Polymeric Nanogel for Oral Delivery of the Chemotherapeutic Agent: Fabrication and Evaluation Alongside Toxicological Studies and Histopathological Examination.

Nanogel has attracted considerable attention as one of the most versatile drug delivery systems, especially for site-specific and/or time-controlled delivery of the chemotherapeutic agent. The main objective of this study was to prepare the polymeric nanogel characterized by Fourier transform infrared spectroscopy, x-ray diffraction, thermogravimetric analysis, differential scanning, and oral acute toxicity. Free radical polymerization was done for the fabrication of polymeric nanogel. Fourier transform infrared spectroscopy was used to confirm the successful free radical polymerization. Various techniques such as x-ray diffraction, differential scanning calorimetric, and thermogravimetric analysis measurement were used to investigate the thermal behavior and crystallinity of developed nanogel. Parameters such as swelling, drug loading, and in vitro drug release is enhanced as polymers and monomers concentrations increase while these parameters decrease in case of increasing crosslinker concentration. The oral biocompatibility results of developed nanogel exhibited no toxicity in rabbits. Histopathological changes were observed between empty and loaded group. The nanosized gel offers a specific surface area which increases the stability of loaded drug (oxaliplatin) and bioavailability of the drug (oxaliplatin) as compared to the conventional drug delivery systems.

Compritol-Based Alprazolam Solid Lipid Nanoparticles for Sustained Release of Alprazolam: Preparation by Hot Melt Encapsulation.

The current study was designed to investigate the feasibility of incorporating the water-insoluble lipophilic drug Alprazolam (Alp) into solid lipid nanoparticles (SLNs) to offer the combined benefits of the quick onset of action along with the sustained release of the drug. Therefore, compritol-based alprazolam-loaded SLNs (Alp-SLNs) would provide early relief from anxiety and sleep disturbances and long-lasting control of symptoms in patients with depression, thereby enhancing patient compliance. The optimized Alp-SLNs analyzed by DLS and SEM showed consistent particle size of 92.9 nm with PI values and standard deviation of the measurements calculated at <0.3 and negative surface charge. These characteristic values demonstrate the desired level of homogeneity and good physical stability of Alp-SLNs. The SLNs had a good entrapment efficiency (89.4%) and high drug-loading capacity (77.9%). SEM analysis revealed the smooth spherical morphology of the SLNs. The physical condition of alprazolam and absence of interaction among formulation components in Alp-SLNs was confirmed by FTIR and DSC analyses. XRD analysis demonstrated the molecular dispersion of crystalline alprazolam in Alp-SLNs. The in vitro release study implied that the release of Alp from the optimized Alp-SLN formulation was sustained as compared to the Alp drug solution because Alp-SLNs exhibited sustained release of alprazolam over 24 h. Alp-SLNs are a promising candidate to achieve sustained release of the short-acting drug Alp, thereby reducing its dosing frequency and enhancing patient compliance.

Natural Polymer-Based Graphene Oxide Bio-nanocomposite Hydrogel Beads: Superstructures with Advanced Potentials for Drug Delivery.

The current study sought to create graphene oxide-based superstructures for gastrointestinal drug delivery. Graphene oxide has a large surface area that can be used to load anti-cancer drugs via non-covalent methods such as surface adsorption and hydrogen bonding. To enhance the bio-applicability of graphene oxide, nano-hybrids were synthesized by encapsulating the graphene oxide into calcium alginate hydrogel beads through the dripping-extrusion technique. These newly developed bio-nanocomposite hybrid hydrogel beads were evaluated in structural analysis, swelling study, drug release parameters, haemolytic assay, and antibacterial activity. Doxorubicin served as a model drug. The drug entrapment efficiency was determined by UV-spectroscopy analysis and was found to be high at ⁓89% in graphene oxide hybrid hydrogel beads. These fabricated hydrogel beads ensure the drug release from a hybrid polymeric matrix in a more controlled and sustained pattern avoiding the problems associated with a non-hybrid polymeric system. The drug release study of 12 h shows about 83% release at pH 6.8. In vitro drug release kinetics proved that drug release was a Fickian mechanism. The cytotoxic effect of graphene oxide hybrid alginate beads was also determined by evaluating the morphology of bacterial cells and red blood cells after incubation. Additionally, it was determined that the sequential encapsulation of graphene oxide in alginate hydrogel beads hides its uneven edges and lessens the graphene oxide's negative impacts. Also, the antibacterial study and biocompatibility of fabricated hydrogel beads made them potential candidates for gastrointestinal delivery.

