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Hepatocellular carcinoma (HCC) is a prevalent liver cancer representing the fourth most lethal cancer worldwide. Trans-Resveratrol (T-R) possesses a promising anticancer activity against HCC. However, it suffers from poor bioavailability because of the low solubility, chemical instability, and hepatic metabolism. Herein, we developed T-R-loaded nanocochleates using a simple trapping method. Nanocarriers were optimized using a comprehensive in-vitro characterization toolset and evaluated for the anticancer activity against HepG2 cell line. T-R-loaded nanocochleates demonstrated monodispersed cylinders (163.27 ± 2.68 nm and 0.25 ± 0.011 PDI) and −46.6 mV ζ-potential. They exhibited a controlled biphasic pattern with minimal burst followed by sustained release for 72 h. Significant enhancements of Caco-2 transport and ex-vivo intestinal permeation over liposomes, with 1.8 and 2.1-folds respectively, were observed. Nanocochleates showed significant reduction of 24 h IC50 values compared to liposomes and free T-R. Moreover, an efficient knockdown of anti-apoptotic (Bcl-2) and cancer stemness (NANOG) genes was demonstrated. To the best of our knowledge, we are the first to develop T-R loaded nanocochleates and scrutinize its potential in suppressing NANOG expression, 2-folds lower, compared to free T-R. According to these auspicious outcomes, nanocochleates represent a promising nanoplatform to enhance T-R oral permeability and augment its anticancer efficacy in the treatment of HCC.

Acute lung injury (ALI) and its more serious form; acute respiratory distress syndrome are major causes of COVID-19 related mortality. Finding new therapeutic targets for ALI is thus of great interest. This work aimed to prepare a biocompatible nanoformulation for effective pulmonary delivery of the herbal drug; tanshinone-IIA (TSIIA) for ALI management. A nanoemulsion (NE) formulation based on bioactive natural ingredients; rhamnolipid biosurfactant and tea-tree oil, was developed using a simple ultrasonication technique, optimized by varying oil concentration and surfactant:oil ratio. The selected TSIIA-NE formulation showed 105.7 nm diameter and a PDI ∼ 0.3. EE exceeded 98 % with biphasic sustained drug release and good stability over 3-months. In-vivo efficacy was evaluated in lipopolysaccharide (LPS)-induced ALI model. TSIIA-NE (30 µg/kg) was administered once intratracheally 2 h after LPS instillation. Evaluation was performed 7days post-treatment. Pulmonary function assessment, inflammatory, oxidative stress and glycocalyx shedding markers analysis in addition to histopathological examination of lung tissue were performed. When compared to untreated rats, in-vivo efficacy study demonstrated 1.4 and 1.9-fold increases in tidal volume and minute respiratory volume, respectively, with 32 % drop in wet/dry lung weight ratio and improved levels of arterial blood gases. Lung histopathology and biochemical analysis of different biomarkers in tissue homogenate and bronchoalveolar lavage fluid indicated that treatment may ameliorate LPS-induced ALI symptoms thorough anti-oxidative, anti-inflammatory effects and inhibition of glycocalyx degradation. TSIIA-NE efficacy was superior to free medication and blank-NE. The enhanced efficacy of TSIIA bioactive nanoemulsion significantly suggests the pharmacotherapeutic potential of bioactive TSIIA-NE as a promising nanoplatform for ALI.

