Captopril Polyvinyl Alcohol/Sodium Alginate/Gelatin-Based Oral Dispersible Films (ODFs) with Modified Release and Advanced Oral Bioavailability for the Treatment of Pediatric Hypertension.

Hypertension can begin in childhood; elevated blood pressure in children is known as pediatric hypertension. Contrary to adult hypertension, there is a scarcity of commercial medications suitable for the treatment of pediatric hypertension. The aim of this study was to develop orally dispersible films (ODFs) loaded with captopril for the treatment of hypertension in children. Captopril-loaded ODFs were composed of different blends of synthetic polymers, such as polyvinyl alcohol (PVA) and polyvinyl pyrrolidone, and natural polymers, such as sodium alginate (SA) and gelatin. The ODFs were characterized based on their mechanical and thermal properties, drug content, surface morphology, in vitro disintegration, in vitro release, and bioavailability. A novel HPLC method with precolumn derivatization was developed to precisely and selectively determine captopril levels in plasma. A low concentration of PVA and a high concentration of SA generated ODFs with faster hydration and disintegration rates. SA-based films exhibited fast disintegration properties (1-2 min). The optimized modified-release film (F2) showed significant (p < 0.05) enhancement in bioavailability (AUC = 1000 ng min/mL), with a value 1.43 times that of Capoten® tablets (701 ng min/mL). While the plasma concentration peaking was in favor of the immediate-release tablet, Tmax was significantly prolonged by 5.4 times for the optimized ODF (3.59 h) compared with that of the tablets (0.66 h). These findings indicate uniform and sustained plasma concentrations, as opposed to the pulsatile and rapid plasma peaking of captopril from the immediate-release tablets. These findings suggest that the modified release of oral films could offer more favorable plasma profiles and better control of hypertension than the conventional release tablets.

Impact of the functional coating of silver nanoparticles on their in vivo performance and biosafety.

OBJECTIVE AND SIGNIFICANCE: Silver nanoparticles (AgNPs) have become an interesting therapeutic modality and drug delivery platform. Herein, we aimed to investigate the impact of functional coating on the in vivo performance of AgNPs as an economic and scalable method to modulate their behavior. METHODS: AgNPs were coated with chitosan (CHI) as a model biopolymer using a one-pot reduction-based method, where CHI of two molecular weight ranges were investigated. The resultant CHI-coated AgNPs (AgNPs-CHI) were characterized using UV-VIS spectroscopy, DLS, and TEM. AgNPs were administered intravenously to rats and their biodistribution and serum levels of hepato-renal function markers were monitored 24 h later compared to plain AgNO3 as a positive control. RESULTS: UV-VIS spectroscopy confirmed the successful coating of AgNPs with CHI. DLS revealed the superiority of medium molecular weight CHI over its low molecular weight counterpart. AgNPs-CHI demonstrated a semi-complete clearance from the systemic circulation, a liver-dominated tissue tropism, and limited renal exposure. On the other hand, AgNO3 was poorly cleared from the circulation, with relatively high renal exposure and a non-specific tissue tropism. AgNPs-CHI were well-tolerated by the liver and kidney without signs of toxicity or inflammation, in contrary with AgNO3 which resulted in a significant elevation of Creatinine (CRE), Urea, and Total Protein (TP), suggesting a significant nephrotoxicity and inflammation. CONCLUSIONS: Functional coating of AgNPs with CHI substantially modulated their in vivo behavior, promoting their hepatic selectivity and biotolerability, which can be invested in the development of drug delivery systems for the treatment of liver diseases.

Exploration of the Safety and Solubilization, Dissolution, Analgesic Effects of Common Basic Excipients on the NSAID Drug Ketoprofen.

