A current era in pulsatile drug delivery system: Drug journey based on chronobiology.

Almost all biological processes in the human body are regulated by circadian rhythm, which results in drastically different biochemical and physiological conditions throughout a 24 h period. Hence, suitable drug delivery systems should be efficiently monitored to attain the required therapeutic plasma concentration and therapeutic drug responses when needed as per chrono pharmacological concepts. "Chronotherapy" is the fast and transient release of a particular quantity of drug substance post a predetermined off-release period, termed as 'lag time'. Due to rhythmic variations, it is typically unnecessary to administer a medicine drug in an unhealthy condition constantly. Pulsatile drug delivery systems have received a lot of attention in pharmaceutical development because they give a quick or rate-controlled drug release after administration, followed by an anticipated lag period. Patients with various illnesses, such as asthma, hypertension, joint inflammation, and ulcers, can benefit from a pulsatile drug delivery system. Thus, a pulsatile drug delivery system may be a potential system for managing different diseases. This review mainly focuses on pulsatile drug delivery systems. It reviews and discusses the rationale, drug release mechanism, need, and system classification. In addition, it covers mainly externally regulated pulsatile drug delivery systems and recent advances in pulsatile systems like artificial intelligence and 3D printing. It also covers the ethical issues associated with pulsatile drug delivery systems.

Unlocking the potential of nanocarrier-mediated mRNA delivery across diverse biomedical frontiers: A comprehensive review.

Messenger RNA (mRNA) has gained marvelous attention for managing and preventing various conditions like cancer, Alzheimer's, infectious diseases, etc. Due to the quick development and success of the COVID-19 mRNA-based vaccines, mRNA has recently grown in prominence. A lot of products are in clinical trials and some are already FDA-approved. However, still improvements in line of optimizing stability and delivery, reducing immunogenicity, increasing efficiency, expanding therapeutic applications, scalability and manufacturing, and long-term safety monitoring are needed. The delivery of mRNA via a nanocarrier system gives a synergistic outcome for managing chronic and complicated conditions. The modified nanocarrier-loaded mRNA has excellent potential as a therapeutic strategy. This emerging platform covers a wide range of diseases, recently, several clinical studies are ongoing and numerous publications are coming out every year. Still, many unexplained physical, biological, and technical problems of mRNA for safer human consumption. These complications were addressed with various nanocarrier formulations. This review systematically summarizes the solved problems and applications of nanocarrier-based mRNA delivery. The modified nanocarrier mRNA meaningfully improved mRNA stability and abridged its immunogenicity issues. Furthermore, several strategies were discussed that can be an effective solution in the future for managing complicated diseases.

Nanofibers: A current era in drug delivery system.

Nanofibers have a large area of surface variable 3D topography, porosity, and adaptable surface functions. Several researchers are researching nanofiber technology as a potential solution to the current problems in several fields. It manages cardiovascular disorders, infectious diseases, gastrointestinal tract-associated diseases, neurodegenerative diseases, pain treatment, contraception, and wound healing. The nanofibers are fabricated using various fabrication techniques, such as electrospinning, phase separation, physical Fabrication, and chemical fabrication. Depending on their intended use, nanofibers are manufactured using a variety of polymers. It comprises natural polymers, semi-synthetic polymers, synthetic polymers, metals, metal oxides, ceramics, carbon, nonporous materials, mesoporous materials, hollow structures, core-shell structures, biocomponents, and multi-component materials. Nanofiber composites are a good alternative for targeted gene delivery, protein and peptide delivery, and growth factor delivery. Thus, nanofibers have huge potential in drug delivery, which enables them to be used for various applications and can revolutionize these therapeutic areas. This review systematically studied nanofibers' history, advantages, disadvantages, types, and polymers used in nanofiber technology. Further, polymers and their types used in the preparation of nanofibers were summarised. Mainly review article focuses on the fabrication method, i.e., electrospinning and its types. Finally, the article discussed the applications and recent advancements of nanofabrication technology.

An emerging era in manufacturing of drug delivery systems: Nanofabrication techniques.

Nanotechnology has the capability of making significant contributions to healthcare. Nanofabrication of multifunctional nano- or micro-character systems is becoming incredibly influential in various sectors like electronics, photonics, energy, and biomedical gadgets worldwide. The invention of such items led to the merger of moderate cost and excellent quality nano or micro-characters into 3D structures. Nanofabrication techniques have many benefits as the primary technology for manipulating cellular surroundings to research signaling processes. The inherent nanoscale mechanisms of cyto-reactions include the existence and death of cells, stem cell segmentation, multiplication, cellular relocation, etc. Nanofabrication is essential in developing various nano-formulations like solid lipid nanoparticles, nanostructured lipid carriers, liposomes, niosomes, nanoemulsions, microemulsions etc. Despite the initial development cost in designing the nanofabrication-based products, it has also reduced the total cost of the healthcare system by considering the added benefits compared to the other standard formulations. Thus, the current review mainly focuses on nanofabrication techniques, advantages, disadvantages, applications in developing various nanocarrier systems, challenges and future perspectives.

