Pectin nanoparticles loaded with nitric oxide donor drug: A potential approach for tissue regeneration.

The process of wound healing and tissue regeneration involves several key mechanisms to ensure the production of new tissues with similar cellular functions. This study investigates the impact of pectin, a natural polysaccharide, and nebivolol hydrochloride (NBV), a nitric oxide (NO) donor drug, on wound healing. Utilizing ionotropic gelation, NBV-loaded pectin nanoparticles were developed following a 2231 full factorial design. The optimized formulation, determined using Design expert® software, exhibited an encapsulation efficiency percentage of 70.68%, zeta potential of -51.4 mV, and a particle size of 572 nm, characterized by a spherical, discrete morphology. An in vivo study was conducted to evaluate the effectiveness of the optimal formulation in wound healing compared to various controls. The results demonstrated the enhanced ability of the optimal formulation to accelerate wound healing. Moreover, histopathological examination further confirmed the formulation's benefits in tissue proliferation and collagen deposition at the wound site 15 days post-injury. This suggests that the developed formulation not only promotes faster healing but does so with minimal side effects, positioning it as a promising agent for effective wound healing and tissue regeneration.

Formulation and optimization of ivermectin nanocrystals for enhanced topical delivery.

The increasing resistance to antiparasitic drugs and limited availability of new agents highlight the need to improve the efficacy of existing treatments. Ivermectin (IVM) is commonly used for parasite treatment in humans and animals, however its efficacy is not optimal and the emergence of IVM-resistant parasites presents a challenge. In this context, the physico-chemical characteristics of IVM were modified by nanocrystallization to improve its equilibrium water-solubility and skin penetration, potentially improving its therapeutic effectiveness when applied topically. IVM-nanocrystals (IVM-NC) were prepared using microfluidization technique. The impact of several process/formulation variables on IVM-NC characteristics were studied using D-optimal statistical design. The optimized formulation was further lyophilized and evaluated using several in vitro and ex vivo tests. The optimal IVM-NC produced monodisperse particles with average diameter of 186 nm and polydispersity index of 0.4. In vitro results showed an impressive 730-fold increase in the equilibrium solubility and substantial 24-fold increase in dissolution rate. Ex vivo permeation study using pig's ear skin demonstrated 3-fold increase in dermal deposition of IVM-NC. Additionally, lyophilized IVM-NC was integrated into topical cream, and the resulting drug release profile was superior compared to that of the marketed product. Overall, IVM-NC presents a promising approach to improving the effectiveness of topically applied IVM in treating local parasitic infections.

Unmasking the enigma: An in-depth analysis of COVID-19 impact on the pediatric population.

OBJECTIVES: COVID-19, caused by the novel coronavirus, has had a profound and wide-reaching impact on individuals of all age groups across the globe, including children. This review article aims to provide a comprehensive analysis of COVID-19 in children, covering essential topics such as epidemiology, transmission, pathogenesis, clinical features, risk factors, diagnosis, treatment, vaccination, and others. By delving into the current understanding of the disease and addressing the challenges that lie ahead, this article seeks to shed light on the unique considerations surrounding COVID-19 in children and contribute to a deeper comprehension of this global health crisis affecting our youngest population. METHODS: A comprehensive literature search was conducted to gather the most recent and relevant information regarding COVID-19 in children. Multiple renowned databases, including MEDLINE, PubMed, Scopus, as well as authoritative sources such as the World Health Organization (WHO), the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the National Institutes of Health (NIH) websites and others were thoroughly searched. The search included articles, guidelines, reports, clinical trials results and expert opinions published within the past three years, ensuring the inclusion of the latest research findings on COVID-19 in children. Several relevant keywords, including "COVID-19," "SARS-CoV-2," "children," "pediatrics," and related terms were used to maximize the scope of the search and retrieve a comprehensive set of articles. RESULTS AND CONCLUSION: Three years since the onset of the COVID-19 pandemic, our understanding of its impact on children has evolved, but many questions remain unanswered. While SAR-CoV-2 generally leads to mild illness in children, the occurrence of severe cases and the potential for long-term effects cannot be overlooked. Efforts to comprehensively study COVID-19 in children must continue to improve preventive strategies, identify high-risk populations, and ensure optimal management. By unraveling the enigma surrounding COVID-19 in children, we can strive towards safeguarding their health and well-being in the face of future global health challenges.