Since its introduction to the market in the 1970s, ketoprofen has been widely used due to its high efficacy in moderate pain management. However, its poor solubility and ulcer side effects have diminished its popularity. This study prepared forms of ketoprofen modified with three basic excipients: tris, L-lysine, and L-arginine, and investigated their ability to improve water solubility and reduce ulcerogenic potential. The complexation/salt formation of ketoprofen and the basic excipients was prepared using physical mixing and coprecipitation methods. The prepared mixtures were studied for solubility, docking, dissolution, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), in vivo evaluation for efficacy (the writhing test), and safety (ulcerogenic liability). Phase solubility diagrams were constructed, and a linear solubility (AL type) curve was obtained with tris. Docking studies suggested a possible salt formation with L-arginine using Hirshfeld surface analysis. The order of enhancement of solubility and dissolution rates was as follows: L-arginine > L-lysine > tris. In vivo analgesic evaluation indicated a significant enhancement of the onset of action of analgesic activities for the three basic excipients. However, safety and gastric protection indicated that both ketoprofen arginine and ketoprofen lysine salts were more favorable than ketoprofen tris.

A Novel C@Fe@Cu Nanocomposite Loaded with Doxorubicin Tailored for the Treatment of Hepatocellular Carcinoma.

High mortality and morbidity rates are related to hepatocellular carcinoma (HCC), which is the most prevalent type of liver cancer. A new vision for cancer treatment and cancer cell targeting has emerged with the application of nanotechnology, which reduces the systemic toxicity and adverse effects of chemotherapy medications while increasing their effectiveness. It was the goal of the proposed work to create and investigate an anticancer C@Fe@Cu nanocomposite (NC) loaded with Doxorubicin (DOX) for the treatment of HCC. Scanning and transmission electron microscopes (SEM and TEM) were used to examine the morphology of the produced NC. The formulation variables (DOX content, C@Fe@Cu NC weight, and stirring speed) were analyzed and optimized using Box-Behnken Design (BBD) and Response Surface Methodology (RSM). Additionally, X-ray diffraction patterns (XRD) and Fourier Transform Infrared (FTIR) were investigated. Doxorubicin and DOX- loaded C@Fe@Cu NC (DOX-C@Fe@Cu NC) were also assessed against HEPG2 cells for anticancer efficacy (Hepatic cancer cell line). The results revealed the formation of C@Fe@Cu NC with a mean size of 7.8 nm. A D-R model with a mean size of 24.1 nm best fits the adsorption behavior of DOX onto the C@Fe@Cu NC surface. DOX-C@Fe@Cu NC has also been demonstrated to have a considerably lower IC50 and higher cytotoxicity than DOX alone in an in vitro investigation. Therefore, DOX-C@Fe@Cu NC is a promising DOX delivery vehicle for the full recovery of HCC.

Compositional characteristics of dairy products and their potential nondairy applications after shelf-life.

Many dairy products are discarded and useless after end of shelf-life, which causes economic and environmental challenges. The objective of this study was to study the compositional characteristics of some dairy products before and after shelf-life, and develop a process to utilize those dairy products after end of shelf-life in non dairy applications (cosmetic cream and soap). Several dairy products, such as sterilized milk, yogurt, soft cheese, hard cheese, cream, and butter were collected from markets in Egypt before shelf-life and after three months of shelf-life. Electrophoresis analysis was conducted to estimate the changes in the protein fractions of protein products (sterilized milk, yogurt, and cheese) before and after expiration. Also, gas chromatography (GS) was performed to compare the fatty acids of fat products (cream and butter) before and after end of shelf-life. Sterilized milk, yogurt, soft, and hard cheese were turned into powder (Expired dairy products powder; EDPP) to be used as a raw material in manufacturing of cosmetic creams. The fat was separated from cream, butter, and hard cheese (Expired dairy products fat; EDPF) to be utilized in making soap. The formulated cosmetic creams were examined in vitro. Functional properties of cream were determined, such as appearance, spreadability, irritancy, and pH. Additionally, the soap quality was tested after manufacture. We found that dairy products, such as milk, yogurt, and cheese after shelf-life can be utilized as raw materials for the production of cosmetic creams, as well as production of soap from butter and cream. The produced products were similar to those in commercial markets. This study is an endeavor to conquer the dairy industry challenges, which are considered a huge loss from the economic and environmental aspects.

Tailoring of Novel Azithromycin-Loaded Zinc Oxide Nanoparticles for Wound Healing.

