Repurposing celecoxib for colorectal cancer targeting via pH-triggered ultra-elastic nanovesicles: Pronounced efficacy through up-regulation of Wnt/ß-catenin pathway in DMH-induced tumorigenesis.

Celecoxib (CLX), a selective inhibitor for cyclooxygenase 2 (COX-2), has manifested potential activity against diverse types of cancer. However, low bioavailability and cardiovascular side effects remain the major challenges that limit its exploitation. In this work, we developed ultra-elastic nanovesicles (UENVs) with pH-triggered surface charge reversal traits that could efficiently deliver CLX to colorectal segments for snowballed tumor targeting. CLX-UENVs were fabricated via a thin-film hydration approach. The impact of formulation factors (Span 80, Tween 80, and sonication time) on the nanovesicular features was evaluated using Box-Behnken design, and the optimal formulation was computed. The optimum formulation was positively coated with polyethyleneimine (CLX-PEI-UENVs) and then coated with Eudragit S100 (CLX-ES-PEI-UENVs). The activity of the optimized nano-cargo was explored in 1,2-dimethylhydrazine-induced colorectal cancer in Wistar rats. Levels of COX-2, Wnt-2 and ß-catenin were assessed in rats' colon. The diameter of the optimized CLX-ES-PEI-UENVs formulation was 253.62 nm, with a zeta potential of -23.24 mV, 85.64% entrapment, and 87.20% cumulative release (24 h). ES coating hindered the rapid release of CLX under acidic milieu (stomach and early small intestine) and showed extended release in the colon section. In colonic environments, the ES coating layer was removed due to high pH, and the charge on the nanovesicular corona was shifted from negative to positive. Besides, a pharmacokinetics study revealed that CLX-ES-PEI-UENVs had superior oral bioavailability by 2.13-fold compared with CLX suspension. Collectively, these findings implied that CLX-ES-PEI-UENVs could be a promising colorectal-targeted nanoplatform for effective tumor management through up-regulation of the Wnt/ß-catenin pathway.

Antibacterial and Wound-Healing Activities of Statistically Optimized Nitrofurazone- and Lidocaine-Loaded Silica Microspheres by the Box-Behnken Design.

In the current study, nitrofurazone- (NFZ) and lidocaine-loaded (LD) silica microspheres were fabricated to address pathological indications of skin infections. The microspheres were prepared by the sol-gel method applying the Box-Behnken design and evaluated for size distribution, morphology, zeta potential, physico-chemical compatibility, XRD, thermogravimetric analysis, antibacterial and cytotoxicity activities. The comparative in vitro drug release study of microspheres revealed a 30% release of NFZ and 33% of LD after 8 h. The microspheres showed 81% percentage yield (PY) and 71.9% entrapment efficiency. XRD patterns confirmed the entrapment of NFZ-LD in silica microspheres with a significant reduction in crystallinity of the drugs. Thermal and FTIR studies proved the absence of any profound interactions of the formulation ingredients. The smooth spherical microspheres had a -28 mV zeta potential and a 10-100 µm size distribution. In vitro antibacterial activities of the NFZ-LD microspheres showed an increased zone of inhibition compared to pure drug suspensions. The in vivo efficacy tested on rabbits showed a comparatively rapid wound healing with complete lack of skin irritation impact. The cytotoxicity studies revealed more acceptability of silica microspheres with negligible harm to cells. The study suggests that the NFZ- and LD-loaded silica microspheres would be an ideal system for accelerating and promoting rapid healing of various acute and chronic wounds.

Enhancement of the Solubility and Bioavailability of Pitavastatin through a Self-Nanoemulsifying Drug Delivery System (SNEDDS).

The purpose of the study was to develop an SNEDDS to improve the solubility and bioavailability of pitavastatin. The solubility of pitavastatin in different oils, surfactants, and co-surfactants was determined and a pseudo-ternary phase diagram was constructed. The SNEDDS was characterized by zeta-sizer, zeta-potential, FTIR, DSC, and TGA. Release and permeation of pitavastatin from the SNEDDS was studied for 12 and 24 h, respectively. The lipolysis test, RBC lysis, effect on lipid profile, and pharmacokinetics were studied. The SPC3 formulation showed a 104 ± 1.50 nm particle size, a 0.198 polydispersity index (PDI), and a -29 zeta potential. FTIR, DSC, and TGA showed the chemical compatibility and thermal stability. The release and permeation of pitavastatin from SPC3 was 88.5 ± 2.5% and 96%, respectively. In the lipolysis test, the digestion of SPC3 yielded a high amount of pitavastatin and showed little RBC lysis. The lipid profile suggested that after 35 days of administration of the SNEDDS, there was a marked decrease in TC, LDL, and triglyceride levels. The SNEDDS of SPC3 showed an 86% viability of Caco-2 cells. Pharmacokinetics of SPC3 showed improved values of Cmax, Tmax, half-life, MRT, AUC, and AUMC compared to the reference formulation. Our study demonstrated that the SNEDDS effectively enhanced the solubility and bioavailability of a BCS class II drug.

