Development and Optimization of Proniosomal Formulation of Irbesartan Using a Box-Behnken Design to Enhance Oral Bioavailability: Physicochemical Characterization and In Vivo Assessment.

This research work aimed to develop and evaluate proniosomes for the oral delivery of the lipophilic drug Irbesartan (IRB) to improve its solubility and bioavailability. Proniosomes of Irbesartan were formulated using a lipid, surfactant, and carrier by a slurry method. Based on the prepared preliminary trial batches and their evaluation, the formulation was optimized by employing a Box-Behnken design (BBD) in which concentrations of span 60 (X1), cholesterol (X2), and mannitol (X3) were used as three independent variables and the vesicular size (VS) (Y1), % entrapment efficiency (% EE) (Y2), and % cumulative drug release (% CDR) (Y3) were used as dependent variables. The optimized batch B1 was obtained from the BBD experiment after validation of checkpoint analysis, and their characterization was done for VS, % EE, % CDR, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) analysis. The optimized batch showed a VS of 199 ± 5.4 nm, a % EE of 99.25 ± 2.24%, and a % CDR of 97.36 ± 1.13% at 24 h. Scanning electron microscopy (SEM) study showed a smooth surface of batch B1. DSC and XRD studies indicated the amorphous nature of the proniosomal formulation. The proniosomal formulation showed increased solubility (2.65 ± 0.2 mg/mL) in phosphate buffer, pH 6.8, as compared to water (0.059 ± 0.02 mg/mL). The pharmacokinetic study in rats confirmed the increased bioavailability of the drug in optimized proniosomal formulation compared with its pure drug suspension. Cmax, Tmax, and AUC0-t of the drug also increased by 2-fold compared to those of drug suspension. Thus, in conclusion, the proniosomal formulation proved to be an efficient carrier for improved oral delivery of Irbesartan by improving the solubility and bioavailability of the drug.

A Comprehensive Review of Various Therapeutic Strategies for the Management of Skin Cancer.

Skin cancer (SC) poses a global threat to the healthcare system and is expected to increase significantly over the next two decades if not diagnosed at an early stage. Early diagnosis is crucial for successful treatment, as the disease becomes more challenging to cure as it progresses. However, identifying new drugs, achieving clinical success, and overcoming drug resistance remain significant challenges. To overcome these obstacles and provide effective treatment, it is crucial to understand the causes of skin cancer, how cells grow and divide, factors that affect cell growth, and how drug resistance occurs. In this review, we have explained various therapeutic approaches for SC treatment via ligands, targeted photosensitizers, natural and synthetic drugs for the treatment of SC, an epigenetic approach for management of melanoma, photodynamic therapy, and targeted therapy for BRAF-mutated melanoma. This article also provides a detailed summary of the various natural drugs that are effective in managing melanoma and reducing the occurrence of skin cancer at early stages and focuses on the current status and future prospects of various therapies available for the management of skin cancer.

Self-Emulsifying Drug Delivery System for Enhanced Oral Delivery of Tenofovir: Formulation, Physicochemical Characterization, and Bioavailability Assessment.

Tenofovir (TNF) is a common component of many antiretroviral therapy regimens, but it is associated with poor membrane permeability and low oral bioavailability. To improve its oral bioavailability and membrane permeability, a self-emulsifying drug delivery system (SEDDS) was developed and characterized, and its relative bioavailability was compared to the marketed tablets (Tenof). Based on solubility and ternary phase diagram analysis, eucalyptus oil was selected as an oil phase, Kolliphor EL, and Kollisolv MCT 70 were chosen as surfactant and cosurfactant, respectively, while glycerol was used as cosolvent in surfactant mixture. Optimized SEDDS formulation F6 showed an oil droplet size of 98.82 nm and zeta potential of -13.03 mV, indicating the high stability of oil droplets. Differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy characterization studies were also carried out to assess the amorphous and morphological states of the drug in the prepared SEDDS formulation. The in vitro dissolution profile of SEDDS shows the rapid release of the drug. SEDDS F6 demonstrates a higher drug permeability than the plain TNF and TNF-marketed tablets (Tenof). A pharmacokinetic study in rats revealed that SEDDS F6 showed significantly higher Cmax and AUC0-t than the marketed tablets and pure drug suspension. In addition, the relative bioavailability of SEDDS formulation dramatically improved by 21.53-fold compared to marketed tablets and 66.27-fold compared to pure drugs. These findings show that SEDDS composed of eucalyptus oil, glycerol, Kolliphor EL, and Kollisolv MCT 70 could be a useful tool for enhancing physiochemical properties and oral TNF absorption. Therefore, SEDDS has shown promise in improving the oral bioavailability of poorly water-soluble drugs.

