Transdermal Delivery Devices: Fabrication,Mechanics and Drug Release from Silk

Microneedles are a relatively simple, minimally invasive and painless approach to deliver drugs across the skin. However, there remain limitations with this approach because of the materials most commonly utilized for such systems. Silk protein, with tunable and biocompatibility properties, is a useful biomaterial to overcome the current limitations with microneedles. Silk devices preserve drug activity, offer superior mechanical properties and biocompatibility, can be tuned for biodegradability, and can be processed under aqueous, benign conditions. In the present work, the fabrication of dense microneedle arrays from silk with different drug release kinetics is reported. The mechanical properties of the microneedle patches are tuned by post‐fabrication treatments or by loading the needles with silk microparticles, to increase capacity and mechanical strength. Drug release is further enhanced by the encapsulation of the drugs in the silk matrix and coating with a thin dissolvable drug layer. The microneedles are used on human cadaver skin and drugs are delivered successfully. The various attributes demonstrated suggest that silk‐based microneedle devices can provide significant benefit as a platform material for transdermal drug delivery.     

Ocular delivery systems for topical application of anti-infective agents

For the treatment of anterior eye segment infections using anti-infective agents, topical ocular application is the most convenient route of administration. However, topical delivery of anti-infective agents is associated with a number of problems and challenges owing to the unique structure of the eye and the physicochemical properties of these compounds. Topical ocular drug delivery systems can be classified into two forms: conventional and non-conventional. The efficacy of conventional ocular formulations is limited by poor corneal retention and permeation resulting in low ocular bioavailability. Recently, attention has been focused on improving topical ocular delivery of anti-infective agents using advanced drug delivery systems. This review will focus on the challenges of efficient topical ocular delivery of anti-infective agents and will discuss the various types of delivery systems used to improve the treatment anterior segment infections.     

Issues and strategies in composite fabrication via friction stir processing: A review

Friction stir processing (FSP) is an expeditiously emerging novel technique involving exterior layer modification, which enables one to successfully fabricate surface composites (SCs) as well as bulk composites of the metal matrix. SCs constitute an exclusive class of composites which exhibit improved surface properties while retaining the bulk properties unaltered. During initiative years, FSP was employed in development of SCs of light metal alloys like aluminum. But, nowadays, it has gained a shining role in the field of SC fabrication of various nonferrous alloys like aluminum, magnesium, copper, and even ferrous metals like steel etc. This article reviews the current trends, various issues, and strategies used to enhance the efficiency of the fabrication process of SCs. Factors involved in the process of SC fabrication are discussed and classified with a new approach. Also, variation of microstructural and mechanical characteristics with these factors is reviewed. In addition to a brief presentation on the interaction between various inputs and their effects on properties, a summary of literature on SC fabrication for different metals is tabulated with prominent results. Subsequently, shortfalls and future perspectives of FSP on SC fabrication domain are discussed.     

Reduced Graphene Oxide Nanohybrid–Assembled Microneedles as Mini‐Invasive Electrodes for Real‐Time Transdermal Biosensing

A variety of nanomaterial‐based biosensors have been developed to sensitively detect biomolecules in vitro, yet limited success has been achieved in real‐time sensing in vivo. The application of microneedles (MN) may offer a solution for painless and minimally‐invasive transdermal biosensing. However, integration of nanostructural materials on microneedle surface as transdermal electrodes remains challenging in applications. Here, a transdermal H₂O₂ electrochemical biosensor based on MNs integrated with nanohybrid consisting of reduced graphene oxide and Pt nanoparticles (Pt/rGO) is developed. The Pt/rGO significantly improves the detection sensitivity of the MN electrode, while the MNs are utilized as a painless transdermal tool to access the in vivo environment. The Pt/rGO nanostructures are protected by a water‐soluble polymer layer to avoid mechanical destruction during the MN skin insertion process. The polymer layer can readily be dissolved by the interstitial fluid and exposes the Pt/rGO on MNs for biosensing in vivo. The applications of the Pt/rGO‐integrated MNs for in situ and real‐time sensing of H₂O₂ in vivo are demonstrated both on pigskin and living mice. This work offers a unique real‐time transdermal biosensing system, which is a promising tool for sensing in vivo with high sensitivity but in a minimally‐invasive manner.     