Formulation and evaluation of antiviral drug sofosbuvir fast dissolving tablets using natural super disintegrants.

The main objective of this study to formulate of fast dissolving tablets of sofosbuvir, an antiviral drug used for hepatitis C virus. The direct compression method was employed for the formulation of sofosbuvir FDT and optimized for weight variation test, thickness, hardness, friability, wetting time, water absorption ratio, in-vitro disintegration test, and in-vitro dissolution studies, assay identification by using HPLC and stability studies. Master formulation of F4, Sofosbuvir showed promising results compared to others formulations and selected as the most suitable and best formulation among them. It also has better efficacy, disintegration and dissolution time. F4 was fabricated with both super disintegrants like croscarmellose sodium and sodium starch glycolate that lead to its required features. This formulation would be a good alternate for the management of viral diseases with better dissolution profile, stability and improved bioavailability for the patients.

Multifaceted behavior of PEST sequence enriched nuclear proteins in cancer biology and role in gene therapy.

The amino acid sequence enriched with proline (P), glutamic acid (E), serine (S), and threonine (T) (PEST) is a signal-transducing agent providing unique features to its substrate nuclear proteins (PEST-NPs). The PEST motif is responsible for particular posttranslational modifications (PTMs). These PTMs impart distinct properties to PEST-NPs that are responsible for their activation/inhibition, intracellular localization, and stability/degradation. PEST-NPs participate in cancer metabolism, immunity, and protein transcription as oncogenes or as tumor suppressors. Gene-based therapeutics are getting the attention of researchers because of their cell specificity. PEST-NPs are good targets to explore as cancer therapeutics. Insights into PTMs of PEST-NPs demonstrate that these proteins not only interact with each other but also recruit other proteins to/from their active site to promote/inhibit tumors. Thus, the role of PEST-NPs in cancer biology is multivariate. It is hard to obtain therapeutic objectives with single gene therapy. An especially designed combination gene therapy might be a promising strategy in cancer treatment. This review highlights the multifaceted behavior of PEST-NPs in cancer biology. We have summarized a number of studies to address the influence of structure and PEST-mediated PTMs on activation, localization, stability, and protein-protein interactions of PEST-NPs. We also recommend researchers to adopt a pragmatic approach in gene-based cancer therapy.

Emergence of novel coronavirus and progress toward treatment and vaccine.

In late December 2019, a group of patients was observed with pneumonia-like symptoms that were linked with a wet market in Wuhan, China. The patients were found to have a novel coronavirus genetically related to a bat coronavirus that was termed SARS-CoV-2. The virus gradually spread worldwide and was declared a pandemic by WHO. Scientists have started trials on potential preventive and treatment options. Currently, there is no specific approved treatment for SARS-CoV-2, and various clinical trials are underway to explore better treatments. Some previously approved antiviral and other drugs have shown some in vitro activity. Here we summarize the fight against this novel coronavirus with particular focus on the different treatment options and clinical trials exploring treatment as well as work done toward development of vaccines.

Fabrication, Evaluation, In Vivo Pharmacokinetic and Toxicological Analysis of pH-Sensitive Eudragit S-100-Coated Hydrogel Beads: a Promising Strategy for Colon Targeting.

The aim of present research aims to fabricate a system of enteric coating of hydrogel beads with pH-sensitive polymer, which shows solubility at pH > 7, and explore their potential to target the colon for drug delivery. Hydrogel beads were fabricated through the extrusion-dripping technique followed by ion gelation crosslinking. Moreover, freeze-thaw cycle was implemented for crosslinking of polyvinyl alcohol (PVA)/Ca-alginate blend beads. The oil-in-oil solvent evaporation method was adopted for the Eudragit coating of hydrogel beads using different coat: core ratios (4:1 or 8:1). Coated and uncoated hydrogel beads were evaluated by in vitro physicochemical properties, swelling and drug release behaviours, and in vivo pharmacokinetics, swelling, and toxicity evaluation. Diclofenac sodium was loaded as an experimental drug. Drug entrapment efficiency for the PVA/Ca-alginate beads was calculated as 98%, and for Ca-alginate beads, it came out to a maximum of 74%. Drug release study at various pH suggested that, unlike uncoated hydrogel beads, the coated beads delay the release of diclofenac sodium in low pH of the gastric and intestinal environment, thus targeting the colon for the drug release. It was concluded that Eudragit S-100-coated hydrogel beads could serve as a more promising and reliable way to target the colon for drug delivery.Graphical abstract.