A Systematic Review of Chronic Diseases and Their Prevalence Among the Population of Northern Borders Province (NBP) in Saudi Arabia.

Estimation of the prevalence of chronic conditions is pivotal to effective healthcare planning and management. Therefore, our objective was to systemically review previous literature about the prevalence of chronic diseases among residents of Northern Borders Province (NBP) in Saudi Arabia. The electronic search has been done using scientific databases (PubMed, Ebsco, SciFinder, and Web of Science) and search engines up to September 2021. The following main key terms: chronic disease OR chronic conditions AND prevalence AND Northern Borders Province OR Northern Borders AND Saudi Arabia were applied. Other related terms with a more specific search were done with names of the main cities in the province and the most common diseases in Saudi Arabia. Duplicates were removed electronically by Endnote and manually. Extracted data were tabulated in the literature matrix. The risk of bias and quality of included studies were assessed using the "Strengthening the Reporting of Observational Studies in Epidemiology" (STROBE) checklist. Out of 63 observational studies that were assessed for eligibility, 21 observational studies were included to synthesize the evidence. These studies were conducted on Arar (n=16), Turaif (n=2), and Rafha (n=1), while the remaining were national studies in which NBP was one of the included regions (n=2). The most frequently studied diseases were diabetes (4 records), psychological diseases (4 records), and obesity (3 records). The most prevalent disease was gastroesophageal reflux disease (GERD), with an estimated prevalence of 61% among adults in Arar city. In conclusion, although some research is conducted about chronic diseases somewhere in NBP, further studies are needed to study chronic diseases using a representative sample of the whole NBP population.

Accelerated stability evaluation and in vitro antimicrobial activity of a preformed ciprofloxacin nanocrystal formulation.

Ciprofloxacin (CIP) is frequently used to treat variety of bacterial illnesses. Drugs can lose their therapeutic efficiency due to physical and chemical deterioration. Therefore, the objective was to evaluate CIP nanocrystals stability and antibacterial activity. Nanocrystals were formulated using CIP drug (250 mg) and poloxamer 188 (2.5% w/v) using probe sonication method. Stability investigations were carried out under International Conference on Harmonization guidelines. Various stability parameters like particle size, zeta potential and polydispersity index were examined at different storage conditions. Positive outcomes from the formulation's stability were observed and formulation was stable up to three months. The test parameters shown no discernible changes during stability. Accelerated stability testing was done to calculate shelf-life and was found 2.96 years. The antibacterial activity was evaluated by calculating the minimum inhibitory concentration (MIC) against S. aureus and E. coli and CIP nanocrystals shown lower MIC than pure drug. This study revealed that the antibacterial activity of the formulation was maintained for 3 months at both temperatures (4 and 25°C) and CIP nanocrystals have excellent potential to treat infections caused by such microorganisms. Therefore, CIP nanocrystals could significantly increases its antimicrobial activity, which may translate into a significant improvement in therapeutic outcomes.

Solid-Phase Extraction (SPE) Technique to Quantify Cefdinir in Human Plasma Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).

