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.     

Intelligent drug delivery systems: polymeric micelles and hydrogels

Advanced drug delivery systems try to adjust the site and/or the rate of the release to the physiological conditions of the patient, to the progression of the illness, or to the circadian rhythms. Being different from classical pre-programmed controlled release dosage forms, the new devices aim to provide the drug release profile best for the needs of each patient. Intelligent drug delivery systems are mostly based on stimuli-responsive polymers which sense a change in a specific variable and activate the delivery; this phenomenon being reversible. This review reports on recent advances in the development of open-loop and closed-loop control systems based on stimuli-responsive polymers and their application in the drug delivery field as pulsatile and self-regulated devices. The aim of this review is to describe the most recent advances in the development of intelligent micelles and hydrogels which are sensitive to pH, specific molecules (with a mention to the molecular imprinting), temperature, irradiation or electric field, and the applications of which these mechanisms are intended.     

Hydrogels in controlled release formulations: network design and mathematical modeling

Over the past few decades, advances in hydrogel technologies have spurred development in many biomedical applications including controlled drug delivery. Many novel hydrogel-based delivery matrices have been designed and fabricated to fulfill the ever-increasing needs of the pharmaceutical and medical fields. Mathematical modeling plays an important role in facilitating hydrogel network design by identifying key parameters and molecule release mechanisms. The objective of this article is to review the fundamentals and recent advances in hydrogel network design as well as mathematical modeling approaches related to controlled molecule release from hydrogels. In the first section, the niche roles of hydrogels in controlled release, molecule release mechanisms, and hydrogel design criteria for controlled release applications are discussed. Novel hydrogel systems for drug delivery including biodegradable, smart, and biomimetic hydrogels are reviewed in the second section. Several mechanisms have been elucidated to describe molecule release from polymer hydrogel systems including diffusion, swelling, and chemically-controlled release. The focus of the final part of this article is discussion of emerging hydrogel delivery systems and challenges associated with modeling the performance of these devices.     

Hydrogels: Swelling,Drug Loading,and Release

Hydrogels have been used by many investigators in controlled-release drug delivery systems because of their good tissue compatibility and easy manipulation of swelling level and, thereby, solute permeability. The desired kinetics, duration, and rate of solute release from hydrogels are limited to specific conditions, such as hydrogel properties, amount of incorporated drug, drug solubility, and drug–polymer interactions. This review summarizes the compositional and structural effects of polymers on swelling, loading, and release and approaches to characterize solute release behavior in a dynamic state. A new approach is introduced to compensate drug effects (solubility and loading) with the release kinetics by varying the structure of heterogeneous polymers. Modulated or pulsatile drug delivery using functional hydrogels is a recent trend in hydrogel drug delivery.     

Oral pulsatile delivery systems based on swellable hydrophilic polymers.

Upon contact with aqueous fluids, swellable hydrophilic polymers undergo typical chain relaxation phenomena that coincide with a glassy-rubbery transition. In the rubbery phase, these polymers may be subject to swelling, dissolution and erosion processes or, alternatively, form an enduring gel barrier when cross-linked networks (hydrogels) are dealt with. Because of the peculiar hydration and biocompatibility properties, such materials are widely exploited in the pharmaceutical field, particularly as far as hydrophilic cellulose derivatives are concerned. In oral delivery, they have for long been employed in the manufacturing of prolonged release matrices and, more recently, for pulsatile (delayed) release devices as well. 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. In pursuit of pulsatile release, various design strategies have been proposed, chiefly including reservoir, capsular and osmotic formulations. In most cases, water-swellable polymers play a key role in the overall delivery mechanism after being activated by physiological media. Based on these premises, the aim of the present review is to survey the main oral pulsatile delivery systems, for which swelling, dissolution and/or erosion of hydrophilic polymers are primarily involved in the control of release.     

Chitosan-based hydrogels for controlled, localized drug delivery

Hydrogels are high-water content materials prepared from cross-linked polymers that are able to provide sustained, local delivery of a variety of therapeutic agents. Use of the natural polymer, chitosan, as the scaffold material in hydrogels has been highly pursued thanks to the polymer's biocompatibility, low toxicity, and biodegradability. The advanced development of chitosan hydrogels has led to new drug delivery systems that release their payloads under varying environmental stimuli. In addition, thermosensitive hydrogel variants have been developed to form a chitosan hydrogel in situ, precluding the need for surgical implantation. The development of these intelligent drug delivery devices requires a foundation in the chemical and physical characteristics of chitosan-based hydrogels, as well as the therapeutics to be delivered. In this review, we investigate the newest developments in chitosan hydrogel preparation and define the design parameters in the development of physically and chemically cross-linked hydrogels.     