Buccal Drug Delivery Systems

Buccal administration offers certain unique advantages for the drugs which cannot be easily or efficiently administered by oral or intravenous route. However, transbucccal delivery receiived relatively little attention and few well-controlled studies of buccal mucosa permeability have been conducted. The oral mucosa provides a protective covering for the underlying tissue, being as a barrier for microorganisms and toxins. This article extensively reviews the histology of buccal mucosa, permeation studies (both invitro and in vivo) of buccal drug delivery system, their development and various types of techniques and devices available for the delivery of drugs through buccal mucosa.     

Critical evaluation of permeation enhancers for oral mucosal drug delivery

Background: Drug delivery via oral mucosa is an alternative method of systemic administration for various classes of therapeutic agents. Among the oral mucosae, buccal and sublingual mucosae are the primary focus for drug delivery. Buccal delivery offers a clear advantage over the peroral route by avoidance of intestinal and hepatic first-pass metabolism. However, despite offering the possibility of improved systemic drug delivery, buccal administration has been utilized for relatively few pharmaceutical products so far. One of the major limitations associated with buccal delivery is low permeation of therapeutic agents across the mucosa. Various substances have been explored as permeation enhancers to increase the flux/absorption of drugs through the mucosa, but irritation, membrane damage, and toxicity are always associated with them and limit their use. A clinically accepted permeation enhancer must increase membrane permeability without causing toxicity and permanent membrane damage. To date, the information available on oral mucosal permeation enhancement is much less than transdermal enhancement, though oral mucosa is more resistant to damage than other mucosal membranes. This article reviews the various categories of permeation enhancers for oral mucosal drug delivery, their mechanism of action, their usefulness, and the limitations associated with their use. Conclusion: To optimize the concentration of enhancer to limit its toxicity while facilitating an enhancing effect reproducibly will be a big challenge for future developments. Advances in permeability modulation and formulation with appropriate enhancers can provide for effective and feasible buccal drug delivery for many drugs, which otherwise have to be injected or ingested with water.     

Buccal Drug Delivery Systems

Abstract

Buccal administration offers certain unique advantages for the drugs which cannot be easily or efficiently administered by oral or intravenous route. However, transbucccal delivery receiived relatively little attention and few well-controlled studies of buccal mucosa permeability have been conducted. The oral mucosa provides a protective covering for the underlying tissue, being as a barrier for microorganisms and toxins. This article extensively reviews the histology of buccal mucosa, permeation studies (both invitro and in vivo) of buccal drug delivery system, their development and various types of techniques and devices available for the delivery of drugs through buccal mucosa.     

Xenon Difluoride Dry Etching for the Microfabrication of Solid Microneedles as a Potential Strategy in Transdermal Drug Delivery

Although hypodermic needles are a “gold standard” for transdermal drug delivery (TDD), microneedle (MN)-mediated TDD denotes an unconventional approach in which drug compounds are delivered via micron-size needles. Herein, an isotropic XeF₂ dry etching process is explored to fabricate silicon-based solid MNs. A photolithographic process, including mask writing, UV exposure, and dry etching with XeF₂ is employed, and the MN fabrication is successfully customized by modifying the CAD designs, photolithographic process, and etching conditions. This study enables fabrication of a very dense MNs (up to 1452 MNs cm⁻²) with height varying between 80 and 300 µm. Geometrical features are also assessed using scanning electron microscopy (SEM) and 3D laser scanning microscope. Roughness of the MNs are improved from 0.71 to 0.35 µm after titanium and chromium coating. Mechanical failure test is conducted using dynamic mechanical analyzer to determine displacement and stress/strain values. The coated MNs are subjected to less displacement (≈15 µm) upon the applied force. COMSOL Multiphysics analysis indicates that MNs are safe to use in real-life applications with no fracture. This technique also enables the production of MNs with distinct shape and dimensions. The optimized process provides a wide range of solid MN types to be utilized for epidermis targeting.     