Advances in 4D printing: from stimulation to simulation.

The advancement of four-dimensional (4D) printing has been fueled by the rise in demand for additive manufacturing and the expansion in shape-memory materials. The printing of smart substances that respond to external stimuli is known as 4D printing. 4D printing allows highly controlled shapes to simulate the physiological milieu by adding time dimensions. The 4D printing is suitable with current progress in smart compounds, printers, and its mechanism of action. The 4D printing paradigm, a revolutionary enhancement of 3D printing, was anticipated by various engineering disciplines. Tissue engineering, medicinal, consumer items, aerospace, and organ engineering use 4D printing technology. The current review mainly focuses on the basics of 4D printing and the methods used therein. It also discusses the time-dependent behavior of stimulus-sensitive compounds, which are widely used in 4D printing. In addition, this review highlights material aspects, specifically related to shape-memory polymers, stimuli-responsive materials (classified as physical, chemical, and biological), and modified materials, the backbone of 4D printing technology. Finally, potential applications of 4D printing in the biomedical sector are also discussed with challenges and future perspectives.

Development and characterization of amphotericin B nanoemulsion-loaded mucoadhesive gel for treatment of vulvovaginal candidiasis.

Despite being recognized as the "gold standard" for treating azole-resistant vulvovaginal candidiasis, amphotericin B (AmB), an amphoteric molecule, has not been widely used due to serious issues with solubility and permeability. In light of the aforementioned, the objective of the present study was to increase AmB's therapeutic efficacy by formulating it into an o/w nanoemulsion (AmB-NE) system. Furthermore, to facilitate AmB-NE's retention within the vaginal cavity, it was loaded into a mixture of Carbopol® 974P and Aloe vera-based gel (CA gel). Briefly, in the present study, a kinetically stable batch of formulated AmB-NE having a globule size of 76.52 ± 3.11 nm, PDI of 0.342 ± 0.032, and zeta potential of -22.32 ± 0.88 mV was incorporated into the CA gel base. This AmB-NE loaded gel (AmB-NE gel) exhibited a non-Fickian/anomalous diffusion from the hydrophilic matrix. The texture analysis of AmB-NE gel revealed that the prepared gel was a non-drip, soft, easy to spread, and sufficiently cohesive gel that could reside in the vaginal cavity, which was confirmed by our ex-vivo retention test, which revealed that AmB-NE loaded gel could stay in the vaginal cavity for approximately 11 h. Ex-vivo skin permeation studies revealed that AmB-NE is 4.26 times more permeable than AmB-coarse gel, implying that AmB-NE facilitates AmB entry into the vaginal epithelial layers. Furthermore, in-vivo vaginal lavage studies revealed that AmB-NE gel permeated 7.03-fold more than AmB-coarse gel. Prepared AmB-NE gel was stable in refrigerated condition and showed no histopathological toxicity. Thus, the present study suggests that AmB-NE gel could eliminate the existing problem of AmB and that it could serve as an alternative option to treat vulvovaginal candidiasis.

Exosomes as New Generation Vehicles for Drug Delivery: Biomedical Applications and Future Perspectives.

Currently, particular interest among the scientific community is focused on exploring the use of exosomes for several pharmaceutical and biomedical applications. This is due to the identification of the role of exosomes as an excellent intercellular communicator by delivering the requisite cargo comprising of functional proteins, metabolites and nucleic acids. Exosomes are the smallest extracellular vesicles (EV) with sizes ranging from 30-100 nm and are derived from endosomes. Exosomes have similar surface morphology to cells and act as a signal transduction channel between cells. They encompass different biomolecules, such as proteins, nucleic acids and lipids, thus rendering them naturally as an attractive drug delivery vehicle. Like the other advanced drug delivery systems, such as polymeric nanoparticles and liposomes to encapsulate drug substances, exosomes also gained much attention in enhancing therapeutic activity. Exosomes present many advantages, such as compatibility with living tissues, low toxicity, extended blood circulation, capability to pass contents from one cell to another, non-immunogenic and special targeting of various cells, making them an excellent therapeutic carrier. Exosome-based molecules for drug delivery are still in the early stages of research and clinical trials. The problems and clinical transition issues related to exosome-based drugs need to be overcome using advanced tools for better understanding and systemic evaluation of exosomes. In this current review, we summarize the most up-to-date knowledge about the complex biological journey of exosomes from biogenesis and secretion, isolation techniques, characterization, loading methods, pharmaceutical and therapeutic applications, challenges and future perspectives of exosomes.