Graphene Oxide/Chitosan Injectable Composite Hydrogel for Controlled Release of Doxorubicin: An Approach for Enhanced Intratumoral Delivery.

Intratumoral (IT) injection of chemotherapeutics into needle-accessible solid tumors can directly localize the anticancer drug in the tumor site, thus increasing its local bioavailability and reducing its undesirable effects compared to systemic administration. In this study, graphene oxide (GO)-based chitosan/ß-glycerophosphate (CS/GP) thermosensitive injectable composite hydrogels (CH) were prepared and optimized for the localized controlled delivery of doxorubicin (DOX). A quality-by-design (QbD) approach was used to study the individual and combined effects of several formulation variables to produce optimal DOX-loaded GO/CS/GP CH with predetermined characteristics, including gelation time, injectability, porosity, and swelling capacity. The surface morphology of the optimal formulation (DOX/opt CH), chemical interaction between its ingredients and in vitro release of DOX in comparison to GO-free CS/GP CH were investigated. Cell viability and cellular uptake after treatment with DOX/opt CH were studied on MCF 7, MDB-MB-231 and FaDu cell lines. The statistical analysis of the measured responses revealed significant effects of the concentration of GO, the concentration of CS, and the CS:GP ratio on the physicochemical characteristics of the prepared GO/CS/GP CH. The optimization process showed that DOX-loaded GO/CS/GP CH prepared using 0.1% GO and 1.7% CS at a CS: GO ratio of 3:1 (v/v) had the highest desirability value. DOX/opt CH showed a porous microstructure and chemical compatibility between its ingredients. The incorporation of GO resulted in an increase in the ability of the CH matrices to control DOX release in vitro. Finally, cellular characterization showed a time-dependent increase in cytotoxicity and cellular uptake of DOX after treatment with DOX/opt CH. The proposed DOX/opt CH might be considered a promising injectable platform to control the release and increase the local bioavailability of chemotherapeutics in the treatment of solid tumors.

Pharmaceutical equivalency of locally and regionally manufactured generic pharmaceutical products in UAE.

Generic drugs or generic medicines are pharmaceutical products manufactured to be equivalent to the brand/innovator drug products. They represent the majority of worldwide prescribed medicines; therefore, their quality is critical to maximize patients' therapeutic outcomes. This study aimed to evaluate the pharmaceutical equivalency of locally and regionally manufactured generic pharmaceutical products being sold in the United Arab Emirates (UAE) market to enhance public confidence, promote their utilization, and reduce treatment costs. Three drugs (tadalafil, rosuvastatin, and acetaminophen) from three different pharmacological classes were selected from the UAE market as representatives for generic drugs. At least two generic products for each locally (L) and regionally (R) manufactured generic were evaluated according to the USP criteria in comparison to the brand (B) comparator product. All comparative tests were performed before storage and 3 and 6 months after storage during the accelerated stability study performed under the conditions for climatic zone IV (40 °C ± 2 °C /75% RH ± 5% RH). Although results were statistically different from the comparators using ANOVA and Tukey's Kremer post hoc tests, all tests were within the USP acceptance limits, except one, for friability, disintegration, content uniformity, and dissolution. Significant changes were observed following their storage over 6 months during accelerated stability studies, however, without failing the USP limits. Only one locally manufactured acetaminophen generic failed the USP dissolution tests before and after its storage and failed the disintegration test following its storage under accelerated conditions for zone IV. In conclusion, the majority of the locally and regionally manufactured generic products being sold in the UAE market were of good quality and performed similarly to their comparators. However, a continuous independent quality evaluation for the marketed generic drugs is essential to enhance public confidence.