脉冲给药系统的研究进展

脉冲给药系统是根据时辰药理学与时辰治疗学特点研究而设计的一种新型迟释给药制剂。文章查阅了近几年国内外相关文献,阐述了脉冲给药系统的释药机制,包括生物化学刺激(胃肠道酸碱度、酶敏感度、葡萄糖敏感度等),物理化学刺激(声波、磁场、电场、温度等),膨胀爆破释药机制以及定时脉冲塞胶囊释药机制,并总结了基于各类释药机制的脉冲释药系统在药剂学中的应用研究进展。     

Implantable microchip: the futuristic controlled drug delivery system

There is no doubt that controlled and pulsatile drug delivery system is an important challenge in medicine over the conventional drug delivery system in case of therapeutic efficacy. However, the conventional drug delivery systems often offer a limited by their inability to drug delivery which consists of systemic toxicity, narrow therapeutic window, complex dosing schedule for long term treatment etc. Therefore, there has been a search for the drug delivery system that exhibit broad enhancing activity for more drugs with less complication. More recently, some elegant study has noted that, a new type of micro-electrochemical system or MEMS-based drug delivery systems called microchip has been improved to overcome the problems related to conventional drug delivery. Moreover, micro-fabrication technology has enabled to develop the implantable controlled released microchip devices with improved drug administration and patient compliance. In this article, we have presented an overview of the investigations on the feasibility and application of microchip as an advanced drug delivery system. Commercial manufacturing materials and methods, related other research works and current advancement of the microchips for controlled drug delivery have also been summarized.     

Thermosensitive hydrogels for drug delivery

INTRODUCTION: Controlled drug delivery has been widely applied in areas such as cancer therapy and tissue regeneration. Thermosensitive hydrogel-based drug delivery systems have increasingly attracted the attention of the drug delivery community, as the drugs can be readily encapsulated and released by the hydrogels. AREAS COVERED: Thermosensitive hydrogels that can serve as drug carriers are discussed in this paper. Strategies used to control hydrogel properties, in order to tailor drug release kinetics, are also reviewed. This paper also introduces applications of the thermosensitive hydrogel-based drug delivery systems in cancer therapy and tissue regeneration. EXPERT OPINION: When designing a drug delivery system using thermosensitive hydrogels, one needs to consider what type of thermosensitive hydrogel needs to be used, and how to manipulate its properties to meet the desired drug release kinetics. For material selection, both naturally derived and synthetic thermosensitive polymers can be used. Various methods can be used to tailor thermosensitive hydrogel properties in order to achieve the desired drug release profile.     

Oral pulsatile drug delivery systems

In the field of modified release, there has been a growing interest in pulsatile delivery, which generally refers to the liberation of drugs following a programmable lag phase from the time of administration. In particular, the recent literature reports on a variety of pulsatile release systems intended for the oral route, which have been recognised as potentially beneficial to the chronotherapy of widespread diseases, such as bronchial asthma or angina pectoris, with mainly night or early morning symptoms. In addition, time-dependent colon delivery may also represent an appealing related application. The delayed liberation of orally administered drugs has been achieved through a range of formulation approaches, including single- or multiple-unit systems provided with release-controlling coatings, capsular devices and osmotic pumps. Based on these premises, the aim of this review is to outline the rational and prominent design strategies behind oral pulsatile delivery.     

Oral pulsatile drug delivery systems

In the field of modified release, there has been a growing interest in pulsatile delivery, which generally refers to the liberation of drugs following a programmable lag phase from the time of administration. In particular, the recent literature reports on a variety of pulsatile release systems intended for the oral route, which have been recognised as potentially beneficial to the chronotherapy of widespread diseases, such as bronchial asthma or angina pectoris, with mainly night or early morning symptoms. In addition, time-dependent colon delivery may also represent an appealing related application. The delayed liberation of orally administered drugs has been achieved through a range of formulation approaches, including single- or multiple-unit systems provided with release-controlling coatings, capsular devices and osmotic pumps. Based on these premises, the aim of this review is to outline the rational and prominent design strategies behind oral pulsatile delivery.     