Nanocubosomal based in situ gel loaded with natamycin for ocular fungal diseases: development, optimization, in-vitro, and in-vivo assessment.

Natamycin (NT) is a synthetic broad-spectrum antifungal used in eye drops. However, it has low solubility and high molecular weight, limiting its permeation, and generally causes eye discomfort or irritation when administered. Therefore, the present study aimed to develop an ophthalmic in situ gel formulation with NT-loaded cubosomes to enhance ocular permeation, improve antifungal activity, and prolong the retention time within the eye. The NT-loaded cubosome (NT-Cub) formula was first optimized using an I-optimal design utilizing phytantriol, PolyMulse, and NT as the independent formulation factors and particle size, entrapment efficiency %, and inhibition zone as responses. Phytantriol was found to increase particle size and entrapment efficiency %. Higher levels of PolyMulse slightly increased the inhibition zone whereas a decrease in particle size and EE% was observed. Increasing the NT level initially increased the entrapment efficiency % and inhibition zone. The optimized NT-Cub formulation was converted into an in situ gel system using 1.5% Carbopol 934. The optimum formula showed a pH-sensitive increase in viscosity, favoring prolonged retention in the eye. The in vitro release of NT was found to be 71 ± 4% in simulated tear fluid. The optimum formulation enhanced the ex vivo permeation of NT by 3.3 times compared to a commercial formulation and 5.2 times compared to the NT suspension. The in vivo ocular irritation test proved that the optimum formulation is less irritating than a commercial formulation of NT. This further implies that the developed formulation produces less ocular irritation and can reduce the required frequency of administration.

Glimepiride-Loaded Nanoemulgel; Development, In Vitro Characterization, Ex Vivo Permeation and In Vivo Antidiabetic Evaluation.

Glimepiride (GMP), an oral hypoglycemic agent is extensively employed in the treatment of type 2 diabetes. Transdermal delivery of GMP has been widely investigated as a promising alternative to an oral approach but the delivery of GMP is hindered owing to its low solubility and permeation. The present study was designed to formulate topical nanoemulgel GMP system and previously reported solubility enhanced glimepiride (GMP/ßCD/GEL-44/16) in combination with anti-diabetic oil to enhance the hypoglycemic effect. Nanoemulsions were developed using clove oil, Tween-80, and PEG-400 and were gelled using xanthan gum (3%, w/w) to achieve the final nanoemulgel formulations. All of the formulations were evaluated in terms of particle size, zeta potential, pH, conductivity, viscosity, and in vitro skin permeation studies. In vivo hypoglycemic activity of the optimized nanoemulgel formulations was evaluated using a streptozocin-induced diabetes model. It was found that a synergistic combination of GMP with clove oil improved the overall drug permeation across the skin membrane and the hypoglycemic activity of GMP. The results showed that GMP/ßCD/GEL-44/16-loaded nanoemulgel enhanced the in vitro skin permeation and improved the hypoglycemic activity in comparison with pure and marketed GMP. It is suggested that topical nano emulsion-based GMP gel and GMP/ßCD/GEL-44/16 could be an effective alternative for oral therapy in the treatment of diabetes.

Sesame Oil-Based Nanostructured Lipid Carriers of Nicergoline, Intranasal Delivery System for Brain Targeting of Synergistic Cerebrovascular Protection.

