Comparative pharmacokinetic evaluation of glimepiride orodispersable and conventional tablets in rabbits.

OBJECTIVES: Glimepiride Orodispersable Tablets (ODT) were prepared with the goal to have rapid onset of action and higher bioavailability with ease administration to individuals with swallowing difficulty to ameliorate patient compliance. SIGNIFICANCE: Glimepiride is a contemporary hypoglycemic medication that belongs to the family of sulfonylurea derivatives. It is used in type 2 diabetes mellitus. Compliance adherence remains one of the limitations with the conventional drug delivery system especially in pediatric, geriatric, psychiatric, and traveling patients, for such population ODT provides a good alternate dosage form compared with Commercial Tablets. METHOD: The Comparative in vivo pharmacokinetic parameters of the prepared ODT and conventional tablets (CT) were evaluated using an animal model. The plasma concentration of Glimepiride after oral administration of a single dose was determined at predetermined time intervals with HPLC. The pharmacokinetic parameters were calculated using PK Solutions 2.0 from Summit PK® software. RESULTS: The Cmax obtained with ODT (22.08 µg/ml) was significantly (p = 0.006) high, a lower tmax of 3.0 hr was achieved with the orodispersable formulation of the drug. The ODT showed 104.34% relative bioavailability as compared to CT and left shift of tmax as well. CONCLUSION: As per findings of the in vivo investigation, the Glimepiride ODT would be beneficial in terms of patient compliance, quick onset of action, and increased bioavailability.

Skin cancer: understanding the journey of transformation from conventional to advanced treatment approaches.

Skin cancer is a global threat to the healthcare system and is estimated to incline tremendously in the next 20 years, if not diagnosed at an early stage. Even though it is curable at an early stage, novel drug identification, clinical success, and drug resistance is another major challenge. To bridge the gap and bring effective treatment, it is important to understand the etiology of skin carcinoma, the mechanism of cell proliferation, factors affecting cell growth, and the mechanism of drug resistance. The current article focusses on understanding the structural diversity of skin cancers, treatments available till date including phytocompounds, chemotherapy, radiotherapy, photothermal therapy, surgery, combination therapy, molecular targets associated with cancer growth and metastasis, and special emphasis on nanotechnology-based approaches for downregulating the deleterious disease. A detailed analysis with respect to types of nanoparticles and their scope in overcoming multidrug resistance as well as associated clinical trials has been discussed.

A Comprehensive review on Pharmacokinetic Studies of Vaccines: Impact of delivery route, carrier-and its modulation on immune response.

The lack of knowledge about the absorption, distribution, metabolism, and excretion (ADME) of vaccines makes former biopharmaceutical optimization difficult. This was shown during the COVID-19 immunization campaign, where gradual booster doses were introduced.. Thus, understanding vaccine ADME and its effects on immunization effectiveness could result in a more logical vaccine design in terms of formulation, method of administration, and dosing regimens. Herein, we will cover the information available on vaccine pharmacokinetics, impacts of delivery routes and carriers on ADME, utilization and efficiency of nanoparticulate delivery vehicles, impact of dose level and dosing schedule on the therapeutic efficacy of vaccines, intracellular and endosomal trafficking and in vivo fate, perspective on DNA and mRNA vaccines, new generation sequencing and mathematical models to improve cancer vaccination and pharmacology, and the reported toxicological study of COVID-19 vaccines. Altogether, this review will enhance the reader's understanding of the pharmacokinetics of vaccines and methods that can be implied in delivery vehicle design to improve the absorption and distribution of immunizing agents and estimate the appropriate dose to achieve better immunogenic responses and prevent toxicities.

Advanced targeted drug delivery by bioengineered white blood cell-membrane camouflaged nanoparticulate delivery nanostructures.