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.     

Temperature-sensitive hydrogels by graft polymerization of chitosan and N-isopropylacrylamide for drug release

Thermo-responsive polysaccharidic hydrogels were designed and synthesized by a free radical induced grafting procedure. Chitosan was chosen as biopolymer to impart biocompatibility and biodegradability to the macromolecular systems, while N-isopropylacrylamide (NIPAAm) was selected as co-monomer responsive for the thermo-sensitive properties. Ammonium persulfate was the initiator system and different polymeric networks have been synthesized by modulating the amount of NIPAAm in the polymerization feed. The resulting hydrogels were proposed as drug delivery devices and their performance was evaluated by using Diclofenac sodium salt as a model drug. Hydrogels were carefully characterized by FT-IR spectrophotometry, calorimetric analyses and swelling behavior in a temperature range of 15–45°C. Finally, to verify the suitability of these hydrogels as thermo-responsive devices, the drug release profiles were studied performing in vitro experiments around the swelling-shrinking transition temperatures of the macromolecular systems.     

Thermosensitive hydrogels for drug delivery

Introduction: Controlled drug delivery has been widely applied in areas such as cancer therapy and tissue regeneration. Thermosensitive hydrogel-based drug delivery systems have increasingly attracted the attention of the drug delivery community, as the drugs can be readily encapsulated and released by the hydrogels.

Areas covered: Thermosensitive hydrogels that can serve as drug carriers are discussed in this paper. Strategies used to control hydrogel properties, in order to tailor drug release kinetics, are also reviewed. This paper also introduces applications of the thermosensitive hydrogel-based drug delivery systems in cancer therapy and tissue regeneration.

Expert opinion: When designing a drug delivery system using thermosensitive hydrogels, one needs to consider what type of thermosensitive hydrogel needs to be used, and how to manipulate its properties to meet the desired drug release kinetics. For material selection, both naturally derived and synthetic thermosensitive polymers can be used. Various methods can be used to tailor thermosensitive hydrogel properties in order to achieve the desired drug release profile.     

Improving the loading and release of NSAIDs from pHEMA hydrogels by copolymerization with functionalized monomers

Poly(hydroxyethyl methacrylate), pHEMA, hydrogels are widely used for preparing implants, contact lenses, and other biomedical devices, which in many circumstances should load drugs to deliver them in the adjacent tissues. To enhance the potential of pHEMA hydrogels as nonsteroidal anti-inflammatory drugs (NSAIDs) delivery systems, 4-vinyl-pyridine (VP) and N-(3-aminopropyl) methacrylamide (APMA) were incorporated to the network (25-150 mM). The incorporated monomers did not change the viscoelastic properties neither the state of water, but remarkably increased the amount of ibuprofen (up to 10-fold) and diclofenac (up to 20-fold) loaded. Dried loaded pHEMA-APMA and pHEMA-VP hydrogels quickly swelled in water but ionic/hydrophobic interactions prevented the amount of drug released to be above 10%. By contrast, once the water-swollen hydrogels were transferred to pH 5.8 or 8.0 phosphate buffers or NaCl solutions, the release was prompted by competition with ions of the medium. The remaining of hydrophobic interactions and the high polymeric density of the pHEMA hydrogels contributed to sustain the release process for at least 24 h for ibuprofen and almost 1 week for diclofenac. The release rate was independent of the salt content and pH in the physiological range of values, which enables the design of hydrogel-based delivery systems with predictable release rate.     

Hydrogels: from controlled release to pH-responsive drug delivery

Hydrogels are one of the upcoming classes of polymer-based controlled-release drug delivery systems. Besides exhibiting swelling-controlled drug release, hydrogels also show stimuli-responsive changes in their structural network and hence, the drug release. Because of large variations in physiological pH at various body sites in normal as well as pathological conditions, pH-responsive polymeric networks have been extensively studied. This review highlights the use of hydrogels (a class of polymeric systems) in controlled drug delivery, and their application in stimuli-responsive, especially pH-responsive, drug release.     

