Intranasal nanoemulsion-based in-situ gel containing dexlansoprazole: formulation development, in-vitro and ex-vivo evaluation

Nebivolol hydrochloride (NEB) is third generation beta‑blocker, approved by the FDA to treat a hypertension. It’s a racemic mixture of a d‑Nebivolol and l‑Nebivolol. Oral delivery of the NEB shows a lower bioavailability due to its poor solubility and permeability. In present study, self nano emulsifying drug delivery is formulated to increase the bioavailability of drug by increasing solubility and permeability through the gastro intestinal membrane. Excipients are selected on basis of results obtained from solubility studies of drug in various surfactants and oils. Selected system of oil, surfactant and co‑surfactant were screened for their miscibility and emulsification ability. The ternary phase diagram was constructed using system Capmul MCM EP as oil, Tween‑60 as surfactant, Transcutol HP and PEG‑400 as co‑surfactant. Five compositions were prepared from the self‑emulsifying area of the ternary diagram, loaded with NEB and then tested for robustness to dilution, pH effect on globule size, mean globule size and polydispersity index (PDI), zeta potential, viscosity and drug release for the selection of optimized formulation. Further, the effect of viscosity and pH on the globule size and PDI of optimized SNEDDS was studied. In‑vitro drug release study was performed using dialysis bag method. Ex‑vivo drug release studies were also carried out to determine the permeability of drug loaded SNEDDS through the stomach and intestinal membrane. The optimum concentration of a system determined Capmul MCM EP 25%, Tween‑60 50%, Transcutol HP 12.5%, PEG‑400 12.5% with a globule size of 124.5 nm, cloud point at 770C and zeta potential of ‑5.123 mV. In‑vitro drug release study and ex‑vivo permeation study showed significant increase in dissolution rate and permeability respectively, as compared to the drug suspension and marketed preparation (NEBISTAR™). Key words: Dissolution, ex‑vivo drug release, nebivolol hydrochloride, self‑nanoemulsifying drug delivery systems, solubility studies

Introduction: Rosuvastatin (ROS) calcium is the latest synthetic drug in the statin group that has an anti-hyperlipidemic activity. It is available as tablets, and its poor aqueous solubility, slow dissolution rate and low-absorption extent result in less than 20% bioavailability and about 80% being excreted unchanged in the feces without absorption. The present study aimed at developing an optimal oral nanoemulsion formulation containing rosuvastatin using different proportions of oil and surfactant system for enhancing its water solubility and bioavailability. Methods and results: The solubility of ROS in different oils, surfactants and co-surfactants was tested. Based on the solubility study, liquid formulations were prepared using Arachis oil as oil phase and Tween 80 as surfactant and polyethylene 400 as co-surfactant. Pseudo-ternary phase diagrams were developed and various nanoemulsion formulations were prepared and evaluated for globule size, zeta potential, and emulsion properties. The formulations were subjected to different thermodynamic stability studies such as centrifugation, heating-cooling cycle and freeze-thaw cycle, to avoid the selection of metastable formulations. Transmittance study and in-vitro dissolution studies were carried out. An optimal nanoemulsion system was successfully developed with the droplet size of 260 nm and a composition of (Arachis oil; 20%), Tween 80 (40%) and PEG 400 (40%). The cumulative percentage drug release from optimal nanoemulsion formulation was found to be 93.29±1.11% for 50 minutes, which was significantly higher than the drug suspension (43.42±1.30%). Thus, in vitro results reveal that the prepared nanoemulsion formulations showed improved solubility of ROS. Conclusions : Nanoemulsion formulations of ROS represent a promising novel formula with a higher dissolution rate when compared to the drug in suspension. Key Words: Nanoemulsion; Rosuvastatin calcium; Ternary Phase Diagram; In vitro release

Oil based nanocarrier for improved oral delivery of silymarin: In vitro and in vivo studies

Tacrolimus-loaded nanostructured lipid carriers for oral delivery – Optimization of production and characterization

Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption

Furosemide has a low solubility in water and leads to absorption profile this drug is highly variable after oral administration. Self-nano emulsifying drug delivery system (SNEDDS) is a drug delivery system that can be developed for furosemide to improve its absorption profile. Selection of oil phase, surfactant and cosurfactant has an important role in furosemide SNEDDS. The solubility of furosemide performed in the oil phase: oleic acid, red palm oil, and olive oil. The solubility of furosemide was also measured in a surfactant: tween 80, tween 20 and cremophor RH40 and the cosurfactant: propilenglikol (PG), polyethylene glycol (PEG) 400 and glycerol. The solubility test was performed at a temperature of 37°C and furosemide levels in the oil phase, surfactant and cosurfactant were determined by a spectrophotometer. Furosemide solubility in the oil phase of oleic acid, red palm oil, and olive oil are (158, 80 and 32) mg/mL respectively. Meanwhile, furosemide solubility in surfactant tween 80, tween 20 and cremophor RH40 are (278.889; 202.527 and 237.250) mg/mL respectively. In addition, the solubility of furosemide in a cosurfactant PG, PEG 400 and glycerol are (92.0; 1374.867 and 225.044) mg/mL respectively. This study concluded that the greatest furosemide solubility in the oil phase, surfactant and cosurfactant respectively is oleic acid, tween 80 and PEG 400. These materials can be selected as a component of furosemide SNEDDS. Key words: furosemide, SNEDDS, oil phase, surfactant, cosurfactant

Artemether, a potent lipophilic antimalarial drug, suffers from poor aqueous solubility and low, variable oral bioavailability, which can compromise its therapeutic efficacy and contribute to the emergence of drug-resistant malaria strains. The present study aimed to develop and evaluate a Self-Emulsifying Drug Delivery System (SMEDDS) to enhance the solubility, dissolution, and intestinal permeability of artemether. Solubility studies were conducted to identify suitable excipients, and Capryol 90 (oil), Cremophor EL (surfactant), and Transcutol P (co-surfactant) were selected based on their superior drug solubilizing capacity. The optimized SMEDDS formulation was subjected to in vitro dissolution and ex vivo permeability studies using the Caco-2 cell model. The in vitro dissolution study demonstrated a significant improvement in drug release from the SMEDDS formulation, with more than 95% of artemether released within 30 minutes, compared to less than 20% release from the conventional suspension. This enhancement is attributed to the spontaneous formation of a fine oil-inwater nanoemulsion, providing a large surface area and maintaining the drug in a solubilized state. Furthermore, ex vivo permeability studies revealed a marked increase in drug transport across intestinal cell monolayers, with the SMEDDS formulation showing approximately 3.8-fold higher apparent permeability compared to the suspension. These findings confirm that the SMEDDS formulation effectively overcomes the dissolution and permeability limitations of artemether. The developed system offers a promising strategy to enhance oral bioavailability and therapeutic performance of lipophilic drugs. This approach may significantly contribute to improving malaria treatment outcomes and reducing variability in drug absorption.

The preparation of emulsions without heating is an ideal production process for the heat-sensitive ingredients and energy saving. This study investigated the utilization feasibility of emulsifying polymers in cream base prepared without heating for clotrimazole. A stable and acceptable cream base readily for mixing with clotrimazole was prepared at room temperature using isopropyl isostearate as an oil phase, emulsifying polymer as an emulsifier, concentrated paraben as a preservative, polyethylene glycol 400 as a solubilizer and distilled water as a water phase at a ratio of 15:3:1:5:75, respectively. Clotrimazole creams comprising emulsifying polymer were evaluated for their viscosity and pH. The evaluations were also performed on the drug release using Franz diffusion cells and the inhibition of Candida albicans using agar diffusion method compared with a commercial product. The drug loading and the viscosity of cream influenced the drug release and the antifungal activity of this developed clotrimazole cream. The types of emulsifying polymer also affected the drug release but not the antifungal activity. The drug release and antifungal activity of this clotrimazole cream were not significantly different from Canesten ® cream. There was a possibility to prepare clotrimazole cream without heating using the emulsifying polymer.