Targeted drug delivery has emerged as a pivotal approach within precision medicine, aiming to optimize therapeutic efficacy while minimizing systemic side effects. Leukocyte membrane coated nanoparticles (NPs) have attracted a lot of interest as an effective approach for delivering targeted drugs, capitalizing on the natural attributes of leukocytes to achieve site-specific accumulation, and heightened therapeutic outcomes. An overview of the present state of the targeted medication delivery research is given in this review. Notably, Leukocyte membrane-coated NPs offer inherent advantages such as immune evasion, extended circulation half-life, and precise homing to inflamed or diseased tissues through specific interactions with adhesion molecules. leukocyte membrane-coated NPs hold significant promise in advancing targeted drug delivery for precision medicine. As research progresses, they are anticipated to contribute to improved therapeutic outcomes, enabling personalized and effective treatments for a wide range of diseases and conditions. The review covers the method of preparation, characterization, and biological applications of leucocytic membrane coated NPs. Further, patents related factors, gap of translation from laboratory to clinic, and future prospective were discussed in detail. Overall, the review covers extensive literature to establish leucocytic membrane NPs for targeted drug delivery.

Biocompatible phospholipid-based nanovesicular drug delivery system of ketoprofen: Systematic development, optimization, and preclinical evaluation.

The present work involved development of phospholipid-based permeation enhancing nanovesicles (PENVs) for topical delivery of ketoprofen. Screening of phospholipids and process parameters was performed. Central composite design was used for optimization of factors, that is, amount (%, w/w) of phospholipid and ethanol at three levels. The optimized nanovesicles (NVs) were loaded with different terpenes and then incorporated into a gel base. Optimized NVs exhibited 69% entrapment efficiency, 51% transmittance, 328 nm mean vesicle size, and polydispersity index of 0.25. In vitro release kinetics evaluation indicated best fitting as per Korsemeyer-Peppa's model and drug release via Fickian-diffusion mechanism. The optimized NVs loaded with mint terpene showed minimal degree of deformability and maximal elasticity as compared with the conventional NVs and liposomes. Rheology and texture analysis indicated pseudoplastic flow and smooth texture of the vesicle gel formulation. Ex vivo permeation studies across Wistar rat skin indicated low penetration (0.43-fold decrease) and high skin retention (4.26-fold increase) of ketoprofen from the optimized PENVs gel vis-à-vis the conventional gel. Skin irritancy study indicated lower scores for PENVs gel construing its biocompatible nature. Stability studies confirmed cold storage is best suitable for vesicle gel, and optimized PENVs were found to be suitable for topical delivery of ketoprofen.

A review of various analytical methods for the estimation of olanzapine: An antipsychotic drug.

Olanzapine (OLZ) is an antipsychotic agent and is a thienobenzodiazepine derivative. It is used either in combination with other drugs like carbamazepine, simvastatin, and clozapine or as a single drug. The present work is mainly focused on various approaches for OLZ analysis in bulk drugs as well as on their pharmaceutical formulations. It is also focused on various bioanalytical methods used for analysis. Our survey showed that many analytical techniques were carried out using UV spectrophotometry, MS, LC-MS/MS techniques, and chromatographic techniques like HPLC and high-performance thin layer chromatography in both bulk and solid dosage forms. Bioanalytical techniques were also performed using human plasma or serum. The analysis was carried out either for a single drug or for a combination of drugs. This review shows the rate of use of the different methodologies for OLZ analysis. A considerable amount of information was collected and utilized for the strategies.

EGF-functionalized lipid-polymer hybrid nanoparticles of 5-fluorouracil and sulforaphane with enhanced bioavailability and anticancer activity against colon carcinoma.