Nicergoline (NIC) is a semisynthetic ergot alkaloid derivative applied for treatment of dementia and other cerebrovascular disorders. The efficacy of sesame oil to slow and reverse the symptoms of neurodegenerative cognitive disorders has been proven. This work aimed to formulate and optimize sesame oil-based NIC-nanostructured lipid carriers (NIC-NLCs) for intranasal (IN) delivery with expected synergistic and augmented neuroprotective properties. The NIC-NLC were prepared using sesame oil as a liquid lipid. A three-level, three-factor Box-Behnken design was applied to statistically optimize the effect of sesame oil (%) of the total lipid, surfactant concentration, and sonication time on particle size, zeta potential, and entrapment efficacy as responses. Solid-state characterization, release profile, and ex vivo nasal permeation in comparison to NIC solution (NIC-SOL) was studied. In vivo bioavailability from optimized NIC-NLC and NIC-SOL following IN and IV administration was evaluated and compared. The optimized NIC-NLC formula showed an average particle size of 111.18 nm, zeta potential of -15.4 mV, 95.11% entrapment efficacy (%), and 4.6% loading capacity. The NIC-NLC formula showed a biphasic, extended-release profile (72% after 48 h). Permeation of the NIC-NLC formula showed a 2.3 enhancement ratio. Bioavailability studies showed a 1.67 and 4.57 fold increase in plasma and brain following IN administration. The results also indicated efficient direct nose-to-brain targeting properties with the brain-targeting efficiency (BTE%) and direct transport percentage (DTP%) of 187.3% and 56.6%, respectively, after IN administration. Thus, sesame oil-based NIC-NLC can be considered as a promising IN delivery system for direct and efficient brain targeting with improved bioavailability and expected augmented neuroprotective action for the treatment of dementia.

Fabrication, optimization, and in vitro/in vivo evaluation of diclofenac epolamine flash tablet.

The objective of this work was to design a diclofenac epolamine (DE) flash tablets (FTs) intended to dissolve in the mouth saliva, thereby improving the DE bioavailability and reducing its first-pass liver metabolism. Design-Expert software was used to build a 31.22 full factorial design (12 runs). FTs were fabricated using lyophilization process. The dissolution response was selected to pick the optimized run. The results indicate that the optimized run (R1) showed the fastest drug dissolution (total dissolution in 12 min). The predicted run (Rp) showed a desirability of about 0.93. Differential scanning calorimetry(DSC) analysis results showed a decrease in the drug melting point of the R1 formulation. Fourier-transform infrared spectroscopy (FTIR) showed the compatibility of the drug with other components of formulation, X-ray powder diffraction (XRPD) analysis showed the evolution of the drug physical state from a crystalline to an amorphous form and scanning electron microscopy(SEM) divugled the disappearance of drug crystals in gelatin strands. The results of the pharmacokinetic study performed in 6 human volunteers evidenced an increase in the maximum DE concentration in plasma and, consequently, an increased bioavailability of the FT formulation as compared with a reference formulation(Fr). Concisely, the developed FTs (R1) showed promising results which could be able to enhance oral bioavailability, reduce the therapeutic dose of the drug, and abate of the complications accompanied with conventional dosage forms. Graphical abstract.

Preparation, Optimization, and Evaluation of Hyaluronic Acid-Based Hydrogel Loaded with Miconazole Self-Nanoemulsion for the Treatment of Oral Thrush.

Miconazole nitrate (MZ) is a BCS class II antifungal poorly water-soluble drug with limited dissolution properties and gastrointestinal side effects. Self-nanoemulsifying delivery system-based gel of MZ can improve both solubility and oral mucosal absorption with enhanced antifungal activity. The study aims to formulate MZ self-nanoemulsion (MZ-NE) and combine it within hyaluronic acid-based gel. MZ solubility in various oils, surfactants, and cosurfactant used in NE formulations were evaluated. Mixture design was implemented to optimize the levels of NE components as a formulation variable to study their effects on the mean globule size and antifungal inhibition zones. Further, the optimized MZ-NE was loaded into a hyaluronic acid gel base. Rheological behavior of the prepared gel was assessed. Ex vivo permeability of optimized formulation across buccal mucous of sheep and inhibition against Candida albicans were examined. Mixture design was used to optimize the composition of MZ-NE formulation as 22, 67, and 10% for clove oil, Labrasol, and propylene glycol, respectively. The optimized formulation indicated globule size of 113 nm with 29 mm inhibition zone. Pseudoplastic flow with thixotropic behavior was observed, which is desirable for oral gels. The optimized formulation exhibited higher ex vivo skin permeability and enhanced antifungal activity by 1.85 and 2.179, respectively, compared to MZ-SNEDDS, and by 1.52 and 1.72 folds, respectively, compared to marketed gel. Optimized MZ-NE hyaluronic acid-based oral gel demonstrated better antifungal activity, indicating its potential in oral thrush pharmacotherapy.

Nanogel loaded with surfactant based nanovesicles for enhanced ocular delivery of acetazolamide.