Folate targeted lipid chitosan hybrid nanoparticles for enhanced anti-tumor efficacy.

Folic acid is often used for active targeting of tumor cells to enhance therapeutic outcomes. Here, folic acid was conjugated with chitosan and folate-conjugated chitosan-lipid hybrid nanoparticles were prepared by ionic gelation method using anionic lipid. These nanoparticles were in size range of 200 to 400 nm with spherical shape. In vitro drug release data suggested a sustained release of cisplatin. The therapeutic efficacy of the folate-conjugated hybrid nanoparticles was evaluated in SK-OV-3, A2780 and MCF-7 cancer cell lines. A significant increase in cytotoxicity was observed with folate targeted LPHNPs compared to non-targeted LPHNPs. Significantly enhanced cellular uptake and cell cycle arrest resulting from folate-targeted nanoparticles were confirmed using fluorescence microscopy and flow cytometry. The therapeutic efficacy and tumor penetration were further evaluated in 3D spheroid tumor models. These studies suggest that folate-conjugated lipid-chitosan nanoparticles could enhance therapeutic activity and may represent a promising platform for active targeting of tumor cells.

Mechanistic Approaches of Internalization, Subcellular Trafficking, and Cytotoxicity of Nanoparticles for Targeting the Small Intestine.

Targeting the small intestine employing nanotechnology has proved to be a more effective way for site-specific drug delivery. The drug targeting to the small intestine can be achieved via nanoparticles for its optimum bioavailability within the systemic circulation. The small intestine is a remarkable candidate for localized drug delivery. The intestine has its unique properties. It has a less harsh environment than the stomach, provides comparatively more retention time, and possesses a greater surface area than other parts of the gastrointestinal tract. This review focuses on elaborating the intestinal barriers and approaches to overcome these barriers for internalizing nanoparticles and adopting different cellular trafficking pathways. We have discussed various factors that contribute to nanocarriers' cellular uptake, including their surface chemistry, surface morphology, and functionalization of nanoparticles. Furthermore, the fate of nanoparticles after their uptake at cellular and subcellular levels is also briefly explained. Finally, we have delineated the strategies that are adopted to determine the cytotoxicity of nanoparticles.

Enhancement of Dissolution and Skin Permeability of Pentazocine by Proniosomes and Niosomal Gel.

Proniosomes (PN) are the dry water-soluble carrier systems that may enhance the oral bioavailability, stability, and topical permeability of therapeutic agents. The low solubility and low oral bioavailability due to extensive first pass metabolism make Pentazocine as an ideal candidate for oral and topical sustained release delivery. The present study was aimed to formulate the PNs by quick slurry method that are converted to niosomes (liquid dispersion) by hydration, and subsequently formulated to semisolid niosomal gel. The PNs were found in spherical shape in the SEM and stable in the physicochemical and thermal analysis (FTIR, TGA, and XRD). The quick slurry method produced high recovery (> 80% yield) and better flow properties (θ = 28.1-37.4°). After hydration, the niosomes exhibited desirable entrapment efficiency (44.45-76.23%), size (4.98-21.3 µm), and zeta potential (- 9.81 to - 21.53 mV). The in vitro drug release (T100%) was extended to more than three half-lives (2-4 h) and showed good fit to Fickian diffusion indicated by Korsmeyer-Peppas model (n = 0.136-0.365 and R2 = 0.9747-0.9954). The permeation of niosomal gel was significantly enhanced across rabbit skin compared to the pure drug-derived gel. Therefore, the PNs are found promising candidates for oral as dissolution enhancement and sustained release for oral and topical delivery of pentazocine for the management of cancer pain.

Ultrasonic Processing Technique as a Green Preparation Approach for Diacerein-Loaded Niosomes.

In this study, the feasibility of ultrasonic processing (UP) technique as green preparation method for production of poorly soluble model drug substance, diacerein, loaded niosomes was demonstrated. Also, the effects of different surfactant systems on niosomes' characteristics were analyzed. Niosomes were prepared using both the green UP technique and traditional thin-film hydration (TFH) technique, which requires the use of environmentally hazardous organic solvents. The studied surfactant systems were Span 20, Pluronic L64, and their mixture (Span 20 and Pluronic L64). Both the production techniques produced well-defined spherical vesicles, but the UP technique produced smaller and more monodisperse niosomes than TFH. The entrapment efficiencies with the UP method were lower than with TFH, but still at a feasible level. All the niosomal formulations released diacerein faster than pure drug, and the drug release rates from the niosomes produced by the UP method were higher than those from the TFH-produced niosomes. With UP technique, the optimum process conditions for small niosomal products with low PDI values and high entrapment efficiencies were obtained when 70% amplitude and 45-min sonication time were used. The overall results demonstrated the potency of UP technique as an alternative fast, cost-effective, and green preparation approach for production of niosomes, which can be utilized as drug carrier systems for poorly soluble drug materials.

