸-羟基乙酸(pdy lactic-co-glycolic acid,PLGA)因其良好的生物相容性和生物可降解性备受关注。近年来,PLGA微球的研究一直是热门,针对其释放缺陷出现了很多复合修饰方法,主要包括环糊精、壳聚糖、聚乳酸、明胶、泊洛沙姆、聚乙烯亚胺等高分子材料的联用、针对末端基团进行化学修饰以及制备成核壳型微球,在保证包封率的情况下大大降低突释,改善药物释放曲线,从而在药物传递、基因治疗、影像诊断、组织工程等领域得到了广泛的应用。     

Advanced drug delivery devices via self-assembly of amphiphilic block copolymers.

Amphiphilic block copolymers are well established as building blocks for the preparation of micellar drug carriers. Over the past decade, the effectiveness of such self-assembled drug delivery devices has been demonstrated numerous times. This review will discuss two approaches that can be used to further improve the effectiveness of amphiphilic block copolymer-based drug delivery systems. The first approach involves the chemical modification of the block copolymer building blocks. Several examples will be discussed of amphiphilic block copolymers modified with crosslinkable groups in order to increase the stability of the micellar drug carriers, or of block copolymers containing specific ligands that could ultimately allow targeted drug delivery. The second approach to improve the performance of micellar drug carriers is the addition of auxiliary agents. To illustrate this approach, the feasibility of channel proteins and metal (nano)particles to improve temporal control over the drug release process is discussed.     

Advanced drug delivery devices via self-assembly of amphiphilic block copolymers

Amphiphilic block copolymers are well established as building blocks for the preparation of micellar drug carriers. Over the past decade, the effectiveness of such self-assembled drug delivery devices has been demonstrated numerous times. This review will discuss two approaches that can be used to further improve the effectiveness of amphiphilic block copolymer-based drug delivery systems. The first approach involves the chemical modification of the block copolymer building blocks. Several examples will be discussed of amphiphilic block copolymers modified with crosslinkable groups in order to increase the stability of the micellar drug carriers, or of block copolymers containing specific ligands that could ultimately allow targeted drug delivery. The second approach to improve the performance of micellar drug carriers is the addition of auxiliary agents. To illustrate this approach, the feasibility of channel proteins and metal (nano)particles to improve temporal control over the drug release process is discussed.     

Drug delivery systems for differential release in combination therapy

INTRODUCTION: Combination therapy with multiple therapeutic agents has wide applicability in medical and surgical treatment, especially in the treatment of cancer. Thus, new drug delivery systems that can differentially release two or more drugs are desired. Utilizing new techniques to engineer the established drug delivery systems and synthesizing new materials and designing carriers with new structures are feasible ways to fabricate proper multi-agent delivery systems, which are critical to meet requirements in the clinic and improve therapeutic efficacy. AREAS COVERED: This paper aims to give an overview about the multi-agent delivery systems developed in the last decade for differential release in combination therapy. Multi-agent delivery systems from nanoscale to bulk scale, such as liposomes, micelles, polymer conjugates, nano/microparticles and hydrogels, developed over the last 10 years, have been collected and summarized. The characteristics of different delivery systems are described and discussed, including the structure of drug carriers, drug-loading techniques, release behaviors and consequent evaluation in biological assays. EXPERT OPINION: The chemical structure of drug delivery systems is the key to controlling the release of therapeutic agents in combination therapy, and the differential release of multiple drugs could be realized by the successful design of a proper delivery system. Besides biological evaluation in vitro and in vivo, it is important to speed up practical application of the resulting delivery systems.     

Sustained release from mesoporous nanoparticles: evaluation of structural properties associated with release rate

We present here a detailed study of the controlled release of amino acid derived amphiphilic molecules from the internal pore structure of mesoporous nanoparticle drug delivery systems with different structural properties; namely cubic and hexagonal structures of various degrees of complexity. The internal pore surface of the nanomaterials presented has been functionalised with amine moieties through a one pot method. Release profiles obtained by Alternating Ionic Current measurements are interpreted in terms of specific structural and textural parameters of the porous nanoparticles such as pore geometry and connectivity. Results indicate that diffusion coefficients are lower by as much as four orders of magnitude in 2-dimensional structures in comparison to 3-dimensional mesoporous solids. A fast release in turn is observed from mesocaged materials AMS-9 and AMS-8 where the presence of structural defects is thought to lead to a slightly lower diffusion coefficient in the latter. Amount of pore wall functionalisation and number of binding sites on the model drug are found to have little effect on the drug release rate.     