Objective: Intraocular pressure has always been a great challenge for topical ophthalmic drugs. The study aimed to develop ocular surfactant based nanovesicles (NVs) carried in mucoadhesive nanogel providing efficient topical delivery of acetazolamide (ACZ). Methods: For the sake of optimizing formulation parameters, the effect of the type of edge activator and its ratio to sorbitan monostearate (Span 60) on the mean particle size, entrapment efficiency (%EE), and zeta potential (ZP) of produced NVs was investigated. Results: The selected formulation composed of Span 60:sodium deoxycholate with ratio 80:20 showed an average diameter of 202.90 nm, %EE of 90.2%, and ZP of -38.1 mV with a spherical and smooth surface. The ACZ loaded nanovesicles (ACZ-NVs) were embedded in different concentrations of Chitosan-sodium tripolyphosphate (CS-TPP) nanogels. The nanogel prepared using 1.5% CS showed the most promising viscosity, adhesion time, and rheological behavior (118,246 cP, 290 min, and thixotropic behavior, respectively). The in vitro release of ACZ showed a controlled release profile after incorporation in nanogels. The in vivo irritation test showed minimal irritation for the nanogel formulation compared to ACZ topical suspension. The effect of intraocular pressure lowering was significantly prolonged using ACZ-NV nanogels compared to ACZ oral tablets. Histopathological examination emphasized the healing power of CS on retinal atrophy. Conclusion: The research work indicated a promising potential for successful topical delivery of ACZ.

Preparation and optimization of lidocaine transferosomal gel containing permeation enhancers: a promising approach for enhancement of skin permeation.

AIM: To develop the topical gel containing transferosomal lidocaine as alternative to painful local anesthetic injection. MATERIALS AND METHODS: The transfersomes were prepared by film hydration technique using soybean phosphatidylcholine and cholesterol. The prepared transfersomes were evaluated for the morphology, drug loading, %EE, particle size and in vitro release. The transferosomal gel of lidocaine was prepared using HPMC k15 as gelling agent and propylene glycol, dimethyl sulfoxide (DMSO), and polyamidoamine dendrimer third generation (PAMAM G3) solutions were used as permeation enhancer. The formulated gels were evaluated for pH, viscosity, drug content and ex-vivo permeation of the gel. The analgesic effect of the formulation was tested using tail flick test. RESULTS: The transfersomes showed that transfersomes (F4) had the highest entrapment efficiency (%EE) approaching 79.87±2.35, low particle size 179.5 nm, and zeta potential of -43.5±4.74 mV. According to the rat tail flick test, the AUC0-90 minutes of the control formulation (lidocaine solution, A) was 352.32±5.87 seconds minutes. While the maximum AUC0-90 minutes value was found to be 570.5±6.81 seconds minutes for gel formulation (F) containing transfersomal lidocaine with PAMAM G3 dendrimer as permeation enhancer. In this case, the local anesthetic efficacy was increased by 1.62-folds as compared to control formulation. CONCLUSION: From the present study, it can be concluded that the topical gel loaded with transfersomal lidocaine shows enhanced skin permeation effect along with increase in local anesthetic action of lidocaine.

Development and Evaluation of in-situ Nasal Gel Formulations of Nanosized Transferosomal Sumatriptan: Design, Optimization, in vitro and in vivo Evaluation.

BACKGROUND: Sumatriptan succinate (SUT) is a potent drug used for relieving or ending migraine and cluster headaches. SUT bioavailability is low (15%) when it is taken orally owing to its gastric breakdown and bloodstream before reaching the target arteries. AIM: The aim of the study was to enhance SUT bioavailability through developing an intranasal transferosomal mucoadhesive gel. METHODS: SUT-loaded nanotransferosomes were prepared by thin film hydration method and characterized for various parameters such as vesicle diameter, percent entrapment efficiency (%EE), in vitro release and ex vivo permeation studies. The in-situ gels were prepared using various ratios of poloxamer 407, poloxamer 188, and carrageenan and characterized for gelation temperature, mucoadhesive strength, and rheological properties. RESULTS: The prepared transferosomes exhibited percent entrapment efficiencies (%EE) of 40.41±3.02 to 77.47±2.85%, mean diameters of 97.25 to 245.01 nm, sustained drug release over 6 hours, and acceptable ex vivo permeation findings. The optimum formulae were incorporated into poloxamer 407 and poloxamer 188-based thermosensitive in-situ gel using carrageenan as a mucoadhesive polymer. Pharmacokinetic evaluation showed that the prepared in-situ gel of SUT-loaded nano-transferosomes gave enhanced bioavailability, 4.09-fold, as compared to oral drug solution. CONCLUSION: Based on enhancing the bioavailability and sustaining the drug release, it can be concluded that the in-situ gel of SUT-loaded nano-transferosomes were developed as a promising non-invasive drug delivery system for treating migraine.