Development of Eudragit RS 100 Microparticles Loaded with Ropinirole: Optimization and In Vitro Evaluation Studies.

The current study aimed to develop novel pH independent microparticles loaded with ropinirole (ROP) for sustained drug release. Eudragit RS 100 was used as release retardant and microparticles were fabricated by oil-in-oil emulsion solvent evaporation method. A three-factor three-level Box-Behnken design using Design-Expert software was employed to optimize formulation variables. Ropinirole loaded microparticles were evaluated with respect to morphology, particle size, encapsulation efficiency, and in vitro release profile. Optical microscopy and SEM micrographs indicated spherical shape with smooth surface and well-defined boundary. The particle size was in the range of 98.86 to 236.29 µm, being significantly increased with increasing polymer concentration. Higher polymer load also increased the thickness of internal polymer network, which led to reduced drug loss and higher entrapment efficiency (89%). The cumulative in vitro release was found to be in the range of 54.96 to 99.36% during the release studies (12 h) following zero order release kinetics and non-Fickian diffusion pattern. The developed microparticles have the potential to sustain the release of ropinirole, which may lead to a reduction in its adverse effects and improved management of Parkinson's disease.

SOCIO-ECONOMIC CONSTRAINS FACED BY TB PATIENTS THAT LEAD TO NON-COMPLIANCE - A CROSS SECTIONAL STUDY IN SOUTHERN PUNJAB, PAKISTAN.

Tuberculosis (TB) is an infectious disease that is communicable from one person to another. Pakistan stands forefront among few unfortunate countries that still have heavy burden of TB infection. Being a developing country, TB patients in Pakistan have to face different socio-economic constraints that upset life of the patients as well as their families. A cross sectional survey was conducted in three selected districts, Lodharan, Bahawalpur and Bahawalnagar during February 2011 to June 2011. From three hundred selected patients 210 Were enrolled in study after receiving written consents. Data were collected though structured questionnaire and verbal-interviews and statistically analyzes by using the univariate analysis. The survey results showed that the low educational status (p < 0.0012, CI 95%), unawareness of disease (88.7%), crowded population (p = 0.0000, CI, 95%), poverty, high treatment cost and distant access to public health facilities were directly related to prevalence of TB. Different disease related constraints including poor attitude of family members, colleagues, society and even health care professionals (p = 0.0000, CI 95%) were also found to be major social factors leading to non-compliance and denial of TB treatment. Socio-economic constraints such as low literacy rate, unemployment, unawareness of disease, high treatment cost, poor attitude of family, society and healthcare professionals were directly related to noncompliance and should be given high priority consideration for achieving better TB management and mitigation.

Nanotoxicity of Inert Materials: The Case of Gold, Silver and Iron.

Nanotechnology has opened a new horizon of research in various fields including applied physics, chemistry, electronics, optics, robotics, biotechnology and medicine. In the biomedical field, nanomaterials have shown remarkable potential as theranostic agents. Materials which are considered inert are often used in nanomedicine owning to their nontoxic profile. At nanoscale, these inert materials have shown unique properties that differ from bulk and dissolved counterparts. In the case of metals, this unique behavior not only imparts paramount advantages but also confers toxicity due to their unwanted interaction with different cellular processes. In the literature, the toxicity of nanoparticles made from inert materials has been investigated and many of these have revealed toxic potential under specific conditions. The surge to understand underlying mechanism of toxicity has increased and different means have been employed to overcome toxicity problems associated with these agents. In this review, we have focused nanoparticles of three inert metallic materials i.e. gold, silver and iron as these are regarded as biologically inert in the bulk and dissolved form. These materials have gained wider research interest and studies indicating the toxicity of these materials are also emerging. Oxidative stress, physical binding and interference with intracellular signaling are the major role player in nanotoxicity and their predominance is highly dependent upon size, surface coating and administered dose of nanoparticles. Current strategies to overcome toxicity have also been reviewed in the light of recent literature. The authors also suggested that uniform testing standards and well-designed studies are needed to evaluate nanotoxicity of these materials that are otherwise considered as inert. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

SOCIO-ECONOMIC CONSTRAINS FACED BY TB PATIENTS THAT LEAD TO NON-COMPLIANCE - A CROSS SECTIONAL STUDY IN SOUTHERN PUNJAB, PAKISTAN.