The present research work describes development of dual drug-loaded lipid-polymer hybrid nanoparticles (LPHNPs) of anticancer therapeutics for the management of colon cancer. The epidermal growth factor (EGF)-functionalized LPHNPs coloaded with 5-fluorouracil (FU) and sulforaphane (SFN) were prepared by one-step nanoprecipitation method. Box-Behnken design was applied for optimizing the material attributes and process parameters. The optimized LPHNPs revealed particle size 198 nm, polydispersity index 0.3, zeta potential -25.3 mV, and drug loading efficiency 19-20.3% for 5-FU and SFN, respectively. EGF functionalization on LPHNPs was confirmed from positive magnitude of zeta potential to 21.3 mV as compared with the plain LPHNPs. In vitro drug release performance indicated sustained and non-Fickian mechanism release nature of the drugs from LPHNPs. Anticancer activity evaluation in HCT-15 colon cancer cells showed significant reduction (p < 0.001) in the cell growth and cytotoxicity of the investigated drugs from various treatments in the order: EGF-functionalized LPHNPs > plain LPHNPs > free drug suspensions. Overall, the research work corroborated improved treatment efficacy of EGF-functionalized LPHNPs for delivering chemotherapeutic agents for the management of colon carcinoma.

Nano lipidic carriers for codelivery of sorafenib and ganoderic acid for enhanced synergistic antitumor efficacy against hepatocellular carcinoma.

The current study focuses on the development and evaluation of nano lipidic carriers (NLCs) for codelivery of sorafenib (SRF) and ganoderic acid (GA) therapy in order to treat hepatocellular carcinoma (HCC). The dual drug-loaded NLCs were prepared by hot microemulsion technique, where SRF and GA as the drugs, Precirol ATO5, Capmul PG8 as the lipids, while Solutol HS15 and ethanol was used as surfactant and cosolvents. The optimized drug-loaded NLCs were extensively characterized through in vitro and in vivo studies. The optimized formulation had particle size 29.28 nm, entrapment efficiency 93.1%, and loading capacity 14.21%. In vitro drug release studies revealed>64% of the drug was released in the first 6 h. The enzymatic stability analysis revealed stable nature of NLCs in various gastric pH, while accelerated stability analysis at 25◦C/60% RH indicated the insignificant effect of studied condition on particle size, entrapment efficiency, and loading capacity of NLCs. The cytotoxicity performed on HepG2 cells indicated higher cytotoxicity of SRF and GA-loaded NLCs as compared to the free drugs (p < 0.05). Furthermore, the optimized formulation suppressed the development of hepatic nodules in the Wistar rats and significantly reduced the levels of hepatic enzymes and nonhepatic elements against DEN intoxication. The SRF and GA-loaded NLCs also showed a significant effect in suppressing the tumor growth and inflammatory cytokines in the experimental study. Further, histopathology study of rats treated SRF and GA-loaded NLCs and DEN showed absence of necrosis, apoptosis, and disorganized hepatic parenchyma, etc. over other treated groups of rats. Overall, the dual drug-loaded NLCs outperformed over the plain drugs in terms of chemoprotection, implying superior therapeutic action and most significantly eliminating the hepatic toxicity induced by DEN in Wistar rat model.

Design, Synthesis, and Biological Evaluation of Some Novel Pyrrolizine Derivatives as COX Inhibitors with Anti-Inflammatory/Analgesic Activities and Low Ulcerogenic Liability.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed anti-inflammatory and pain relief medications. However, their use is associated with many drawbacks, including mainly serious gastric and renal complications. In an attempt to circumvent these risks, a set of N-(4-bromophenyl)-7-cyano-6-substituted-H-pyrrolizine-5-carboxamide derivatives were designed, synthesized and evaluated as dual COX/5-LOX inhibitors. The structural elucidation, in vivo anti-inflammatory and analgesic activities using a carrageenan-induced rat paw edema model and hot plate assay, were performed, respectively. From the results obtained, it was found that the newly synthesized pyrrolizines exhibited IC50 values in the range of 2.45-5.69 µM and 0.85-3.44 µM for COX-1 and COX-2, respectively. Interestingly, compounds 12, 13, 16 and 17 showed higher anti-inflammatory and analgesic activities compared to ibuprofen. Among these derivatives, compounds 16 and 19 displayed better safety profile than ibuprofen in acute ulcerogenicity and histopathological studies. Furthermore, the docking studies revealed that compound 17 fits nicely into COX-1 and COX-2 binding sites with the highest binding affinity, while compound 16 exerted the highest binding affinity for 5-LOX. In light of these findings, these novel pyrrolizine-5-carboxamide derivatives represent a promising scaffold for further development into potential dual COX/5-LOX inhibitors with safer gastric profile.