A simple method of microneedle array fabrication for transdermal drug delivery

Abstract

The outermost layer of skin, stratum corneum, being lipophilic limits the passive transport of hydrophilic and large molecular weight drugs. Microfabrication technology has been adapted to fabricate micron scale needles, which are minimally invasive, yet able to deliver the drugs across this barrier layer. In this study, we fabricated microneedles from a biocompatible polymer, namely, poly (ethylene glycol) diacrylate. A simple lithographical approach was developed for microneedle array fabrication. Several factors including polymerization time, ultraviolet light intensity and distance from light source were studied for their effects on microneedle formation. The microneedle length and tip diameter can be controlled by varying these factors. The microneedles were shown to be able to penetrate cadaver pig skin. Model drug rhodamine B was encapsulated in the range of 50 µg to 450 µg per microneedle array. The fabricated microneedles containing rhodamine B increased the permeability by four times than the control. Altogether, we demonstrated that the microneedle arrays can be fabricated through a simple single-step process and needles were mechanically strong to penetrate skin, increasing the permeability of encapsulated drug through skin.     

Permeation Enhancers for Transdermal Drug Delivery

The transdermal route has been recognized as one of the highly potential routes of systemic drug delivery and provides the advantage of avoidance of the first-pass effect, ease of use and withdrawal (in case of side effects), and better patient compliance. However, the major limitation of this route is the difficulty of permeation of drug through the skin. Studies have been carried out to find safe and suitable permeation enhancers to promote the percutaneous absorption of a number of drugs. The present review includes the classification of permeation enhancers and their mechanism of action; thus, it will help in the selection of a suitable enhancer(s) for improving the transdermal permeation of poorly absorbed drugs.     

Permeation enhancers for transdermal drug delivery

The transdermal route has been recognized as one of the highly potential routes of systemic drug delivery and provides the advantage of avoidance of the first-pass effect, ease of use and withdrawal (in case of side effects), and better patient compliance. However, the major limitation of this route is the difficulty of permeation of drug through the skin. Studies have been carried out to find safe and suitable permeation enhancers to promote the percutaneous absorption of a number of drugs. The present review includes the classification of permeation enhancers and their mechanism of action; thus, it will help in the selection of a suitable enhancer(s) for improving the transdermal permeation of poorly absorbed drugs.     

Microemulsions as transdermal drug delivery systems for nonsteroidal anti-inflammatory drugs (NSAIDs): a literature review

Abstract

Pain is a global crisis and significant efforts have gone into the development of drugs that can be used to treat pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of analgesics that act to selectively relieve pain and inflammation without significantly altering consciousness. Although there have been many advancements with NSAIDs drug development; these drugs still present with severe adverse effects and toxicities, which often limits their use in many patients. Moreover, others are inadequate in relieving specific types of pain such as localized or nerve pain because of poor systemic absorption with conventional delivery systems. The topical route of drug delivery has been used to avoid many of these effects, but not without challenges of its own. The skin acts as an impermeable barrier to most polar drug candidate and absorption across the dermal membranes is often too slow and incomplete to produce meaningful therapeutic benefit. Nevertheless, the use of microemulsions as topical delivery systems for small molecule drug candidates like NSAIDs has been posited as a solution to this problem for years. This review focuses on the recent use of microemulsions as a probable solution to the challenges of transdermal drug delivery of NSAIDs and how microemulsions may be used to enhance the development of more effective but safer analgesic drug products for patients.     

Designing drug-loaded multi-layered polymeric microparticles

This work reports how novel multi-layered (from double-layered to quadruple-layered) microparticles comprising immiscible polymers can be fabricated through a simple, economical, reliable and versatile one-step solvent evaporation method. These multi-layered microparticles would be excellent candidates to overcome problems inherent in single-layered microparticles for drug delivery. Particle morphologies, layer configurations, and drug distribution were determined by scanning electron microscopy and Raman mapping. Key process parameters achieving the formation of the multi-layered structure were identified. Encapsulation of multiple drugs and layer localization of these drugs within these multi-layered microparticles have also shown to be possible, which were driven by drug-polymer affinity. This one-step fabrication technique can therefore be used for tailoring particle designs, thus facilitating the development of multiparticulate drug delivery devices.     