Repurposing Potential of the Antiparasitic Agent Ivermectin for the Treatment and/or Prophylaxis of COVID-19.

Due to the rapid, vast, and emerging global spread of the Coronavirus Disease 2019 (COVID-19) pandemic, many drugs were quickly repurposed in a desperate attempt to unveil a miracle drug. Ivermectin (IVM), an antiparasitic macrocyclic lactone, was tested and confirmed for its in vitro antiviral activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in early 2020. Along with its potential antiviral activity, the affordability and availability of IVM resulted in a wide public interest. Across the world, trials have put IVM to test for both the treatment and prophylaxis of COVID-19, as well as its potential role in combination therapy. Additionally, the targeted delivery of IVM was studied in animals and COVID-19 patients. Through this conducted literature review, the potential value and effectiveness of the repurposed antiparasitic agent in the ongoing global emergency were summarized. The reviewed trials suggested a value of IVM as a treatment in mild COVID-19 cases, though the benefit was not extensive. On the other hand, IVM efficacy as a prophylactic agent was more evident and widely reported. In the most recent trials, novel nasal formulations of IVM were explored with the hope of an improved optimized effect.

A Nano-Liposomal Formulation of Caffeic Acid Phenethyl Ester Modulates Nrf2 and NF-κß Signaling and Alleviates Experimentally Induced Acute Pancreatitis in a Rat Model.

The currently available management strategies for acute pancreatitis are inadequately effective which calls for exploration of new approaches to treat this condition. Caffeic acid phenethyl ester (CAPE) is a major bioactive constituent of honeybee propolis with promising therapeutic and preventive applications. However, its pharmaceutical potential and clinical use are hindered by its poor water solubility and limited plasma stability. In this study, we aimed to prepare, characterize and evaluate a CAPE-loaded nanoliposomal formulation to improve the efficacy of CAPE for the management of acute pancreatitis. The CAPE-loaded nanoliposomes (CAPE-loaded-NL) were prepared by a thin layer evaporation technique and were optimized using three edge activators. CAPE-loaded-NL were characterized for their vesicle size (VS), zeta potential (ZP), encapsulation efficiency (EE), polydispersity index (PDI), crystalline state and morphology. The protective effect of the optimal CAPE-loaded-NL was evaluated in a rat model of acute pancreatitis induced by administering a single intraperitoneal injection of L-ornithine. Oral pretreatment with CAPE-loaded-NL significantly counteracted ornithine-induced elevation in serum activities of pancreatic digestive enzymes and pancreatic levels of malondialdehyde, nuclear factor kappa B (NF-κB) p65, tumor necrosis factor-alpha, nitrite/nitrate, cleaved caspase-3 and myeloperoxidase activity. Moreover, pretreatment with CAPE-loaded-NL significantly reinstated the ornithine-lowered glutathione reductase activity, glutathione, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 levels and ATP/ADP ratio, and potentiated the Bcl-2/Bax ratio in pancreatic tissue. CAPE-loaded-NL displayed superior antioxidant, anti-inflammatory and anti-apoptotic effects compared to free CAPE oral suspension and achieved a more potent correction of the derangements in serum amylase and pancreatic myeloperoxidase activities. The histological observations were in line with the biochemical findings. Our results suggest that CAPE-loaded-NL provide a promising interventional approach for acute pancreatitis mainly through the enhancement of the exerted antioxidant, anti-inflammatory and anti-apoptotic effects which may be mediated, at least in part, through modulation of Nrf2 and NF-κß signaling.

Modulation of the sublingual microenvironment and pH-dependent transport pathways to enhance atropine sulfate permeability for the treatment of organophosphates poisoning.