Passive transdermal drug delivery systems

The skin has evolved as a formidable barrier against invasion by external microorganisms and against the prevention of water loss. Notwithstanding this, transdermal drug delivery systems have been designed with the aim of providing continuous controlled delivery of drugs via this barrier to the systemic circulation. There are numerous systems now available that effectively deliver drugs across the skin. These include reservoir devices, matrix diffusion-controlled devices, multiple polymer devices, and multilayer matrix systems. This review article focuses on the design characteristics and composition of the main categories of passive transdermal delivery device available. Mechanisms controlling release of the active drug from these systems as well as patch size and irritation problems will be considered. Recent developments in the field are highlighted including advances in patch design as well as the increasing number of drug molecules now amenable to delivery via this route. From the early complex patch designs, devices have now evolved towards simpler, matrix formulations. One of the newer technologies to emerge is the delivery-optimized thermodynamic (DOT) patch system, which allows greater drug loading to be achieved in a much smaller patch size. With the DOT technology, drug is loaded in an acrylic-based adhesive. The drug/acrylic blend is dispersed through silicone adhesive, creating a semi-solid suspension. This overcomes the problem with conventional drug-in-adhesive matrix patches, in which a large drug load in the adhesive reservoir can compromise the adhesive properties or necessitate a large patch size. Transdermal drug delivery remains an attractive and evolving field offering many benefits over alternative routes of drug delivery. Future developments in the field should address problems relating to irritancy and sensitization, which currently exclude a number of therapeutic entities from delivery via this route. It is likely that further innovations in matrix composition and formulation will further expand the number of candidate drugs available for transdermal delivery.     

Surface crosslinking for delayed release of proxyphylline from PHEMA hydrogels

Delayed release systems find applications in chronotherapeutics and colon-specific delivery. They have also been considered suitable carriers for the oral delivery of peptides and proteins. In prior work, our research group has reported surface crosslinking as an effective technique to modify drug release profiles for poly(vinyl alcohol) (PVA) hydrogels, reducing the early burst effect in particular. Here, we demonstrate the feasibility of delayed release of proxyphylline from poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogels via surface crosslinking. Studies on in vitro drug release and the morphology changes of PHEMA hydrogels during swelling and drug release showed that the highly surface crosslinked layers and the ruptures occurring in these layers during swelling were likely responsible for the delayed release. In addition, the initial burst was significantly reduced or even eliminated from the drug release profile for PHEMA to achieve near zero-order release by judicious selection of two surface crosslinking parameters: crosslinking reagent concentration and exposure time used for the surface crosslinking treatment.     

The impact of nanobiotechnology on the development of new drug delivery systems

Nanotechnology, or systems/devices manufactured at the molecular level, is a multidisciplinary scientific field undergoing explosive development. A part of this field is the development of nanoscaled drug delivery devices. Nanoparticles have been developed as an important strategy to deliver conventional drugs, recombinant proteins, vaccines and more recently nucleotides. Nanoparticles and other colloidal drug delivery systems modify the kinetics, body distribution and drug release of an associated drug. Other effects are tissue or cell specific targeting of drugs and the reduction of unwanted side effects by a controlled release. Therefore nanoparticles in the pharmaceutical biotechnology sector improve the therapeutic index and provide solutions for future delivery problems for new classes of so called biotech drugs including recombinant proteins and oligonucleotides. This review discusses nanoparticular drug carrier systems with the exception of liposomes used today, and what the potential and limitations of nanoparticles in the field of pharmaceutical biotechnology are.     

Application of Micro- and Nano-Electromechanical Devices to Drug Delivery

Micro- and nano-electromechanical systems (MEMS and NEMS)-based drug delivery devices have become commercially-feasible due to converging technologies and regulatory accommodation. The FDA Office of Combination Products coordinates review of innovative medical therapies that join elements from multiple established categories: drugs, devices, and biologics. Combination products constructed using MEMS or NEMS technology offer revolutionary opportunities to address unmet medical needs related to dosing. These products have the potential to completely control drug release, meeting requirements for on-demand pulsatile or adjustable continuous administration for extended periods. MEMS or NEMS technologies, materials science, data management, and biological science have all significantly developed in recent years, providing a multidisciplinary foundation for developing integrated therapeutic systems. If small-scale biosensor and drug reservoir units are combined and implanted, a wireless integrated system can regulate drug release, receive sensor feedback, and transmit updates. For example, an “artificial pancreas” implementation of an integrated therapeutic system would improve diabetes management. The tools of microfabrication technology, information science, and systems biology are being combined to design increasingly sophisticated drug delivery systems that promise to significantly improve medical care.