Nasal delivery of neurotherapeutics via nanocarriers: Facets, aspects, and prospects.

Alzheimer's disease (AD) is one of the neurological ailments which continue to represent a major public health challenge, owing to increased life expectancy and aging population. Progressive memory loss and decrease in cognitive behavior, owing to irreversible destruction of neurons along with expensive therapeutic interventions, call for an effective, alternate, yet affordable treatment for Alzheimer's disease. Safe and effective delivery of neurotherapeutics in Alzheimer's like central nervous system (CNS) disorders still remains elusive despite the major advances in both neuroscience and drug delivery research. The blood-brain barrier (BBB) with its tight endothelial cell layer surrounded by astrocyte foot processes poses as a major barrier for the entry of drugs into the brain. Nasal drug delivery has emerged as a reliable method to bypass this blood-brain barrier and deliver a wide range of neurotherapeutic agents to the brain effectively. This nasal route comprises the olfactory or trigeminal nerves originating from the brain and terminating into the nasal cavity at the respiratory epithelium or olfactory neuroepithelium. They represent the most direct method of noninvasive entry into the brain, opening the most suitable therapeutic avenue for treatment of neurological diseases. Also, drugs loaded into nanocarriers can have better interaction with the mucosa that assists in the direct brain delivery of active molecules bypassing the BBB and achieving rapid cerebrospinal fluid levels. Lipid particulate systems, emulsion-based systems, vesicular drug delivery systems, and other nanocarriers have evolved as promising drug delivery approaches for the effective brain delivery of anti-Alzheimer's drugs with improved permeability and bioavailability via the nasal route. Charge, size, nature of neurotherapeutics, and formulation excipients influence the effective and targeted drug delivery using nanocarriers via the nasal route. This article elaborates on the recent advances in nanocarrier-based nasal drug delivery systems for the direct and effective brain delivery of the neurotherapeutic molecules. Additionally, we have attempted to highlight various experimental strategies, underlying mechanisms in the pathogenesis and therapy of central nervous system diseases, computational approaches, and clinical investigations pursued so far to attain and enhance the direct delivery of therapeutic agents to the brain via the nose-to-brain route, using nanocarriers.

Long-acting formulation strategies for protein and peptide delivery in the treatment of PSED.

The invigoration of protein and peptides in serious eye disease includes age-related macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. The transportation of macromolecules like aptamers, recombinant proteins, and monoclonal antibodies to the posterior segment of the eye is challenging due to their high molecular weight, rapid degradation, and low solubility. Moreover, it requires frequent administration for prolonged therapy. The long-acting novel formulation strategies are helpful to overcome these issues and provide superior therapy. It avoids frequent administration, improves stability, high retention time, and avoids burst release. This review briefly enlightens posterior segments of eye diseases with their diagnosis techniques and treatments. This article mainly focuses on recent advanced approaches like intravitreal implants and injectables, electrospun injectables, 3D printed drug-loaded implants, nanostructure thin-film polymer devices encapsulated cell technology-based intravitreal implants, injectable and depots, microneedles, PDS with ranibizumab, polymer nanoparticles, inorganic nanoparticles, hydrogels and microparticles for delivering macromolecules in the eye for intended therapy. Furthermore, novel techniques like aptamer, small Interference RNA, and stem cell therapy were also discussed. It is predicted that these systems will make revolutionary changes in treating posterior segment eye diseases in future.

Levonorgestrel Microneedle Array Patch for Sustained Release Contraception: Formulation, Optimization and In Vivo Characterization.

BACKGROUND: The goal of this work was to develop a levonorgestrel liposome-loaded microneedle array patch for contraception. METHODS: Levonorgestrel-loaded liposome was formulated by a solvent injection technique, characterized, and studied. RESULTS: The formulated liposomes were characterized for particle size (147 ± 8 nm), polydispersity index (0.207 ± 0.03), zeta potential (-23 ± 4.25 mV), drug loading (18 ± 3.22%) and entrapment efficiency (85 ± 4.34%). A cryo high-resolution transmission electron microscopy and cryo field emission gun scanning electron microscopy study showed spherical shaped particles with a smooth surface. The in vitro drug release and in vivo pharmacokinetic study showed sustained behaviour of Levonorgestrel for 28 days. CONCLUSION: The levonorgestrel liposome-loaded microneedle array patch showed better contraception than the drug-loaded microneedle array patch.