Skin is the largest mechanical barrier against invading pathogens. Following skin injury, the healing process immediately starts to regenerate the damaged tissues and to avoid complications that usually include colonization by pathogenic bacteria, leading to fever and sepsis, which further impairs and complicates the healing process. So, there is an urgent need to develop a novel pharmaceutical material that promotes the healing of infected wounds. The present work aimed to prepare and evaluate the efficacy of novel azithromycin-loaded zinc oxide nanoparticles (AZM-ZnONPs) in the treatment of infected wounds. The Box-Behnken design and response surface methodology were used to evaluate loading efficiency and release characteristics of the prepared NPs. The minimum inhibitory concentration (MIC) of the formulations was determined against Staphylococcus aureus and Escherichia coli. Moreover, the anti-bacterial and wound-healing activities of the AZM-loaded ZnONPs impregnated into hydroxyl propyl methylcellulose (HPMC) gel were evaluated in an excisional wound model in rats. The prepared ZnONPs were loaded with AZM by adsorption. The prepared ZnONPs were fully characterized by XRD, EDAX, SEM, TEM, and FT-IR analysis. Particle size distribution for the prepared ZnO and AZM-ZnONPs were determined and found to be 34 and 39 nm, respectively. The mechanism by which AZM adsorbed on the surface of ZnONPs was the best fit by the Freundlich model with a maximum load capacity of 160.4 mg/g. Anti-microbial studies showed that AZM-ZnONPs were more effective than other controls. Using an experimental infection model in rats, AZM-ZnONPs impregnated into HPMC gel enhanced bacterial clearance and epidermal regeneration, and stimulated tissue formation. In conclusion, AZM -loaded ZnONPs are a promising platform for effective and rapid healing of infected wounds.

Clinical translation of nanomedicines: Challenges, opportunities, and keys.

Despite the massive interest and recent developments in the field of nanomedicine, only a limited number of formulations have found their way to the clinics. This shortcoming reveals the challenges facing the clinical translation of this technology. In the current article, we summarize and evaluate the status, market situation, and clinical profiles of the reported nanomedicines, the shortcomings limiting their clinical translation, as well as some approaches designed to break through this barrier. Moreover, some emerging technologies that have the potential to compete with nanomedicines are highlighted. Lastly, we identify the key factors that should be considered in nanomedicine-related research to be clinically-translatable. These can be classified into five areas: rational design during the research and development stage, the recruitment of representative preclinical models, careful design of clinical trials, development of specific and uniform regulatory protocols, and calls for non-classic sponsorship. This new field of endeavor was firmly established during the last two decades and more in-depth progress is expected in the coming years.

Novel Green Biosynthesis of 5-Fluorouracil Chromium Nanoparticles Using Harpullia pendula Extract for Treatment of Colorectal Cancer.

Colorectal cancer (CRC) is the third highest major cause of morbidity and mortality worldwide. Hence, many strategies and approaches have been widely developed for cancer treatment. This work prepared and evaluated the antitumor activity of 5-Fluorouracil (5-Fu) loaded chromium nanoparticles (5-FuCrNPs). The green biosynthesis approach using Harpullia (H) pendula aqueous extract was used for CrNPs preparation, which was further loaded with 5-Fu. The prepared NPs were characterized for morphology using scanning and transmission electron microscopes (SEM and TEM). The results revealed the formation of uniform, mono-dispersive, and highly stable CrNPs with a mean size of 23 nm. Encapsulation of 5-Fu over CrNPs, with a higher drug loading efficiency, was successful with a mean size of 29 nm being produced. In addition, Fourier transform infrared (FTIR) and X-ray diffraction pattern (XRD) were also used for the investigation. The drug 5-Fu was adsorbed on the surface of biosynthesized CrNPs in order to overcome its clinical resistance and increase its activity against CRC cells. Box-Behnken Design (BBD) and response surface methodology (RSM) were used to characterize and optimize the formulation factors (5-Fu concentration, CrNP weight, and temperature). Furthermore, the antitumor activity of the prepared 5-FuCrNPs was tested against CRC cells (CACO-2). This in vitro antitumor study demonstrated that 5-Fu-loaded CrNPs markedly decreased the IC50 of 5-Fu and exerted more cytotoxicity at nearly all concentrations than 5-Fu alone. In conclusion, 5-FuCrNPs is a promising drug delivery system for the effective treatment of CRC.

Balancing Physicochemical Properties of Phenylthiazole Compounds with Antibacterial Potency by Modifying the Lipophilic Side Chain.