Sustained-release ophthalmic drug delivery systems for treatment of macular disorders: present and future applications

Macular disease currently poses the greatest threat to vision in aging populations. Historically, most of this pathology could only be dealt with surgically, and then only after much damage to the macula had already occurred. Current pathophysiological insights into macular diseases have allowed the development of effective new pharmacotherapies. The field of drug delivery systems has advanced over the last several years with emphasis placed on controlled release of drug to specific areas of the eye. Its unique location and tendency toward chronic disease make the macula an important and attractive target for drug delivery systems, especially sustained-release systems. This review evaluates the current literature on the research and development of sustained-release posterior segment drug delivery systems that are primarily intended for macular disease with an emphasis on age-related macular degeneration.Current effective therapies include corticosteroids and anti-vascular endothelial growth factor compounds. Recent successes have been reported using anti-angiogenic drugs for therapy of age-related macular degeneration. This review also includes information on implantable devices (biodegradable and non-biodegradable), the use of injected particles (microspheres and liposomes) and future enhanced drug delivery systems, such as ultrasound drug delivery. The devices reviewed show significant drug release over a period of days or weeks. However, macular disorders are chronic diseases requiring years of treatment. Currently, there is no 'gold standard' for therapy and/or drug delivery. Future studies will focus on improving the efficiency and effectiveness of drug delivery to the posterior chamber. If successful, therapeutic modalities will significantly delay loss of vision and improve the quality of life for patients with chronic macular disorders.     

Pulmonary drug delivery systems: recent developments and prospects

Targeting drug delivery into the lungs has become one of the most important aspects of systemic or local drug delivery systems. Consequently, in the last few years, techniques and new drug delivery devices intended to deliver drugs into the lungs have been widely developed. Currently, the main drug targeting regimens include direct application of a drug into the lungs, mostly by inhalation therapy using either pressurized metered dose inhalers (pMDI) or dry powder inhalers (DPI). Intratracheal administration is commonly used as a first approach in lung drug delivery in vivo. To convey a sufficient dose of drug to the lungs, suitable drug carriers are required. These can be either solid, liquid, or gaseous excipients. Liposomes, nano- and microparticles, cyclodextrins, microemulsions, micelles, suspensions, or solutions are all examples of this type of pharmaceutical carrier that have been successfully used to target drugs into the lungs. The use of microreservoir-type systems offers clear advantages, such as high loading capacity and the possibility of controlling size and permeability, and thus of controlling the release kinetics of the drugs from the carrier systems. These systems make it possible to use relatively small numbers of vector molecules to deliver substantial amounts of a drug to the target. This review discusses the drug carriers administered or intended to be administered into the lungs. The transition to CFC-free inhalers and drug delivery systems formulated with new propellants are also discussed. Finally, in addition to the various advances made in the field of pulmonary-route administration, we describe new systems based on perfluorooctyl bromide, which guarantee oxygen delivery in the event of respiratory distress and drug delivery into the lungs.     

Capped mesoporous silica nanoparticles as stimuli-responsive controlled release systems for intracellular drug/gene delivery

Importance of the field: The incorporation of stimuli-responsive properties into nanostructured systems has recently attracted significant attention in the research of intracellular drug/gene delivery. In particular, numerous surface-functionalized, end-capped mesoporous silica nanoparticle (MSN) materials have been designed as efficient stimuli-responsive controlled release systems with the advantageous ‘zero premature release’ property.

Areas covered in this review: Herein, the most recent research progress on the design of biocompatible, capped MSN materials for stimuli-responsive intracellular controlled release of therapeutics and genes is reviewed. A series of hard and soft caps for drug encapsulation and a variety of internal and external stimuli for controlled release of different cargoes are summarized. Recent investigations on the biocompatibility of MSN both in vitro and in vivo are also discussed.

What the reader will gain: The reader will gain an understanding of the challenges for the future exploration of biocompatible stimuli-responsive MSN devices.

Take home message: With a better understanding of the unique features of capped MSN and its behaviors in biological environment, these multifunctional materials will find a wide variety of applications in the field of drug/gene delivery.     

Molecularly imprinted polymers in drug delivery: state of art and future perspectives

INTRODUCTION: Molecularly imprinted polymers (MIPs) are synthetic receptors, characterized by a high selectivity for the selected template. Among the different applications of MIPs, their use as controlled/sustained drug delivery devices has been extensively explored, even though the optimization of such devices needs to be performed before they are applied in clinical practice. AREAS COVERED: Within drug delivery, one of the most promising fields is the possibility to modulate the drug release profile in response to a specific external stimulus; MIPs represent potentially suitable vehicles, because of the possibility to insert a stimuli-responsive co-monomer in their structure. This review discusses recent advances in the use of external stimuli to modulate drug release, as well as the synthetic strategies devoted to increase the water compatibility of these systems, which is a base requirement for their application in biomedicine. EXPERT OPINION: Although it is easy to imagine imprinted polymers for biomedical applications, several aspects have to be further investigated, such as the in vivo studies, efficiency and biocompatibility. However, we think that in the next few years it will possible to see unprecedented progress in the preparation of such systems and the translational application of these intelligent structures in medicine.