Recent approaches for the treatment of uveal melanoma: Opportunities and challenges.

Uveal melanoma (UM) is the most prevalent primary intraocular cancer in adult population. Primary methods for treatment of UM involves surgery Proton Beam Therapy (PBT), Plaque Brachytherapy, phototherapy, and Charged Particle Radiation Therapy (CPT). It has been found that approximately 50 % of patients diagnosed with UM ultimately experience development of metastatic disease. Furthermore, it has been identified that majority of the patient experience metastasis in liver with a prevalence of 95 %. Management of metastatic UM (MUM) involves various therapeutic modalities, including systemic chemotherapy, molecular targeted therapy, immunotherapy and liver directed interventions. We outline gene mutation in UM and addresses various treatment modalities, including molecular targeted therapy, miRNA-based therapy, and immunotherapy. Additionally, inclusion of ongoing clinical trials aimed at developing novel therapeutic options for management of UM are also mentioned.

Harnessing the Power of Stimuli-Responsive Nanoparticles as an Effective Therapeutic Drug Delivery System.

The quest for effective and reliable methods of delivering medications, with the aim of improving delivery of therapeutic agent to the intended location, has presented a demanding yet captivating field in biomedical research. The concept of smart drug delivery systems is an evolving therapeutic approach, serving as a model for directing drugs to specific targets or sites. These systems have been developed to specifically target and regulate the administration of therapeutic substances in a diverse array of chronic conditions, including periodontitis, diabetes, cardiac diseases, inflammatory bowel diseases, rheumatoid arthritis, and different cancers. Nevertheless, numerous comprehensive clinical trials are still required to ascertain both the immediate and enduring impacts of such nanosystems on human subjects. This review delves into the benefits of different drug delivery vehicles, aiming to enhance comprehension of their applicability in addressing present medical requirements. Additionally, it touches upon the current applications of these stimuli-reactive nanosystems in biomedicine and outlines future development prospects.

Unravelling the potential of mitochondria-targeted liposomes for enhanced cancer treatment.

Mitochondria are the primary organelles of cells involved in various physiochemical and biochemical processes. Owing to their crucial role in cellular metabolism, mitochondria are favored therapeutic targets for the treatment and prevention of cancers. Recently, there has been growing interest in the use of mitochondria-specific functional nanoparticles for targeted delivery of therapeutic agents to these organelles. Among several nanosystems, liposomes have garnered considerable attention owing to their exceptional drug delivery capabilities, biocompatibility, biodegradability, ease of manufacturing and established regulatory guidelines for market approval. In this context, the present review provides a brief insight into the association between mitochondria and tumor formation and advantages of mitochondrial targeting in cancer therapy. Furthermore, it discusses mitochondria-targeting functional liposomes for the treatment of various cancers, such as breast, lung, colon, among others.

State-of-the-art drug delivery system to target the lymphatics.