Introduction: Luteolin (LUT) is natural flavonoid with multiple therapeutic potentials and is explored for transdermal delivery using a nanocarrier system. LUT loaded cationic nanoemulsions (CNE1–CNE9) using bergamot oil (BO) were developed, optimized, and characterized in terms of in vitro and ex vivo parameters for improved permeation. Materials and methods: The solubility study of LUT was carried out in selected excipients, namely BO, cremophor EL (CEL as surfactant), labrasol (LAB), and oleylamine (OA as cationic charge inducer). Formulations were characterized with globular size, polydispersity index (PDI), zeta potential, pH, and thermodynamic stability studies. The optimized formulation (CNE4) was selected for comparative investigations (% transmittance as %T, morphology, chemical compatibility, drug content, in vitro % drug release, ex vivo skin permeation, and drug deposition, DD) against ANE4 (anionic nanoemulsion for comparison) and drug suspension (DS). Results: Formulations such as CNE1–CNE9 and ANE4 (except CNE6 and CNE8) were found to be stable. The optimized CNE4 based on the lowest value of globular size (112 nm), minimum PDI (0.15), and optimum zeta potential (+26 mV) was selected for comparative assessment against ANE4 and DS. The %T values of CNE1–CNE9 were found to be ˃95% and CEL content slightly improved the %T value. The spherical CNE4 was compatible with excipients and showed % total drug content in the range of 97.9–99.7%. In vitro drug release values from CNE4 and ANE4 were significantly higher than DS. Moreover, permeation flux (138.82 ± 8.4 µg/cm2·h), enhancement ratio (8.23), and DD (10.98%) were remarkably higher than DS. Thus, ex vivo parameters were relatively high as compared to DS which may be attributed to nanonization, surfactant-mediated reversible changes in skin lipid matrix, and electrostatic interaction of nanoglobules with the cellular surface. Conclusion: Transdermal delivery of LUT can be a suitable alternative to oral drug delivery for augmented skin permeation and drug deposition.

Objective: This work aims to choose suitable essential oil formulations to improve the bioavailability and long-term aqueous stability of mefloquine in drug delivery systems. Methods: Oil phases of pomegranate oil, black cumin seed oil, and garlic oil. To choose the proper oil and surfactant for creating pseudo-ternary phase diagrams, cremophore EL, tween®20 and tween®80 (surfactants), and brij 35 (co-surfactants) were used in a variety of concentrations and combinations (Smix). Mefloquine was estimated to be soluble in a variety of oils, surfactants, and co-surfactants. Drug solubility, drug release research, thermodynamic stability, mean hydrodynamic size and zeta potential. Results: Garlic with smix of cremophore EL and brij 35, Pomegranate with Tween 2.0, and Black cumin seed oil with Tween 80 showed the highest solubilization and emulsification capabilities and were further investigated using ternary phase diagrams. When combined with the co-surfactants under investigation, cremophore EL demonstrated a greater self-emulsification zone than tween® 80 and tween 20. Garlic oil, cremophore EL, and brij 35 nanoemulsion showed smaller size, greater zeta potential, less emulsification time, high transmittance, and better drug solubility than microemulsion formulations on especially those made with tween®20 and tween 80. Mefloquine loaded garlic oil nanoemulsion showed considerably low release in body fluid (32.48%) and a good release in intestinal fluid (82.78%) by 12 h in a drug release study. Conclusion: Garlic oil as the oil phase and a mixture of cremophore EL and brij 35 as the surfactant phase are ideal surfactants and co-surfactant for mefloquine loaded garlic oil nanoemulsion with greater drug release in release kinetics investigation.