Tuberculosis (TB) is an infectious disease that is communicable from one person to another. Pakistan stands forefront among few unfortunate countries that still have heavy burden of TB infection. Being a developing country, TB patients in Pakistan have to face different socio-economic constraints that upset life of the patients as well as their families. A cross sectional survey was conducted in three selected districts, Lodharan, Bahawalpur and Bahawalnagar during February 2011 to June 2011. From three hundred selected patients 210 were enrolled in study after receiving written consents. Data were collected though structured questionnaire and verbal interviews and statistically analyzed by using the univariate analysis. The survey results showed that the low educational status (p < 0.0012, CI 95%), unawareness of disease (88.7%), crowded population (p =0.0000, CI, 95%), poverty, high treatment cost and distant access to public health facilities were directly related to prevalence of TB. Different disease related constraints including poor attitude of family members, colleagues, society and even health care professionals (p = 0.0000, CI 95%) were also found to be major social factors leading to non-compliance and denial of TB treatment. Socio-economic constraints such as low literacy rate, unemployment, unawareness of disease, high treatment cost, poor attitude of family, society and health care professionals were directly related to noncompliance and should be given high priority consideration for achieving better TB management and mitigation.

In vitro enzymatic investigation of Ficus carica (Fruit).

The present study demonstrates the biological study of Ficus carica fruit. Methanolic extract of plant fruit was prepared and evaporated under reduced pressure by rota vapor and n- hexane, Chloroform, ethyl acetate and n-butanol soluble fractions were prepared separately from crude methanolic extract. These fractions were then screened for acetyl cholinesterase, butryl cholinesterase and lipoxygenase activities. n-butanol soluble fraction showed significant antiacetylcholinesterase activity (78.55±0.76%) with IC50 of 55.8±0.37µg/ml, ethyl acetate soluble fraction showed significant anti-butrylcholinesterase activity (70.35±0.85%) with IC50 of 276.5±0.64µg/ml and significant antilipoxygenase activity was shown by ethyl acetate soluble fraction (62.52±0.26%) with IC50 of 380±0.08µg/ml.

Liposomal drug delivery: a versatile platform for challenging clinical applications.

Liposomes are lipid based vesicular systems that offer novel platform for versatile drug delivery to target cell. Liposomes were first reported by Bangham and his co-workers in 1964 (1). Since then, liposomes have undergone extensive research with the prime aim to optimize encapsulation, stability, circulation time and target specific drug delivery. Manipulation of a liposome's lipid bilayer and surface decoration with selective ligands has transformed conventional liposomes into adaptable and multifunctional liposomes. Development of liposomes with target specificity provide the prospect of safe and effective therapy for challenging clinical applications. Bioresponsive liposomes offer the opportunity to release payload in response to tissue specific microenvironment. Incorporation of novel natural and synthetic materials has extended their application from stable formulations to controlled release targeted drug delivery systems. Integration and optimization of multiple features into one system revolutionized research in the field of cancer, gene therapy, immunotherapy and infectious diseases. After 50 years since the first publication, this review is aimed to highlight next generation of liposomes, their preparation methods and progress in clinical applications.

Compritol®-based solid lipid nanoparticles of desvenlafaxine prepared by ultrasonication-assisted hot-melt encapsulation to modify its release.

Aims: Desvenlafaxine (DES) in conventional dosage forms shows initial burst release after oral administration, leading to exaggeration of its side effects. These side effects can be overcome by a sustained-release dosage form using the chemically inert, low-melting-point lipid Compritol® 888 ATO, as it reduces initial burst release. Materials & methods: The potential of DES-loaded solid lipid nanoparticles (DES-SLNs) synthesized by ultrasonication-assisted hot-melt encapsulation to modify the release of DES was investigated. Results: The entrapment efficiency of DES-SLNs was 65.90% with the in vitro release profile showing a sustained-release behavior achieving 81% cumulative release within 16 h without initial burst release. Conclusion: DES-SLNs are a potential carrier for sustained release of water-soluble antidepressant drugs such as DES.

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