Donepezil HCl Liposomes: Development, Characterization, Cytotoxicity, and Pharmacokinetic Study.

The current research work aims to study the pharmacokinetic and nasal ciliotoxicity of donepezil liposome-based in situ gel to treat Alzheimer's disease. The physicochemical properties and first-pass metabolism of donepezil HCl result in low concentrations reaching the brain post oral administration. To overcome this problem, donepezil HCl-loaded liposomes were formulated using the ethanol injection method. The donepezil HCl-loaded liposomes were spherical with a size of 103 ± 6.2 nm, polydispersity index of 0.108 ± 0.008, and entrapment efficiency of 93 ± 5.33 %. The optimized in situ gel with donepezil HCl-loaded liposomes showed 80.11 ± 7.77 % drug permeation than donepezil HCl solution-based in situ gel (13.12 ± 4.84 %) across sheep nasal mucosa. The nasal ciliotoxicity study indicated the safety of developed formulation for administration via nasal route. The pharmacokinetics and biodistribution study of developed formulation showed higher drug concentration (1239.61 ± 123.60 pg/g) in the brain after nasal administration indicating its better potential via the nasal pathway. To treat Alzheimer's disease, the administration of liposome-based in situ gel through the nasal pathway can therefore be considered as an effective and promising mode of drug delivery.

A key role by polymers in microneedle technology: a new era.

The skin serves as the major organ in the targeted transdermal drug delivery system for many compounds. The microneedle acts as a novel technique to deliver drugs across the different layers of the skin, including the major barrier stratum corneum, in an effective manner. A microneedle array patch comprises dozens to hundreds of micron-sized needles with numerous structures and advantages resulting from their special and smart designs. The microneedle approach is much more advanced than conventional transdermal delivery pathways due to several benefits like minimally invasive, painless, self-administrable, and enhanced patient compliance. The microneedles are classified into hollow, solid, coated, dissolving, and hydrogel. Several polymers are used to fabricate microneedle, such as natural, semi-synthetic, synthetic, biodegradable, and swellable polymers. Researchers in the preparation of microneedles also explored the combinations of polymers. The safety of the polymer used in microneedle is a crucial aspect to prevent toxicity in vivo. Thus, this review aims to provide a detailed review of microneedles and mainly focus on the various polymers used in the fabrication of microneedles.

Nanocarrier-Based Approaches for the Efficient Delivery of Anti-Tubercular Drugs and Vaccines for Management of Tuberculosis.

Drug-resistant species of tuberculosis (TB), which spread faster than traditiona TB, is a severely infectious disease. The conventional drug therapy used in the management of tuberculosis has several challenges linked with adverse effects. Hence, nanotherapeutics served as an emerging technique to overcome problems associated with current treatment. Nanotherapeutics helps to overcome toxicity and poor solubility issues of several drugs used in the management of tuberculosis. Due to their diameter and surface chemistry, nanocarriers encapsulated with antimicrobial drugs are readily taken up by macrophages. Macrophages play a crucial role as they serve as target sites for active and passive targeting for nanocarriers. The surface of the nanocarriers is coated with ligand-specific receptors, which further enhances drug concentration locally and indicates the therapeutic potential of nanocarriers. This review highlights tuberculosis's current facts, figures, challenges associated with conventional treatment, different nanocarrier-based systems, and its application in vaccine development.

In situ nanostructured hydrogel of resveratrol for brain targeting: in vitro-in vivo characterization.

The purpose of conducting the present research work was to develop resveratrol nanostructured in situ gel for the treatment of Alzheimer's disease. Resveratrol loaded lipid carrier was prepared by melt emulsification-probe sonication method, and the final product was evaluated for particle size (132 ± 11.90 nm), polydispersity index (0.209 ± 0.005), zeta potential (- 23 ± 3.79 mV), drug loading (9.26 ± 3.79%), and entrapment efficiency (74 ± 11.40%). Following incorporation of the resveratrol nanostructured lipid carrier in gellan gum and xanthan gum, in situ gel was formulated and characterized. The optimized in situ gel showed fivefold higher permeation across the nasal mucosa as compared to resveratrol suspension-based in situ gel. Finally, optimized in situ gel was evaluated using in vivo pharmacodynamic study by the scopolamine-induced amnesia model in rats using Morris Water Maze test. It showed significant improvement in memory function in rats treated with optimized in situ gel as compared to orally administered resveratrol suspension. The enhanced permeation across nasal mucosa and improved memory function suggest that the resveratrol nanostructured lipid carrier-based in situ gel could be an effective and promising approach for the treatment of Alzheimer's disease.