In silico exploration of CB2 receptor agonist in the management of neuroinflammatory conditions by pharmacophore modeling.

Endocannabinoid system plays a pivotal role in controlling neuroinflammation, and modulating this system may not only aid in managing symptoms of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Multiple sclerosis, Epilepsy, Central and Peripheral neuropathic pain, but also, have the potential to target these diseases at an early-stage. In the present study, six different pharmacophore hypotheses were generated from Cannabidiol (CBD)-Cannabinoid Receptor subtype-2 (CB2) and then Zinc database was screened for identification of hit molecules. Identified 215 hit molecules were subjected to preliminary screening with ADMET and drug likeness properties, and about 48 molecules were found with no violations and toxicity properties. In molecular docking studies, six compounds showed better binding energy than CBD and ß-caryophyllene (known inhibitor of CB2). These six molecules were designated as leads and subjected to re-docking with glide tool and Lead1 (ZINC000078815430) showed docking score of -9.877 kcal/mol, whereas CBD and ß-caryophyllene showed score of -9.664 and -8.499 kcal/mol, respectively. Lead1 and CBD were evaluated for stability studies with Desmond tool by molecular dynamic simulation studies. Lead1 showed better stability than CBD in all studied parameters such as RMSD, RMSF, SSE, Rg, SASA, etc. In MM-GBSA free energy calculations, ΔGbinding energy of CB2-CBD complex and CB2-Lead1 were found to be -103.13±11.19 and -107.94±5.42 kcal/mol, respectively. Six lead molecules stated in the study hold promise with respect to CBD agonistic activity for treating and/or managing chronic conditions and can be explored as an alternative for early-stage cure, which has not yet been experimentally explored.

Uncovering the Emerging Prospects of Lipid-based Nanoparticulate Vehicles in Lung Cancer Management: A Recent Perspective.

Lung cancer, a leading cause of cancer-related deaths globally, is gaining research interest more than ever before. Owing to the burden of pathogenesis on the quality of life of patients and subsequently the healthcare system, research efforts focus on its management and amelioration. In an effort to improve bioavailability, enhance stability, minimize adverse effects and reduce the incidence of resistance, nanotechnological platforms have been harnessed for drug delivery and improving treatment outcomes. Lipid nanoparticles, in particular, offer an interesting clinical opportunity with respect to the delivery of a variety of agents. These include synthetic chemotherapeutic agents, immunotherapeutic molecules, as well as phytoconstituents with promising anticancer benefits. In addition to this, these systems are being studied for their usage in conjunction with other treatment strategies. However, their applications remain limited owing to a number of challenges, chiefly clinical translation. There is a need to address the scalability of such technologies, in order to improve accessibility. The authors aim to offer a comprehensive understanding of the evolution of lipid nanoparticles and their application in lung cancer, the interplay of disease pathways and their mechanism of action and the potential for delivery of a variety of agents. Additionally, a discussion with respect to results from preclinical studies has also been provided. The authors have also provided a well-rounded insight into the limitations and future perspectives. While the possibilities are endless, there is a need to undertake focused research to expedite clinical translation and offer avenues for wider applications in disease management.

The application of nanoparticles as advanced drug delivery systems in Attenuating COPD.

Chronic Obstructive Pulmonary Disease (COPD) is a dilapidating condition which is characterized by inflammation, an excess in free radical generation and airway obstruction. Currently, the drugs commercially available for the management of COPD pose several limitations such as systemic adverse effects, including bone density loss and an increased risk of developing pneumonia. Moreover, another limitation includes the need for regular and frequent dosing regimens; which can affect the adherence to the therapy. Furthermore, these current treatments provide symptomatic relief; however, they cannot stop the progression of COPD. Comparatively, nanoparticles (NPs) provide great therapeutic potential to treat COPD due to their high specificity, biocompatibility, and higher bioavailability. Furthermore, the NP-based drug delivery systems involve less frequent dosing requirements and in smaller doses which assist in minimizing side effects. In this review, the benefits and limitations of conventional therapies are explored, while providing an in-depth insight on advanced applications of NP-based systems in the treatment of COPD.