Atropine sulfate (AS) auto-injectors are the only approved antidote for out-of-hospital emergency treatment of organophosphates (OP) toxicity. However, they are only available for military use and require the administration of multiple auto-injectors. Therefore, an alternative, patient-friendly and more affordable fast-disintegrating sublingual tablets (FDSTs) of AS were previously developed. In this article, the effect of modifying the microenvironment's pH and/or using penetration enhancers on AS sublingual transport pathways were evaluated in an attempt to further enhance AS sublingual permeability. Ten different AS FDST formulations with or without the incorporation of alkalizer and various penetration enhancers were manufactured and characterized. AS permeability was investigated through excised porcine sublingual membrane using Franz cells. Results showed that the incorporation of either a transcellular enhancer or alkalizer achieved a significantly higher AS permeability enhancement (twofold). Combining sodium bicarbonate (Na Bicarb) 2% as alkalizer with sodium dodecyl sulfate (SDS) 1% as a transcellular enhancer resulted in the greatest synergistic enhancement in AS sublingual permeability (up to twelvefold). In conclusion, the modified AS FDST developed in this work has the potential to improve the pharmacokinetic parameters of AS following sublingual administration for the first-aid treatment of OP toxicity in future animal bioequivalency studies.

Magnetism in drug delivery: The marvels of iron oxides and substituted ferrites nanoparticles.

In modern drug delivery, seeking a drug delivery system (DDS) with a modifiable skeleton for proper targeting of loaded actives to specific sites in the body is of extreme importance for a successful therapy. Magnetically guided nanosystems, where particles such as iron oxides are guided to specific regions using an external magnetic field, can provide magnetic resonance imaging (MRI) while delivering a therapeutic payload at the same time, which represents a breakthrough in disease therapy and make MNPs excellent candidates for several biomedical applications. In this review, magnetic nanoparticles (MNPs) along with their distinguishable properties, including pharmacokinetics and toxicity, especially in cancer therapy will be discussed. The potential perspective of using other elements within the MNP system to reduce toxicity, improve pharmacokinetics, increase the magnetization ability, improve physical targeting precision and/or widen the scope of its biomedical application will be also discussed.

Nanoparticle-Mediated Dual Targeting: An Approach for Enhanced Baicalin Delivery to the Liver.

In this study, water-soluble chitosan lactate (CL) was reacted with lactobionic acid (LA), a disaccharide with remarkable affinity to hepatic asialoglycoprotein (ASGP) receptors, to form dual liver-targeting LA-modified-CL polymer for site-specific drug delivery to the liver. The synthesized polymer was used to encapsulate baicalin (BA), a promising bioactive flavonoid with pH-dependent solubility, into ultrahigh drug-loaded nanoparticles (NPs) via the ionic gelation method. The successful chemical conjugation of LA with CL was tested and the formulated drug-loaded LA-modified-CL-NPs were assessed in terms of particle size (PS), encapsulation efficiency (EE) and zeta potential (ZP) using full factorial design. The in vivo biodistribution and pharmacokinetics of the designed NPs were assessed using 99mTc-radiolabeled BA following oral administration to mice and results were compared to 99mTc-BA-loaded-LA-free-NPs and 99mTc-BA solution as controls. Results showed that the chemical modification of CL with LA was successfully achieved and the method of preparation of the optimized NPs was very efficient in encapsulating BA into nearly spherical particles with an extremely high EE exceeding 90%. The optimized BA-loaded-LA-modified-CL-NPs showed an average PS of 490 nm, EE of 93.7% and ZP of 48.1 mV. Oral administration of 99mTc-BA-loaded-LA-modified-CL-NPs showed a remarkable increase in BA delivery to the liver over 99mTc-BA-loaded-LA-free-CL-NPs and 99mTc-BA oral solution. The mean area under the curve (AUC0-24) estimates from liver data were determined to be 11-fold and 26-fold higher from 99mTc-BA-loaded-LA-modified-CL-NPs relative to 99mTc-BA-loaded-LA-free-CL-NPs and 99mTc-BA solution respectively. In conclusion, the outcome of this study highlights the great potential of using LA-modified-CL-NPs for the ultrahigh encapsulation of therapeutic molecules with pH-dependent/poor water-solubility and for targeting the liver.