For the application of water-in-oil-in-water (w/o/w) emulsions to a nasal dosage form of secretin, permeation tests were conducted in vitro to assess the effects of hydrophilic surfactants in the internal aqueous compartment on the release rate of secretin. The amount of secretin that permeated through an artificial membrane from a donor cell to a receptor cell was affected by the addition of sodium chloride or sodium alkylsulfonate to the internal aqueous compartment of w/o/w emulsions in the donor cell. Sodium chloride decreased apparent permeation rate constants from the internal aqueous compartment to the external aqueous phase (K'1) as the difference in osmolartiy between the internal compartment and the external phase increased. While sodium alkylsulfonates increased K'1 in proportion to the values of (partition coefficient between the oil phase and the internal aqueous phase/partition coefficient between the oil phase and the external aqueous phase)/osmolarity ratio of the internal aqueous phase to the external aqueous phase. These results demonstrate that the release rate of secretion from w/o/w emulsions are affected by partition of the drug between aqueous and oil phases and by osmotic difference between the outer and internal phases.

Chitosan coated synergistically engineered nanoemulsion of Ropinirole and nigella oil in the management of Parkinson's disease: Formulation perspective and In vitro and In vivo assessment

Background and Objectives: Lipid-based self-nanoemulsifying drug delivery systems (SNEDDS) have resurged the eminence of nanoemulsions by modest adjustments and offer many valuable opportunities in drug delivery. Chlorpromazine, an antipsychotic agent with poor aqueous solubility—with extensive first-pass metabolism—can be a suitable candidate for the development of SNEDDS. The current study was designed to develop triglyceride-based SNEDDS of chlorpromazine to achieve improved solubility, stability, and oral bioavailability. Materials and Methods: Fifteen SNEDDS formulations of each short, medium, and long chain, triglycerides were synthesized and characterized to achieve optimized formulation. The optimized formulation was characterized for several in vitro and in vivo parameters. Results: Particle size, zeta potential, and drug loading of the optimized SNEDDS (LCT14) were found to be 178 ± 16, −21.4, and 85.5%, respectively. Long chain triglyceride (LCT14) showed a 1.5-fold increased elimination half-life (p < 0.01), up to 6-fold increased oral bioavailability, and 1.7-fold decreased plasma clearance rate (p < 0.01) compared to a drug suspension. Conclusion: The findings suggest that SNEDDS based on long-chain triglycerides (LCT14) formulations seem to be a promising alternative for improving the oral bioavailability of chlorpromazine.

The purpose of this study was to develop new formulation for an improved oral delivery of Vitex agnus-castus (VAC) extract. After the optimization and validation of analytical method for quali-quantitative characterization of extract, nanoemulsion (NE) was selected as lipid-based nanocarrier. The composition of extract-loaded NE resulted in triacetin as oil phase, labrasol as surfactant, cremophor EL as co-surfactant and water. NE contains until 60 mg/mL of extract. It was characterized by DLS and TEM analyses and its droplets appear dark with an average diameter of 11.82 ± 0.125 nm and a polydispersity index (PdI) of 0.117 ± 0.019. The aqueous solubility of the extract was improved about 10 times: the extract is completely soluble in the NE at the concentration of 60 mg/mL, while its solubility in water results less than 6 mg. The passive intestinal permeation was tested by using parallel artificial membrane permeation assay (PAMPA) and the permeation across Caco-2 cells after preliminary cytotoxicity studies were also evaluated. NE shows a good solubilizing effect of the constituents of the extract, compared with aqueous solution. The total amount of constituents permeated from NE to acceptor compartment is greater than that permeated from saturated aqueous solution. Caco-2 test confirmed PAMPA results and they revealed that NE was successful in increasing the permeation of VAC extract. This formulation could improve oral bioavailability of extract due to enhanced solubility and permeability of phytocomplex.

Tu1113 Dexlansoprazole Modified-Release Orally-Disintegrating Tablet -The Bioavailability of Alternate Dosing Options