Cancer cell fusion: a potential target to tackle drug-resistant and metastatic cancer cells.

Cell fusion is an integral, established phenomenon underlying various physiological processes in the cell cycle. Although research in cancer metastasis has hypothesised numerous molecular mechanisms and signalling pathways responsible for invasion and metastasis, the origin and progression of metastatic cells within primary tumours remains unclear. Recently, the role of cancer cell fusion in cancer metastasis and development of multidrug resistance (MDR) in tumours has gained prominence. However, evidence remains lacking to justify the role of cell fusion in cancer metastasis and drug resistance. Here, we highlight plausible mechanisms governing cell fusion with different cell types in the tumour microenvironment (TME), the clinical relevance of cancer cell fusion, its potential as a target for overcoming MDR and inhibiting metastasis, and putative modes of treatment.

Tumor Microenvironment Targeted Nanotherapy.

Recent developments in nanotechnology have brought new approaches to cancer diagnosis and therapy. While enhanced permeability and retention effect promotes nano-chemotherapeutics extravasation, the abnormal tumor vasculature, high interstitial pressure and dense stroma structure limit homogeneous intratumoral distribution of nano-chemotherapeutics and compromise their imaging and therapeutic effect. Moreover, heterogeneous distribution of nano-chemotherapeutics in non-tumor-stroma cells damages the non-tumor cells, and interferes with tumor-stroma crosstalk. This can lead not only to inhibition of tumor progression, but can also paradoxically induce acquired resistance and facilitate tumor cell proliferation and metastasis. Overall, the tumor microenvironment plays a vital role in regulating nano-chemotherapeutics distribution and their biological effects. In this review, the barriers in tumor microenvironment, its consequential effects on nano-chemotherapeutics, considerations to improve nano-chemotherapeutics delivery and combinatory strategies to overcome acquired resistance induced by tumor microenvironment have been summarized. The various strategies viz., nanotechnology based approach as well as ligand-mediated, redox-responsive, and enzyme-mediated based combinatorial nanoapproaches have been discussed in this review.

Comparison of Nanoemulsion and Aqueous Micelle Systems of Paliperidone for Intranasal Delivery.

The objective of the study was to develop and compare the efficiency of nanoemulsion and aqueous micelle system of Paliperidone on intranasal administration. Both the formulations were evaluated for physical parameters such as globule size, pH, viscosity, conductivity and in vitro drug release studies. The reduction in spontaneous motor activity of L-dopa and Carbidopa-treated Swiss Albino mice on intranasal administration of nanoemulsion and micellar system of Paliperidone was compared with plain drug suspension. Histopathological evaluation of formulation treated nasal mucosal membrane was performed. Nasal spray device was evaluated for spray pattern and volume per actuation. Globule size of micellar system and nanoemulsion was found to be 16.14 & 38.25 nm, respectively. In vitro release of drug from micellar system was found to be 1.8-fold higher than nanoemulsion. The loading of drug in nanoemulsion was found to be superior (2.5 mg/mL) when compared to micellar system (0.41 mg/mL). The spray pattern of micellar system and nanoemulsion from the device was elliptical and circular, respectively. The locomotor activity of L-dopa and Carbidopa-treated Swiss albino mice was found to be 1096.5±78.49, 551.5±13.43 and 535.5±24.75 counts/min in case of plain drug suspension, micellar system and nanoemulsion, respectively. The intranasal administration of developed formulations showed significant difference (p<0.01) in the locomotor activity when compared to intranasal administration of plain drug. Thus it can be concluded that both the developed formulations have shown improved in vivo activity on intranasal administration and pose great potential for delivery of Paliperidone through intranasal route.

Cuboidal lipid polymer nanoparticles of rosuvastatin for oral delivery.