One‐Step Fabrication of Triple‐Layered Polymeric Microparticles with Layer Localization of Drugs as a Novel Drug‐Delivery System

Particulate systems have tremendous potential to achieve controlled release and targeted delivery of drugs. However, conventional single‐layered particles have several inherent limitations, including initial burst release, the inability to provide zero‐order release, and a lack of time‐delayed or pulsatile release of therapeutic agents. Multilayered particles have the potential to overcome these disadvantages. Herein, it is shown how triple‐layered polymeric microparticles can be fabricated through a simple, economical, reliable, and versatile one‐step solvent evaporation technique. Particle morphologies and layer configurations are determined by scanning electron microscopy, polymer dissolution tests, and Raman mapping. Key fabrication parameters that affect the formation of triple‐layered polymeric microparticles comprising poly(DL ‐lactide‐co‐glycolide) (50:50), poly(L ‐lactide), and poly(ethylene‐co‐vinyl acetate) (40 wt% vinyl acetate) are discussed, along with their formation mechanisms. Layer thickness and the configurations of these microparticles are altered by changing the polymer mass ratios. Finally, it is shown that drugs can be localized in specific layers of the microparticles. This fabrication process can therefore be used to tailor microparticle designs, thus allowing such “designer” particulate drug‐delivery systems to function across a wide range of applications.     

Nanomedicine-nanoscale drugs and delivery systems

Significant progress has been made in nanoscale drugs and delivery systems employing diverse chemical formulations to facilitate the rate of drug delivery and release from the human body. The biocompatible nanomaterials have been used in biological markers, contrast agents for biological imaging, healthcare products, pharmaceuticals, drug-delivery systems as well as in detection, diagnosis and treatment of various types of diseases. Nanomedicines offer delivery of potential drugs to human organs which were previously beyond reach of microscale drugs due to specific biological barriers. The nanoscale systems work as nanocarriers for the delivery of drugs. The nanocarriers are made of biocompatible and biodegradable materials such as synthetic proteins, peptides, lipids, polysaccharides, biodegradable polymers and fibers. This review article reports the recent developments in the field of nanomedicine covering biodegradable polymers, nanoparticles, cyclodextrin, dendrimeres, liposomes and lipid-based nanocarriers, nanofibers, nanowires and carbon nanotubes and their chemical functionalization for distribution to different organs, their solubility, surface, chemical and biological properties, stability and release systems. The toxicity and safety of nanomaterials on human health is also briefly discussed.     

Rapidly dissolving fibroin microneedles for transdermal drug delivery

This paper presents rapidly dissolving fibroin microneedles (MNs) for the first time. A reverse PDMS MNs mold was first created and drug-contained fibroin solution was poured into this reverse PDMS MNs mold. Fibroin MNs were successfully fabricated after fan drying and detaching the solidified drug-contained fibroin structure from the PDMS mold. The fibroin serves as a matrix to incorporate drug molecules while maintaining the drug activity. The dimensions of the fabricated fibroin MNs are 500 μm in length, 200 μm in diameter at the base, and 5 μm in radius at the tip. These fibroin MNs can dissolve within minutes under the skin to release the drug molecules and the dissolved fibroin in the skin generates noninflammatory amino acid degradation products usable in cell metabolic functions. The fibroin MNs containing methylene blue as a drug were fabricated and their surface morphology, internal structure, mechanical property, and the dissolving characteristics were analyzed. These rapidly dissolving fibroin MNs provide more benefit than conventional syringes for painless transdermal drug delivery.     

Spatiotemporal Catalytic Nanozymes Microneedle Patches with Opposite Properties for Wound Management

Reactive oxygen species (ROS)-mediated biological catalysis involves serial programmed enzymatic reactions and plays an important part against infectious diseases; while the spatiotemporal control of catalytic treatment to break the limitations of the disease microenvironment is challenging. Here, a novel spatiotemporal catalytic microneedles patch (CMSP-MNs) integrated with dual-effective Cu₂MoS₄ (CMS) and polydopamine (PDA) nanoparticles (NPs) for breaking microenvironment restrictions to treat wound infections is designed. Since CMS NPs are loaded in the needles, CMSP-MNs can catalytically generate diverse ROS to cause effective bacterial inactivation during bacterial infection process. Besides, PDA NPs are encapsulated in the backing layer, which facilitate ROS elimination and oxygen production for solving hypoxic problems in wound microenvironment and alleviating the expression of inflammatory factors during the inflammation process. Based on these features, it is demonstrated through cell and animal experiments that these nanozymes-integrated MNs patches can realize selective regulation of ROS level with bacterial inactivation and inflammatory treatment, resulting in minimized side effects of over-production ROS and effective anti-infected treatment. It is believed that the presented MNs can provide a new therapeutic strategy with spatiotemporal adjustable catalytic properties in biomedical areas.     