Impact of sampling time deviations on the prediction of the area under the curve using regression limited sampling strategies.

The regression limited sampling strategy approach (R-LSS), which is based on a small number of blood samples drawn at selected time points, has been used as an alternative method for the estimation of the area under the concentration-time curve (AUC). However, deviations from planned sampling times may affect the performance of R-LSS, influencing related therapeutic decisions and outcomes. The aim of this study was to investigate the impact of different sampling time deviation (STD) scenarios on the estimation of AUC by the R-LSS using a simulation approach. Three types of scenarios were considered going from the simplest case of fixed deviations, to random deviations and then to a more realistic case where deviations of mixed nature can occur. In addition, the sensitivity of the R-LSS to STD in each involved sampling point was evaluated. A significant impact of STD on the performance of R-LSS was demonstrated. The tolerance of R-LSS to STD was found to depend not only on the number of sampling points but more importantly on the duration of the sampling process. Sensitivity analysis showed that sampling points at which rapid concentration changes occur were relatively more critical for AUC prediction by R-LSS. As a practical approach, nomograms were proposed, where the expected predictive performance of R-LSS was provided as a function of STD information. The investigation of STD impact on the predictive performance of R-LSS is a critical element and should be routinely performed to guide R-LSS selection and use.

Development and optimization of lyophilized orally disintegrating tablets using factorial design.

The aim of this study was to evaluate the use of maltodextrin as a sugar-matrix former along with several cellulosic binders in the preparation of freeze-dried orally disintegrating tablets (ODT). The ODT was prepared by freeze-drying an aqueous dispersion of nimesulide (NM) containing maltodextrin and a cellulosic binder. The influence of formulation parameters on the in vitro/in vivo disintegration time and in vitro dissolution of NM from ODTs along with other tablet characteristics was investigated using full factorial design. The optimized ODT contained 5% w/v maltodextrin DE 29, 2% w/v Methocel E15, and 5% w/v NM, disintegrated in less than 10 s and showed more than 70% of NM in ODTs dissolved within 2 min, compared to only 1.52% of NM plain drug and 7.25% of NM in immediate release commercial tablet. Crystalline state evaluation of NM in the optimized ODT was conducted through differential scanning calorimetry, and X-ray powder diffraction. The study suggests that the optimized ODT formulation developed in this work may be an alternative to conventional formulations of NM inconvenient to the patients such as intramuscular or rectal administration.

In vitro and in vivo evaluation of nimesulide lyophilized orally disintegrating tablets.

Development of a lyophilized orally disintegrating tablet (ODT) that enhanced the in vitro dissolution and in vivo absorption of nimesulide (NM), a drug with poor solubility and poor bioavailability, is presented. The ODTs were prepared by freeze-drying an aqueous dispersion of NM containing a matrix former, a sugar alcohol, and a collapse protectant. In addition, different disintegration accelerators were tested. The influence of formulation parameters on the disintegration time and in vitro dissolution of NM from ODTs along with other tablet characteristics was investigated. Results obtained from disintegration and dissolution studies showed that lyophilized ODTs disintegrated within few seconds and showed significantly faster dissolution rate of NM compared to the plain powder drug and NM in commercially available immediate release tablet Sulide. The ODTs were also examined using differential scanning calorimetry, X-ray diffraction, and scanning electron microscope. Stability results, after 12-month storage of selected ODTs at 25 degrees C and 60% relative humidity, were satisfactory. The extent of absorption of NM from a selected ODT when compared to an conventional immediate release tablet as a reference after administration of 100mg oral dose of NM was determined in healthy subjects using a randomized crossover design. In this study, the rate of absorption of NM from ODT was faster than that from the reference tablet, had a significantly higher (p=0.012) peak plasma concentration, and shortened time to C(max) by 1h (p=0.029). The extent of absorption expressed by AUC was 62% larger when compared to the commercially available tablet.