Bacterial resistance to antibiotics is presently one of the most pressing healthcare challenges and necessitates the discovery of new antibacterials with unique chemical scaffolds. However, the determination of the optimal balance between structural requirements for pharmacological action and pharmacokinetic properties of novel antibacterial compounds is a significant challenge in drug development. The incorporation of lipophilic moieties within a compound's core structure can enhance biological activity but have a deleterious effect on drug-like properties. In this Article, the lipophilicity of alkynylphenylthiazoles, previously identified as novel antibacterial agents, was reduced by introducing cyclic amines to the lipophilic side chain. In this regard, substitution with methylpiperidine (compounds 14-16) and thiomorpholine (compound 19) substituents significantly enhanced the aqueous solubility profile of the new compounds more than 150-fold compared to the first-generation lead compound 1b. Consequently, the pharmacokinetic profile of compound 15 was significantly enhanced with a notable improvement in both half-life and the time the compound's plasma concentration remained above its minimum inhibitory concentration (MIC) against methicillin-resistant Staphylococcus aureus (MRSA). In addition, compounds 14-16 and 19 were found to exert a bactericidal mode of action against MRSA and were not susceptible to resistance formation after 14 serial passages. Moreover, these compounds (at 2× MIC) were superior to the antibiotic vancomycin in the disruption of the mature MRSA biofilm. The modifications to the alkynylphenylthiazoles reported herein successfully improved the pharmacokinetic profile of this new series while maintaining the compounds' biological activity against MRSA.

From Phenylthiazoles to Phenylpyrazoles: Broadening the Antibacterial Spectrum toward Carbapenem-Resistant Bacteria.

The narrow antibacterial spectrum of phenylthiazole antibiotics was expanded by replacing central thiazole with a pyrazole ring while maintaining its other pharmacophoric features. The most promising derivative, compound 23, was more potent than vancomycin against multidrug-resistant Gram-positive clinical isolates, including vancomycin- and linezolid-resistant methicillin-resistant Staphylococcus aureus (MRSA), with a minimum inhibitory concentration (MIC) value as low as 0.5 µg/mL. Moreover, compound 23 was superior to imipenem and meropenem against highly pathogenic carbapenem-resistant strains, such as Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli. In addition to the notable biofilm inhibition activity, compound 23 outperformed both vancomycin and kanamycin in reducing the intracellular burden of both Gram-positive and Gram-negative pathogenic bacteria. Compound 23 cleared 90% of intracellular MRSA and 98% of Salmonella enteritidis at 2× the MIC. Moreover, preliminary pharmacokinetic investigations indicated that this class of novel antibacterial compounds is highly metabolically stable with a biological half-life of 10.5 h, suggesting a once-daily dosing regimen.

Efficacy of ketoconazole gel-flakes in treatment of vaginal candidiasis: Formulation, in vitro and clinical evaluation.

Candida albicans, as the main causative fungus of vaginal candidiasis, is currently a global issue of concern due to its high prevalence, biofilm formation and emergence of resistance. Ketoconazole (KTZ), an antifungal drug, which has poor water-solubility and penetration capacity, is ineffective against deep-seated Candida infection. Considering these issues, this work aimed to develop a novel multifunctional carrier for KTZ via encapsulation of KTZ/ß-cyclodextrin (ß-CD) co-ground mixture into chitosan/gellan gum gel-flakes (threadlike and polygonal structures). Analytical studies revealed existence of electrostatic-derived complexes between negatively charged gellan gum and positively charged chitosan. Gel-flakes were then loaded in in situ gel of pluronic F-127 (PF-127). Based on gelation temperature (Tgel), viscosity and release studies; selected formulation was further evaluated, showing significant in vitro anti-candida activity. Despite reduced dosage regimen (50 mg/daily/three days), KTZ flakes in situ gel was as effective as Gynoconazol vaginal cream® (80 mg terconazole/daily/three days) in improving patient complaints and Candida eradication. Multifunctionality of KTZ carrier was based on efficient spreading and coating of the vagina due to free-flowing properties during application, flakes entanglement within folded vaginal epithelia, sustained release and increased penetration capacity of KTZ to reach deep-seated infections. In conclusion, flakes in situ gel could be considered as a highly promising KTZ delivery option for treatment of vaginal candidiasis.