Currently applied methodologies (acidic or enzymatic chitosanolysis) towards synthesis of Chitosan- Oligosaccharides (COS) are faced with some drawbacks that confine their potential in biotechnological applications. The present work addresses a novel tailored method as an alternate to biosynthesize COS. An empirical statistical-mathematical approach [Plackett-Burman. Design (PBD) followed by Box-Behnken design (BBD)] was employed to optimize COS biosynthesis by an endo -chitosanase non-aflatoxigenic producing Aspergillus sp. section Flavi strain EGY1 DSM 101520 whole cells. Optimal levels localized by BBD for three key determinants were 0.687% (w/v) low molecular weight chitosan (LMWC), 25 °C incubation temperature and 72–96 h incubation time, along with 2.0 gL −1 maximal level of COS, achieving 94.7% model adequacy upon growing the fungus on LMWC-based tap water medium [merely 0.687% (w/v) LMWC]. Batch mode scaling up in the laboratory scale fermenter achieved 5.34 gL −1 of COS after 44 h with 2.67 fold enhancement. Partially acetylated hetero-oligomers with DPs (2–11) of the water-soluble COS were proved by TLC, MALDI-TOF-MS, 1 H NMR, 13 C NMR and FTIR. To the best of the authors' knowledge, the present work is the first study highlighting a novel, robust, cheap, environmentally safe, reproducible approach to biosynthesize COS by fungal whole cells.

3D printing has revolutionized pharmaceutical research, with applications encompassing tissue regeneration and drug delivery. Adopting 3D printing for pharmaceutical drug delivery personalization via nanoparticle-reinforced hydrogel scaffolds promises great regenerative potential. Herein, we engineered novel core/shell, bio-inspired, drug-loaded polymeric hydrogel scaffolds for pharmaceutically personalized drug delivery and superior osteoregeneration. Scaffolds were developed using biopolymeric blends of gelatin, polyvinyl alcohol and hyaluronic acid and integrated with composite doxycycline/hydroxyapatite/polycaprolactone nanoparticles (DX/HAp/PCL) innovatively via 3D printing. The developed scaffolds were optimized for swelling pattern and in-vitro drug release through tailoring the biphasic microstructure and wet/dry state to attain various pharmaceutical personalization platforms. Freeze-dried scaffolds with nanoparticles reinforcing the core phase (DX/HAp/PCL-LCS-FD) demonstrated favorably controlled swelling, preserved structural integrity and controlled drug release over 28 days. DX/HAp/PCL-LCS-FD featured double-ranged pore size (90.4 ± 3.9 and 196.6 ± 38.8 µm for shell and core phases, respectively), interconnected porosity and superior mechanical stiffness (74.5 ± 6.8 kPa) for osteogenic functionality. Cell spreading analysis, computed tomography and histomorphometry in a rabbit tibial model confirmed osteoconduction, bioresorption, immune tolerance and bone regenerative potential of the original scaffolds, affording complete defect healing with bone tissue. Our findings suggest that the developed platforms promise prominent local drug delivery and bone regeneration.

The aim of this study was to formulate and evaluate chitosan (CS)/alginate (ALG) nanoparticles (NPs) loaded with furosemide (FSM) in an attempt to enhance its release, permeability and bioavailability. Non-everted gut sac method was used to evaluate the ex vivo permeation of FSM from its suspension and the selected CS/ALG NPs formulation. The pharmacokinetic parameters of FSM subsequent to oral administration of the selected formulation were assessed in rats. In vivo subacute toxicity study of the prepared blank and FSM loaded formulations was evaluated in rats. The selected optimized formulation (F3) showed optimum particle size (PS), polydispersity index (PDI), zeta potential (ZP) and acceptable percentage entrapment efficiency (%EE) of 253.8nm±4.6, 0.25±0.03, -35mV±1 and 96%±1, respectively. The release profile of FSM from the selected formulation was characterized by initial burst effect in 0.1N HCl. Scanning electron microscope (SEM) demonstrated a smooth surface and spherical shape for the lyophilized optimized NPs. Selected CS/ALG NPs (F3) presented a significant enhancement (p≤0.01) in permeation parameters of FSM as well as in Tmax, Cmax, AUC0-24 and AUC0-∞. Subacute toxicity study results revealed that the selected formulation was safe and nontoxic. The histopathological inspection of the stomach and small intestine tissues of the loaded NPs (F3) and blank groups reflected no obvious signs of cellular toxicity or inflammatory reaction. CS/ALG NPs loaded with FSM enhanced both drug release and mucus-penetrating ability leading to an overall increase in FSM bioavailability. In addition, the in vivo subacute toxicity study results indicated the safety of the prepared NPs for oral drug delivery.