A biosensitive analysis method development and validation was performed for accurate and rapid quantification of cefdinir (CDR) in human plasma by a liquid chromatography-tandem mass spectrometry technique coupled with electrospray ionization. Analysis was carried out using a C18 column with a flow rate of 1.0 mL/min and operating temperature of 30.0 ± 1°C. The drug was eluted by optimizing the m/z ratios of 396.20 â†’ 227.20 and 428.17 â†’ 241.10, for cefdinir and IS (internal standard), respectively. The intraday precision (%CV) for Cefdinir ranged from 2.8% and 6.7% as lower limit of quantification of quality control (LLOQ QC) and higher level of quantification of quality control (HQC QC), respectively, whereas these value were found to be as 3.0% and 5.6% for LLOQ and HQC, respectively after interday precision. Moreover, accuracy ranged from 107.70% (HQC QC) to 95.5% (LLOQ QC). The extraction mean recovery was found to be 83.91 ± 6.0% for cefdinir and 76.7 ± 6.23% for IS. The drug was stable throughout the analysis period. It was possible to analyze several plasma samples every day since each sample took <2.5 min to run. The method demonstrated successful quantification of CDR in human plasma, followed by pharmacokinetic profiles that were simple, accurate, sensitive and cost-effective.

Global Epidemiology, Clinical Features, Diagnosis and Current Therapeutic Novelties in Migraine Therapy and their Prevention: A Narrative Review.

INTRODUCTION: The current article reviews the latest information on epidemiology, clinical features, diagnosis, recent advancements in clinical management, current therapeutic novelties, and the prevention of migraines. In a narrative review, all studies as per developed MeSH terms published until February 2023, excluding those irrelevant, were identified through a PubMed literature search. METHODS: Overall, migraine affects more than a billion people annually and is one of the most common neurological illnesses. A wide range of comorbidities is associated with migraines, including stress and sleep disturbances. To lower the worldwide burden of migraine, comprehensive efforts are required to develop and enhance migraine treatment, which is supported by informed healthcare policy. Numerous migraine therapies have been successful, but not all patients benefit from them. RESULTS: CGRP pathway-targeted therapy demonstrates the importance of translating mechanistic understanding into effective treatment. In this review, we discuss clinical features, diagnosis, and recently approved drugs, as well as a number of potential therapeutic targets, including pituitary adenylate cyclase-activating polypeptide (PACAP), adenosine, opioid receptors, potassium channels, transient receptor potential ion channels (TRP), and acid-sensing ion channels (ASIC). CONCLUSION: In addition to providing more treatment options for improved clinical care, a better understanding of these mechanisms facilitates the discovery of novel therapeutic targets.

Novel Therapeutic Approach in PEGylated Chitosan Nanoparticles of Apigenin for the Treatment of Cancer via Oral Nanomedicine.

The goal of this study was to optimize and formulate apigenin (APG)-loaded pegylated chitosan nanoparticles (PEGylated-CNPs) via ionic gelation techniques using the Box-Behnken design (BBD). Three individual variables, X1(chitosan: TPP concentration), X2 (PEG-400 concentration), and X3 (sonication time), were investigated for their influence on response variables (Y1-particle size (PS); Y2-drug entrapment efficiency (DEE); and Y3-zeta potential (ZP). The optimized formula of APG-PEGylated CNPs was picked from the statistical design and was then examined for physical, morphological, release characterization, anti-oxidant, and anti-tumor potential. The average PS, PDI, %DEE, and ZP were found to be 139.63 ± 5.67 nm, 0.296 ± 0.014, 79.55 ± 3.12%, and 24.68 ± 1.84 mV, respectively. The optimized APG formulation was chosen and reformulated based on the desirability function. Results of the observed and predicted values of responses through the BBD process were found to be nearly identical. The resulting APG-PEGylated CNPs were spherical and smooth, according to surface morphology studies. The release study revealed that PEGylated-CNPs exhibited biphasic release patterns distinguished by an initial burst release of APG only at early phases accompanied by a delayed release near 24 h. Furthermore, APG-PEGylated CNPs demonstrated statistically increased antioxidant activities and cytotoxicity against MCF-7 cells compared to pure APG. Based on the findings, it is possible to conclude that BBD was efficient in optimizing the PEGylated CNPs formulation and recognizing the impacts of formulation variables. In conclusion, the developed formulation has a significant potential for anticancer therapy.