Development of Liposomal Gemcitabine with High Drug Loading Capacity.

Liposomes are widely used for systemic delivery of chemotherapeutic agents to reduce their nonspecific side effects. Gemcitabine (Gem) makes a great candidate for liposomal encapsulation due to the short half-life and nonspecific side effects; however, it has been difficult to achieve liposomal Gem with high drug loading capacity. Remote loading, which uses a transmembrane pH gradient to induce an influx of drug and locks the drug in the core as a sulfate complex, does not serve Gem as efficiently as doxorubicin (Dox) due to the low p Ka value of Gem. Existing studies have attempted to improve Gem loading capacity in liposomes by employing lipophilic Gem derivatives or creating a high-concentration gradient for active loading into the hydrophilic cores (small volume loading). In this study, we combine the remote loading approach and small volume loading or hypertonic loading, a new approach to induce the influx of Gem into the preformed liposomes by high osmotic pressure, to achieve a Gem loading capacity of 9.4-10.3 wt % in contrast to 0.14-3.8 wt % of the conventional methods. Liposomal Gem showed a good stability during storage, sustained-release over 120 h in vitro, enhanced cellular uptake, and improved cytotoxicity as compared to free Gem. Liposomal Gem showed a synergistic effect with liposomal Dox on Huh7 hepatocellular carcinoma cells. A mixture of liposomal Gem and liposomal Dox delivered both drugs to the tumor more efficiently than a free drug mixture and showed a relatively good anti-tumor effect in a xenograft model of hepatocellular carcinoma. This study shows that bioactive liposomal Gem with high drug loading capacity can be produced by remote loading combined with additional approaches to increase drug influx into the liposomes.

Intranasal niosomes of nefopam with improved bioavailability: preparation, optimization, and in-vivo evaluation.

OBJECTIVE: One of the greatest challenges drug formulation is facing is poor bioavailability via oral route. In this regard, nasal drug delivery has been commonly used as an alternative route to improve drug bioavailability. Nefopam hydrochloride (NF) is an analgesic drug that suffers from poor bioavailability due to extensive metabolism in liver. Accordingly, the goal of the present study was to improve NF bioavailability via niosomal-based formulation designed for intranasal delivery. MATERIALS AND METHODS: Vesicles were developed by mixing surfactants (Span 20, Span 40, Span 80, and Span 85) at four molar ratios of 1:1, 1:2, 1:3, and 1:4 of cholesterol to surfactant. Entrapment efficiency, particle size, zeta potential, release percentage, ex-vivo permeation parameters, and niosomes' stability were determined. Also, the pharmacokinetic parameters of the optimized formula in in-situ gel base were measured in rats. RESULTS: Niosomes showed entrapment efficiency .80%, particle size ,550 nm, and zeta potential ranging from -16.8±0.13 to -29.7±0.15. The produced vesicles showed significantly higher amounts of drug permeated across nasal mucosa (2.5 folds) and prolonged NF release compared with NF solution. Stability studies of optimum formula showed nonsignificant changes in niosomes parameters over a storage period of 6 months. The in-vivo studies showed a 4.77-fold increase in bioavailability of optimized nasal niosomes compared with oral solution of drug. CONCLUSION: The obtained results revealed the great ability of the produced NF-loaded nio-somes to enhance drug penetration through nasal mucosa and improve its relative bioavailability compared with NF oral solution.

Naphthylthiazoles: Targeting Multidrug-Resistant and Intracellular Staphylococcus aureus with Biofilm Disruption Activity.

Thirty-two new naphthylthiazole derivatives were synthesized with the aim of exploring their antimicrobial effect on multidrug-resistant Gram-positive bacteria. Compounds 25 and 32, with ethylenediamine and methylguanidine side chains, represent the most promising derivatives, as their antibacterial spectrum includes activity against multidrug-resistant staphylococcal and enterococcal strains. Moreover, the new derivatives are highly advantageous over the existing frontline therapeutics for the treatment of multidrug-resistant Gram-positive bacteria. In this vein, compound 25 possesses three attributes: no bacterial resistance was developed against it even after 15 passages, it was very efficient in targeting intracellular pathogens, and it exhibited a concentration-dependent ability to disrupt the preformed bacterial biofilm.