PRIMARY OBJECTIVE: The primary objective of the review is to assess the potential of lymphatic-targeted drug delivery systems, with a particular emphasis on their role in tumour therapy and vaccination efficacy. REASON FOR LYMPHATIC TARGETING: The lymphatic system's crucial functions in maintaining bodily equilibrium, regulating metabolism, and orchestrating immune responses make it an ideal target for drug delivery. Lymph nodes, being primary sites for tumour metastasis, underscore the importance of targeting the lymphatic system for effective treatment. OUTCOME: Nanotechnologies and innovative biomaterials have facilitated the development of lymphatic-targeted drug carriers, leveraging endogenous macromolecules to enhance drug delivery efficiency. Various systems such as liposomes, micelles, inorganic nanomaterials, hydrogels, and nano-capsules demonstrate significant potential for delivering drugs to the lymphatic system. CONCLUSION: Understanding the physiological functions of the lymphatic system and its involvement in diseases underscores the promise of targeted drug delivery in improving treatment outcomes. The strategic targeting of the lymphatic system presents opportunities to enhance patient prognosis and advance therapeutic interventions across various medical contexts, indicating the importance of ongoing research and development in this area.

Advances in the polymeric nanoparticulate delivery systems for RNA therapeutics.

RNA therapeutics have emerged as potential treatments for genetic disorders, infectious diseases, and cancer. RNA delivery to target cells for efficient therapeutic applications remains challenging due to instability and poor uptake. Polymeric nanoparticulate delivery systems offer stability, protection, and controlled release. These systems shield RNA from degradation, enabling efficient uptake and extended circulation. Various polymeric nanoparticle platforms have been explored, including lipid-based nanoparticles, polymeric micelles, dendrimers, and polymer-drug conjugates. This review outlines recent breakthroughs of recent advances, design principles, characterization techniques, and performance evaluation of these delivery systems. It highlights their potential in translating preclinical studies into clinical applications. Additionally, the review discusses the application of polymeric nanoparticles in ophthalmic drug delivery, particularly for medications that dissolve poorly in water, and the progress made in siRNA-based therapies for viral infections, autoimmune diseases, and cancers. SiRNA holds great promise for precision medicine and therapeutic intervention, with the ability to target specific genes and modulate disease-associated pathways. The versatility and potency of siRNA-based drugs offer a broader scope for therapeutic intervention compared to traditional biological drugs. As research in RNA therapeutics continues to advance, these technologies hold tremendous potential to revolutionize the treatment of various diseases and improve patient outcomes.

Three-dimensional cell culture: Future scope in cancer vaccine development.

Three-dimensional (3D) cell culture techniques, which are superior to 2D methods in viability and functionality, are being used to develop innovative cancer vaccines. Tumor spheroids, which are structurally and functionally similar to actual tumors, can be developed using 3D cell culture. These spheroid vaccines have shown superior antitumor immune responses to 2D cell-based vaccines. Dendritic cell vaccines can also be produced more efficiently using 3D cell culture. Personalized cancer vaccines are being developed using 3D cell culture, providing substantial benefits over 2D methods. The more natural conditions of 3D cell culture might promote the expression of tumor antigens not expressed in 2D culture, potentially allowing for more targeted vaccines by co-culturing tumor cells with other cell types. Advanced cancer vaccines using 3D cell cultures are expected soon.

Peptide spiders are emerging as novel therapeutic interventions for nucleic acid delivery.

The FDA has approved many nucleic acid (NA)-based products. The presence of charges and biological barriers however affect stability and restrict widespread use. The electrostatic complexation of peptide with polyethylene glycol-nucleic acids (PEG-NAs) via nonreducible and reducible agents lead to three parts at one platform.. The reducible linkage made detachment of siRNA from PEG easy compared with a nonreducible linkage. A peptide spider produces a small hydrodynamic particle size, which can improve drug release and pharmacokinetics. Several examples of peptide spiders that enhance stability, protection and transfection efficiency are discussed. Moreover, this review also covers the challenges, future perspectives and unmet needs of peptide-PEG-NAs conjugates for NAs delivery.

Understanding the Novel Approach of Nanoferroptosis for Cancer Therapy.