Tanshinone IIA (TSIIA) is a promising phytomedicine that has been extensively studied due to its numerous biological activities, especially as an anticancer drug. However, it suffers from poor oral bioavailability owing to low aqueous solubility, poor permeability and exposure to first-pass metabolism. This study endeavored to improve TSIIA oral bioavailability by encapsulation into lipid nanocapsules (LNCs) for the first time. A previously reported phase-inversion method was used to prepare Tanshinone II A loaded LNCs (TSIIA-LNCs) with slight modifications based on a constructed phase diagram. They were then in-vitro characterized and their oral pharmacokinetics were studied in rats. TSIIA-LNCs showed excellent colloidal properties (size; 70 nm, PDI 0.2 and zeta-potential; -13.5 mV), a high percent entrapment efficiency (98%) and a good drug payload (2.6 mg/g). Furthermore, the in-vivo pharmacokinetic study revealed a significant enhancement in both the rate and extent of absorption of TSIIA-LNCs compared with TSIIA suspension with about 3.6-fold increase in AUC

Gastroretentive levofloxacin (LVF) floating mini-tablets for the eradication of Helicobacter pylori (H. pylori) were prepared using the matrix forming polymer hydroxypropyl methylcellulose (HPMC K100M), alone or with Carbopol 940P in different ratios by wet granulation technique. Buoyancy of mini-tablets was achieved by an addition of an effervescent mixture consisting of sodium bicarbonate and anhydrous citric acid to some formulations. The prepared mini-tablets were evaluated for weight variation, thickness, friability, hardness, drug content, in vitro buoyancy, water uptake and in vitro release. The optimized formula was subjected to further studies: FT-IR, DSC analysis and in vivo examination in healthy volunteers. The prepared mini-tablets exhibited satisfactory physicochemical characteristics. Incorporation of gas-generating agent improved the floating parameters. HPMC K100M mini-tablet formulation (F1) offered the best controlled drug release (>8h) along with floating lag time 24h. The obtained DSC thermograms and FT-IR charts indicated that there is no positive evidence for the interaction between LVF and ingredients of the optimized formula. The in vivo test confirmed the success of the optimized formula F1 in being retained in the stomach of the volunteers for more than 4h. LVF floating mini-tablets based on HPMC K100M is a promising formulation for eradication of H. pylori.

Size increasing (plug-type) levofloxacin hemihydrate (LVF) tablets for eradication of Helicobacter pylori (H. pylori) were prepared using in situ gel forming polymers including: gellan gum, sodium alginate, pectin and xanthan gum. Effect of cross-linkers: calcium and aluminum chloride, on the drug release was also studied. The prepared tablets were evaluated for their physicochemical parameters: weight variation, thickness, friability, hardness, drug content, water uptake and in vitro drug release. The optimized formula was subjected to further studies such as radial swelling test, FT-IR and DSC. Results revealed that LVF release depends not only on the nature of the matrix but also on the type of cross linker used to form this polymeric matrix. The addition of either calcium chloride or aluminum chloride, as cross-linkers, to gellan gum formulations significantly decreased drug release. Other polymers' formulations resulted in increased drug release upon addition of the same cross-linkers. The formula containing xanthan gum without any cross linker showed the most sustained LVF release with an increase in diameter with time, thus acting as a plug-type dosage form. IR spectra and DSC thermograms of LVF, xanthan gum, and a physical mixture of both, indicated that there was no interaction between the drug and the polymer and confirmed the drug stability.