Relative bioavailability of griseofulvin lyophilized dry emulsion tablet vs. immediate release tablet: a single-dose, randomized, open-label, six-period, crossover study in healthy adult volunteers in the fasted and fed states.

The oral bioavailability of griseofulvin (GF) formulated as a fast disintegrating lyophilized dry emulsion (LDE) tablet was studied and compared to the commercially available immediate release (IR) tablet, as a reference, in both the fasted and fed states in nine healthy volunteers after a single oral dose (125 mg) in a crossover design. Furthermore the LDE tablets were ingested with and without water under both the fasted and fed states. In the fasted state, the rate of absorption was found to be significantly faster from LDE tablets, in the presence and absence of water, as shown by a higher C(max) (more than two times higher, p=0.0001) and a shorter t(max) (by more than 3h, p=0.0001) compared to IR tablets. The extent of absorption, expressed as AUC, from LDE tablets in the presence and absence of water was 65% and 77% larger and statistically significantly different relative to the mean AUC from IR tablets (p=0.006). In the fed state, C(max) from LDE tablets ingested with and without water was found to be about 30% and 50% higher, respectively, than the immediate release tablets. A shorter t(max) was also shown whether LDE tablets were ingested with or without water in the fed state as compared to immediate release tablets. The mean AUC from LDE tablets under fed conditions in the presence of water was about 21% larger and was not statistically significantly different from AUC from immediate release tablets (p=0.517). When ingested without water, AUC from LDE tablets was about 43% larger and statistically significantly different relative to AUC from IR tablets (p=0.033). The mean AUC from the LDE tablet ingested with water under fed conditions relative to AUC from LDE tablet ingested without water was not statistically significantly different (p=0.454). Results show that the food effect of the high fat meal is very pronounced in case of the immediate release tablets, Fulvin, than in case of LDE tablets whether given with or without water.

In vitro and in vivo evaluation of a fast-disintegrating lyophilized dry emulsion tablet containing griseofulvin.

Development of a fast-disintegrating lyophilized dry emulsion (LDE) tablet that enhanced the in vitro dissolution and in vivo absorption of griseofulvin (GF) is presented. The LDE tablets were prepared by freeze-drying o/w emulsions of GF, a drug for which bioavailability is known to be enhanced by fat co-administration. Oil-in-water emulsions were prepared using a gelatin solution (2%, w/v) as the water phase and medium chain triglycerides (Miglyol) or sesame oil as the oil phase. In addition, different emulsifiers were evaluated. The influence of formulation parameters on the disintegration and in vitro dissolution of GF from LDE tablets along with other tablet characteristics were investigated. A significant influence of the emulsifier type on the tablet disintegration time was seen (p<0.01). Results obtained from dissolution studies showed that LDE tablets of GF improved the dissolution rate of the drug compared to the plain drug. The extent of absorption of GF from a selected LDE tablet formulation as compared to an immediate release conventional tablet as reference after single oral dose (125mg) administration was determined in four healthy subjects using a randomized crossover design. In this study, the rate of absorption of GF from LDE tablet was faster than that from the reference tablet and had significantly higher (p=0.02) peak plasma concentration (more than three times higher) and shortened time to C(max) by 4h (p=0.014). The extent of absorption expressed by AUC was 85% larger as compared to the commercial tablet. Stability results, after 6 months storage of LDE tablets at 25 degrees C and 60% relative humidity, showed a slight increase in disintegration time and residual moisture content, while results from dissolution studies showed slightly slower initial drug release.