The present work aimed to develop and characterize sustained release cuboidal lipid polymeric nanoparticles (LPN) of rosuvastatin calcium (ROS) by solvent emulsification-evaporation process. A three factor, two level (23) full-factorial design was applied to study the effect of independent variables, i.e. amount of lipid, surfactant and polymer on dependent variables, i.e. percent entrapment efficiency and particle size. Optimized formulations were further studied for zeta potential, TEM, in vitro drug release and ex vivo intestinal permeability. Cuboidal nanoparticles exhibited average particle size 61.37 ± 3.95 nm, entrapment efficiency 86.77 ± 1.27% and zeta potential -6.72 ± 3.25 mV. Nanoparticles were lyophilized to improve physical stability and obtain free-flowing powder. Effect of type and concentration of cryoprotectant required to lyophilize nanoparticles was optimized using freeze-thaw cycles. Mannitol as cryoprotectant in concentration of 5-8% w/v was found to be optimal providing zeta potential -20.4 ± 4.63 mV. Lyophilized nanoparticles were characterized using FTIR, DSC, XRD and SEM. Absence of C=C and C-F aromatic stretch at 1548 and 1197 cm-1, respectively, in LPN indicated coating of drug by lipid and polymer. In vitro diffusion of ROS using dialysis bag showed pH-independent sustained release of ROS from LPN in comparison to drug suspension. Intestinal permeability by non-everted gut sac model showed prolonged release of ROS from LPN owing to adhesion of polymer to mucus layer. In vivo absorption of ROS from LPN resulted in 3.95-fold increase in AUC0-last and 7.87-fold increase in mean residence time compared to drug suspension. Furthermore modified tyloxapol-induced rat model demonstrated the potential of ROS-loaded LPN in reducing elevated lipid profile.

FTIR assay method for UV inactive drug carisoprodol and identification of degradants by RP-HPLC and ESI-MS.

A new method of analysis has been developed for UV inactive drug carisoprodol using FTIR spectroscopy. These methods were validated for various parameters according to ICH guidelines. The proposed method has also been successfully applied for the determination of the drug concentration in a tablet formulation. The method proved to be accurate (mean percentage recovery between 95 and 105%), precise and reproducible (relative standard deviation<2%), while being simple, economical and less time consuming than other methods and can be used for routine estimation of carisoprodol in the pharmaceutical industry. The developed method also implicates its utility for other UV inactive substances. The stability of the drug under various stress conditions was studied and the drug was found to be particularly susceptible to alkaline hydrolysis. Degradation products of the alkaline hydrolysis were detected by RP-HPLC and tentatively identified by ESI-MS.

Taste Masked Orodispersible Formulation of Fexofenadine Hydrochloride Using Ion Exchange Resins.

The objective of this research work was to mask the intense bitter taste of fexofenadine hydrochloride using weak cation exchange resins and to formulate orodispersible tablet of taste masked drug-resin complex. Five resins indion 204, indion 234, indion 414, kyron T-114 and kyron T-314 were used. Depending on maximum drug loading capacity of resins indion 234 and kyron T-314 were finalized for further study. Drug-resin complex was optimized by considering parameters such as drug to resin ratio, soaking time of resins, stirring time, temperature and pH on maximum drug loading. The drug-resin complex was characterized by Fourier transform infrared spectroscopy. The drug-resin complex was also subjected to various evaluation studies such as taste mask evaluation by panel method, drug content and in vitro drug release at salivary and gastric pH. The orodispersible tablets of taste masked drug-resin complex for indion 234 and kyron T-314 were prepared by direct compression method. Formulated orodispersible tablets were subjected to various evaluation parameters such as diameter and thickness measurement, hardness test, weight variation test, in vitro United States Pharmacopoeia disintegration test, wetting time, test for content uniformity, assay, friability test and in vitro dissolution studies. The results indicate that orodispersible tablets of fexofenadine hydrochloride containing indion 234 and kyron T-314 are palatable and provide quick disintegration and fast drug release without addition of superdisintegrants.