Development of Apigenin-Loaded Niosomes Using Ecological Probe Sonication Technique for Enhanced Oral Delivery: Application of Box- Behnken Design.

BACKGROUND: Apigenin (APG), a natural bioactive flavonoid has multiple pharmacological effects. However, its poor aqueous solubility hinders its clinical benefits. OBJECTIVE AND METHODS: The work aimed to develop novel apigenin-loaded niosomes (APG-NIO) with ecological probe sonication techniques. The formulation was statistically optimized by Box-Behnken design (BBD) and the independent variables were selected as Span 80(X1), Poloxamer 188(X2), and Tween 80(X3) at three levels, and the dependent variables were identified as: particle size (Y1), polydispersity index (Y2), and % entrapment efficiency (Y3). The formulation was characterized for various parameters such as vesicle shape, size, PDI, %EE, solubility, in vitro drug release, and antioxidant potential. RESULTS: The optimized APG-NIO formulation was found to have a spherical shape with homogenous distribution and a low polydispersity index. It has a particle size of 425.77 nm, zeta potential -17.1±0.9 mV, and % EE of 89.63. The aqueous solubility of APG-NIO was found approximately 45 times higher than that of pure APG. The formulation showed a higher drug release rate as compared to pure APG in phosphate buffer pH 7.4 and followed the Higuchi release model with a non-Fickian transport mechanism. The stability was found at 4°C for 3 months. The antioxidant potential of APG-NIO was significantly increased in comparison to the pure drug suspension in the DPPH• assay. CONCLUSION: These findings suggest that the probe sonication technique is an alternative, cost-effective, simple, and green method for the development of niosomes, and BBD is a useful optimization tool for identifying the effect of formulation variables.

An Updated Review on Therapeutic Potential and Recent Advances in Drug Delivery of Berberine: Current Status and Future Prospect.

Natural products are well known for their high potency with minimum side effects. Plant extracts are the most commonly used natural products because of their ease of availability and relatively low production cost. Berberine (BBR), a phytochemical component of some Chinese medicinal herbs (most commonly Berberis vulgaris), is an isoquinoline alkaloid with several biological and pharmacological effects including antioxidant, anti-inflammatory, antitumour, antimicrobial, antidepressant, hepatoprotective, hypolipidemic, and hypoglycemic actions. Interestingly, multiple studies have shown that BBR is a potential drug candidate with a multi-spectrum therapeutic application. However, the oral delivery of BBR is challenged owing to its poor bioavailability. Therefore, its oral bioavailability needs to be enhanced before it can be used in many clinical applications. This review provides an overview of the various studies that support the broad range of pharmacological activities of BBR. Also, it includes a section to address the issues and challenges related to the drug and methods to improve the properties of BBR, such as solubility, stability and bioavailability that may be explored to help patients reap the maximum benefit from this potentially useful drug.

Development, Characterization, and Evaluation of α-Mangostin-Loaded Polymeric Nanoparticle Gel for Topical Therapy in Skin Cancer.