The aim of the present study was to design and evaluate single pulse and floating double pulse valsartan core-in-cup tablets. Core tablets were prepared by direct compression of a homogenous mixture of valsartan, Avicel PH-101, Croscarmellose sodium (CCNa), magnesium stearate & Aerosil. Weight variation, Hardness and Disintegration time were measured for the core tablets. Core-in-cup tablets were formulated using different polymers as a plug layer, including sodium alginate (SA), sodium carboxymethylcellulose (NaCMC) and hydroxypropyl methyl cellulose (HPMC). The floating behavior, water uptake and drug release from the prepared formulations were evaluated. Differential Scanning Calorimetry (DSC) was also performed to detect the possible drug excipient interaction. Stability study of the selected formula was performed at 25 °C & 60% RH and at 40 °C & 75% RH for 3 months. Finally, the existence of the selected formula in the stomach after oral administration to human volunteers was verified via x-ray radiography. The results showed that the release lag time of the tablets increased when the quantity of the plug layer increased thus decreasing the drug release. Plug layer polymers showed a lag time with rank order: SA In conclusion, pulsatile single pulse and floating double pulse stable valsartan core-in-cup tablets were successfully formulated which provided a desirable lag time followed by a rapid drug release.

The aim of this study was to investigate the potential of prodrugs of some non-steroidal anti-inflammatory drugs (NSAIDs) as colon targeted delivery systems for treatment of inflammatory bowel diseases. Naproxen, sulindac and flurbiprofen (Fbp) were used. The carboxylic group of those drugs was conjugated onto the amino group of l-aspartic acid or the hydroxyl group of alpha- or beta-cyclodextrin (CyD). Prodrugs hydrolysis in buffers of pH range 1.2-7.2 and in rat gastrointestinal tract homogenates and the effect of oral pretreatment of rats with clindamycin on the hydrolysis of the prodrugs was examined. Additionally, the effect of oral administration of Fbp-beta-CyD prodrug on the experimentally induced colitis in rats was evaluated. The in vivo inflammatory response was assessed macroscopically, histologically and by measurement of reduced glutathione (GSH) levels in colon tissues. No significant hydrolysis of the proposed seven prodrugs in buffers having pH range of 1.2-7.2 was observed over 72h. Negligible % of drug released from Fbp-alpha-CyD or Fbp-beta-CyD prodrugs was detected in rat stomach contents, intestinal tissues and intestinal contents homogenates. On the other hand, Fbp-alpha-CyD and Fbp-beta-CyD prodrugs released about 60% Fbp within 4h in rat colon homogenate. Oral pretreatment of rats with clindamycin significantly reduced % Fbp released from Fbp-alpha-CyD or Fbp-beta-CyD prodrugs. Oral administration of Fbp-beta-CyD to rats after induction of colitis significantly attenuated the severity of the colonic injury and reduced the score of the macroscopic and microscopic damage. Additionally, there was a significant increase in the level of GSH. The present study provided an evidence that Fbp-beta-CyD prodrug may be beneficial in treatment of inflammatory bowel disease.

A sustained release system for ketoprofen designed to increase its residence time in the stomach without contact with the mucosa was achieved through the preparation of floating microparticles by the emulsion-solvent diffusion technique. Four different ratios of Eudragit S100 (ES) with Eudragit RL (ERL) were used to form the floating microparticles. The drug retained in the floating microparticles decreased with increase in ERL content. All floating microparticle formulations showed good flow properties and packability. Scanning electron microscopy and particle size analysis revealed differences between the formulations as to their appearance and size distribution. X-ray and DSC examination showed the amorphous nature of the drug. Release rates were generally low in 0.1 N HCl especially in presence of high content of ES while in phosphate buffer pH 6.8, high amounts of ES tended to give a higher release rate. Floating ability in 0.1 N HCl, 0.1 N HCl containing 0.02% Tween 20 and simulated gastric fluid without pepsin was also tested. The formulation containing ES:ERL1:1 (FIII) exhibited high percentage of floating particles in all examined media.