Recent advances in ocular drug delivery

Amongst the various routes of drug delivery, the field of ocular drug delivery is one of the most interesting and challenging endeavors facing the pharmaceutical scientist. Recent research has focused on the characteristic advantages and limitations of the various drug delivery systems, and further research will be required before the ideal system can be developed. Administration of drugs to the ocular region with conventional delivery systems leads to short contact time of the formulations on the epithelium and fast elimination of drugs. This transient residence time involves poor bioavailability of drugs which can be explained by the tear production, non-productive absorption and impermeability of corneal epithelium. Anatomy of the eye is shortly presented and is connected with ophthalmic delivery and bioavailability of drugs. In the present update on ocular dosage forms, chemical delivery systems such as prodrugs, the use of cyclodextrins to increase solubility of various drugs, the concept of penetration enhancers and other ocular drug delivery systems such as polymeric gels, bioadhesive hydrogels, in-situ forming gels with temperature-, pH-, or osmotically induced gelation, combination of polymers and colloidal systems such as liposomes, niosomes, cubosomes, microemulsions, nanoemulsions and nanoparticles are discussed. Novel ophthalmic delivery systems propose the use of many excipients to increase the viscosity or the bioadhesion of the product. New formulations like gels or colloidal systems have been tested with numerous active substances by in vitro and in vivo studies. Sustained drug release and increase in drug bioavailability have been obtained, offering the promise of innovation in drug delivery systems for ocular administration. Combining different properties of pharmaceutical formulations appears to offer a genuine synergy in bioavailability and sustained release. Promising results are obtained with colloidal systems which present very comfortable conditions of use and prolonged action.     

The Enhanced Iontophoretic Transport of TRH and Its Impedance Study

The transdermal drug delivery of iontophoresis provides a noninvasive method for the administration of effective drugs. The enhanced iontophoretic transport of thyrotropin-releasing hormone (TRH), a tripeptide with molecular weight of 362 and a pK_a of 6.2, through an excised rabbit skin has been achieved by in vitro iontophoresis. The results indicate that the steady-state flux of TRH in a diffusion cell is proportional to the current density. In addition, the electrochemical properties of rabbit skin were studied with impedance spectroscopy, and it was found that the skin impedance decreased to a low and stable value with respect to its initial skin impedance while a current was applied through the rabbit skin. This is in good agreement with our experimental results on iontophoretic transport. As compared to passive diffusion, the iontophoresis dramatically increased the transport fluxes of TRH, and ethanol pretreatment further enhanced its iontophoretic transport. A practical implication of these results is that iontophoresis with a chemical permeation enhancer (ethanol pretreatment) can be applied to enhance and control the transdermal delivery of peptides.     

Atomic layer deposition on phase-shift lithography generated photoresist patterns for 1D nanochannel fabrication

A versatile, low-cost, and flexible approach is presented for the fabrication of millimeter-long, sub-100 nm wide 1D nanochannels with tunable wall properties (wall thickness and material) over wafer-scale areas on glass, alumina, and silicon surfaces. This approach includes three fabrication steps. First, sub-100 nm photoresist line patterns were generated by near-field contact phase-shift lithography (NFC-PSL) using an inexpensive homemade borosilicate mask (NFC-PSM). Second, various metal oxides were directly coated on the resist patterns with low-temperature atomic layer deposition (ALD). Finally, the remaining photoresist was removed via an acetone dip, and then planar nanochannel arrays were formed on the substrate. In contrast to all the previous fabrication routes, the sub-100 nm photoresist line patterns produced by NFC-PSL are directly employed as a sacrificial layer for the creation of nanochannels. Because both the NFC-PSL and the ALD deposition are highly reproducible processes, the strategy proposed here can be regarded as a general route for nanochannel fabrication in a simplified and reliable manner. In addition, the fabricated nanochannels were used as templates to synthesize various organic and inorganic 1D nanostructures on the substrate surface.