The aim of this study was to prepare and evaluate α-mangostin-loaded polymeric nanoparticle gel (α-MNG-PLGA) formulation to enhance α-mangostin delivery in an epidermal carcinoma. The poly (D, L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were developed using the emulsion-diffusion-evaporation technique with a 3-level 3-factor Box-Behnken design. The NPs were characterized and evaluated for particle size distribution, zeta potential (mV), drug release, and skin permeation. The formulated PLGA NPs were converted into a preformed carbopol gel base and were further evaluated for texture analysis, the cytotoxic effect of PLGA NPs against B16-F10 melanoma cells, and in vitro radical scavenging activity. The nanoscale particles were spherical, consistent, and average in size (168.06 ± 17.02 nm), with an entrapment efficiency (EE) of 84.26 ± 8.23% and a zeta potential of -25.3 ± 7.1 mV. Their drug release percentages in phosphate-buffered solution (PBS) at pH 7.4 and pH 6.5 were 87.07 ± 6.95% and 89.50 ± 9.50%, respectively. The release of α-MNG from NPs in vitro demonstrated that the biphasic release system, namely, immediate release in the initial phase, was accompanied by sustained drug release. The texture study of the developed α-MNG-PLGA NPs gel revealed its characteristics, including viscosity, hardness, consistency, and cohesiveness. The drug flux from α-MNG-PLGA NPs gel and α-MNG gel was 79.32 ± 7.91 and 16.88 ± 7.18 µg/cm2/h in 24 h, respectively. The confocal study showed that α-MNG-PLGA NPs penetrated up to 230.02 µm deep into the skin layer compared to 15.21 µm by dye solution. MTT assay and radical scavenging potential indicated that α-MNG-PLGA NPs gel had a significant cytotoxic effect and antioxidant effect compared to α-MNG gel (p < 0.05). Thus, using the developed α-MNG-PLGA in treating skin cancer could be a promising approach.

Molecular Targets and Nanoparticulate Systems Designed for the Improved Therapeutic Intervention in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most aggressive and fatal CNS related tumors, which is responsible for about 4% of cancer-related deaths. Current GBM therapy includes surgery, radiation, and chemotherapy. The effective chemotherapy of GBM is compromised by two barriers, i. e., the blood-brain barrier (BBB) and the blood tumor barrier (BTB). Therefore, novel therapeutic approaches are needed. Nanoparticles are one of the highly efficient drug delivery systems for a variety of chemotherapeutics that have gained massive attention from the last three decades. Perfectly designed nanoparticles have the ability to cross BBB and BTB and precisely deliver the chemotherapeutics to GBM tissue/cells. Nanoparticles can encapsulate both hydrophilic and lipophilic drugs, genes, proteins, and peptides, increase the stability of drugs by protecting them from degradation, improve plasma half-life, reduce adverse effects and control the release of drugs/genes at the desired site. This review focussed on the different signaling pathways altered in GBM cells to understand the rationale behind selecting new therapeutic targets, challenges in the drug delivery to the GBM, various transport routes in brain delivery, and recent advances in targeted delivery of different drug and gene loaded various lipidic, polymeric and inorganic nanoparticles in the effective management of GBM.

Nanocarriers in advanced drug targeting: setting novel paradigm in cancer therapeutics.

Cancer has been growing nowadays consequently high number of death ascertained worldwide. The medical intervention involves chemotherapy, radiation therapy and surgical removal. This conventional technique lacking targeting potential and harm the normal cells. In drug treatment regimen, the combination therapy is preferred than single drug treatment module due to higher internalization of chemotherapeutics in the cancer cells both by enhance permeation retention effect and by direct cell apoptosis. The cancer therapeutics involves different methodologies of delivering active moiety to the target site. The active and passive transport mode of chemotherapeutic targeting utilizes advance nanocarriers. The nanotechnological strategic treatment applying advance nanocarrier greatly helps in mitigating the cancer prevalence. The nanocarrier-incorporating nanodrug directed for specific area appealed scientist across the globe and issues to be addressed in this regard. Therefore, various techniques and approaches invented to meet the objectives. With the advances in nanomedicine and drug delivery, this review briefly focused on various modes of nanodrug delivery including nanoparticles, liposomes, dendrimer, quantum dots, carbon nanotubes, metallic nanoparticles, nanolipid carrier (NLC), gold nanoshell, nanosize cantilevers and nanowire that looks promising and generates a novel horizon in cancer therapeutics.