As a new form of regulated cell death, ferroptosis has unraveled the unsolicited theory of intrinsic apoptosis resistance by cancer cells. The molecular mechanism of ferroptosis depends on the induction of oxidative stress through excessive reactive oxygen species accumulation and glutathione depletion to damage the structural integrity of cells. Due to their high loading and structural tunability, nanocarriers can escort the delivery of ferro-therapeutics to the desired site through enhanced permeation or retention effect or by active targeting. This review shed light on the necessity of iron in cancer cell growth and the fascinating features of ferroptosis in regulating the cell cycle and metastasis. Additionally, we discussed the effect of ferroptosis-mediated therapy using nanoplatforms and their chemical basis in overcoming the barriers to cancer therapy.

Secondary metabolites in topical infectious diseases and nanomedicine applications.

Topical infection affects nearly one-third of the world's population; it may result from poor sanitation, hygienic conditions and crowded living and working conditions that accelerate the spread of topical infectious diseases. The problems associated with the anti-infective agents are drug resistance and long-term therapy. Secondary metabolites are obtained from plants, microorganisms and animals, but they are metabolized inside the human body. The integration of nanotechnology into secondary metabolites is gaining attention due to their interaction at the subatomic and skin-tissue levels. Hydrogel, liposomes, lipidic nanoparticles, polymeric nanoparticles and metallic nanoparticles are the most suitable carriers for secondary metabolite delivery. Therefore, the present review article extensively discusses the topical applications of nanomedicines for the effective delivery of secondary metabolites.

Baicalin-Loaded Lipid-Polymer Hybrid Nanoparticles Inhibiting the Proliferation of Human Colon Cancer: Pharmacokinetics and In Vivo Evaluation.

This research work is focused on pharmacokinetic and biochemical experiments to assess baicalin-loaded lipid-polymer hybrid nanoparticles (LPHNPs) with colon-targeting specificity. The nanoprecipitation method was used to develop the LPHNPs, and the characterized formulation revealed the 184.3 nm particle size, PDI of 0.177, spherical shape, and zeta potential of -19.8 mV. The baicalin LPHNPs are said to be poorly absorbed in the stomach and small intestine, and in vitro drug release tests have shown that the drug is released mostly in the caecal fluid. Additionally, the LPHNPs showed stability and nonsignificant drug loss at 25 °C for 3 months. The least viable population of baicalin-loaded LPHNPs was detected at a lower IC50 value after 48 h, and no cytotoxicity was observed by blank suspension and blank LPHNPs up to the concentration of 100 µg/mL. Apart from this, the pharmacokinetics study showed that baicalin from LPHNPs is much less absorbed and least available in the blood plasma and maximum available in the colon. Concurrently, organ distribution studies demonstrated that baicalin-loaded LPHNPs were distributed more widely in the colon compared to baicalin suspension. Moreover, baicalin-loaded LPHNPs were found to be superior to a baicalin suspension in reducing elevated liver enzyme levels. In a nutshell, baicalin-loaded LPHNPs show superior efficacy and can be maximally localized into the colon rectal cancer along with systemic availability of the drug.

Reactive oxygen species and its manipulation strategies in cancer treatment.

Cancer is one of the serious diseases of modern times, occurring in all parts of the world and shows a wide range of effects on the human body. Reactive Oxygen Species (ROS) such as oxide and superoxide ions have both advantages and disadvantages during the progression of cancer, dependent on their concentration. It is a necessary part of the normal cellular mechanisms. Changes in its normal level can cause oncogenesis and other relatable problems. Metastasis can also be controlled by ROS levels in the tumor cells, which can be prevented by the use of antioxidants. However, ROS is also used for the initiation of apoptosis in cells by different mediators. There exists a cycle between the production of oxygen reactive species, their effect on the genes, role of mitochondria and the progression of tumors. ROS levels cause DNA damage by the oxidation process, gene damage, altered expression of the genes and signalling mechanisms. They finally lead to mitochondrial disability and mutations, resulting in cancer. This review summarizes the important role and activity of ROS in developing different types of cancers like cervical, gastric, bladder, liver, colorectal and ovarian cancers.