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Purpose: Drug delivery into the inner ear across the intact tympanic membrane (TM) has been a challenge in the treatment of inner ear disorders. In this study, nano-sized carriers were formulated for improving the non- invasive oto-topical delivery of caroverine for the treatment of tinnitus., Methods: Caroverine was loaded into two types of phospholipid-containing systems, namely, nano elastic vesicles (EVs) and phosphatidylcholine-based liquid crystalline nano-particles (PC-LCNPs). The prepared formulations were characterized for their drug loading, particle size, polydispersity index, zeta potential, morphological features by transmission electron microscopy (TEM), and physicochemical stability. In addition, comparative ex vivo transport study was carried out using rabbits' TM for both types of formulations., Results: The findings show a significant superiority of PC-LCNPs over the EVs formulations in the drug payload (1% and 0.25%, respectively), physical stability and the efficiency of permeation across rabbits' TM. The results showed a more than twofold increase in the cumulative drug flux values of PC-LCNPs (699.58 ± 100 µg/cm 2 ) compared to the EVs (250 ± 45 µg/cm 2 ) across the TM., Conclusion: The current study revealed the smart physicochemical properties of PC-LCNPs demonstrating the potential of this carrier as a new attractive candidate for improving the non-invasive oto-topical delivery of caroverine., Competing Interests: The authors report no conflicts of interest for this work., (© 2020 Farrah et al.)

Bone injury is very serious in elder people or osteoporotic patients. In-situ forming implants (IFI) for bone rebuilding are usually poly-lactic-co-glycolic acid (PLGA)-based, which have a burst release effect. This study aimed to prepare novel liquid lipid-based PLGA-IFI loaded with raloxifene hydrochloride for prolonged non-surgical treatment of bone injuries by applying solvent-induced phase inversion technique. Labrasol® and Maisine® were added to the selected IFI forming long lasting lipid-based IFI (LLL-IFI). The formulations were characterized by analysing their in-vitro drug release, solidification time, injectability, rheological properties, and DSC in addition to their morphological properties. Results revealed that the LLL-IFI composed of 10%w/v PLGA with a lactide to glycolide ratio of 75:25 with ester terminal and 10% Maisine® possessed the most sustained drug release and lowest burst effect, as well as delayed pore formation compared to its counterpart lacking Maisine®. The selected LLL-IFI and PLGA-IFI formulations were tested for their capability to enhance bone regeneration in bone injuries induced in rats. Both formulations succeeded in healing the bones completely with the superiority of LLL-IFI in the formation of well-organized bone structures lacking fibrous tissues. The results suggest that LLL-IFI and PLGA-IFI are innovative approaches for treating critical and non-critical sized bone injuries., (Copyright © 2019. Published by Elsevier B.V.)

Daclatasvir is a new direct acting antiviral used in treatment of Hepatitis C virus, in an attempt to increase its hepatocytes specificity and uptake. It was encapsulated within bile based vesicles (BBVs) containing egg phosphatidyl choline, cholesterol and sodium deoxycholate fabricated by thin-film hydration method. A D-optimal mixture design was applied to study the effect of formulation variables on vesicular characteristics. The dependent variables picked were the particle size, polydispersity index, zeta potential and entrapment efficiency. The optimized bile based vesicles were subjected for further modifications to prepare miniaturized anionic (ABBVs), cationic (CBBVs) and Sito-G decorated BBVs (Sito-GBBVs) to be capable to penetrate liver fenestrae (<200 nm). The aim of the current work is to compare the potential of the ABBVs, CBBVs and Sito-GBBVs loaded with Daclatasvir for stability in simulated biological fluids, ex-vivo intestinal transenterocytic transport, HepG2 cellular uptake and resistance to blood protein adsorption. The miniaturized ABBVs, CBBVs and Sito-GBBVs showed acceptable stability in simulated biological fluids. CBBVs had the highest transenterocytic transport through intestinal membrane. The internalization of CBBVs into HepG2 cells was about 2.1 folds that of ABBVs and 1.45 folds that of Sito-GBBVs. ABBVs and Sito-GBBVs showed superior resistance to opsonization compared to CBBVs which showed significant increase in particle size (p˃0.05) due to protein adsorption. The miniaturized Sito-GBBVs constitute a promising strategy to overcome key biological barriers facing hepatocytes specific delivery of Daclatasvir., Competing Interests: The authors have declared that no competing interests exist.

Dapoxetine (D) suffers from poor oral bioavailability (42%) due to extensive metabolism in the liver. The aim of this study was to enhance the bioavailability of D via preparing instantly-dispersible nanocarrier powder system (IDNPs) for intranasal delivery of D. IDNPs were prepared using the thin film hydration technique, followed by freeze-drying to obtain easily reconstituted powder providing rapid and ready method of administration. The produced nanocarrier systems were evaluated for drug content, entrapment efficiency percentage, particle size, polydispersity index, zeta potential, and drug payload. The optimized nanocarrier system was morphologically evaluated via transmission electron microscopy and the optimized freeze-dried IDNPs were evaluated for ex-vivo permeation and in-vivo pharmacokinetic studies in rabbits following intranasal and oral administration. The relative bioavailability of D after intranasal administration of freeze-dried IDNPs was about 235.41% compared to its corresponding oral nanocarrier formulation. The enhanced D permeation and improved bioavailability suggest that IDNPs could be a promising model for intranasal delivery of drugs suffering from hepatic first pass effect.

The novel self- nanoemulsifying self-nanosuspension (SNESNS) combines the advantages of two efficient solubilization technologies; the nanoemulsion and the nanosuspension. The aim of this study is to test the efficiency of phospholipid based self-nanoemulsifying self-nanosuspension (p-SNESNS) formulation as a powerful tool to diminish the food effect on bioavailability of lurasidone hydrochloride as BCS Class II model drug. Phospholipid was incorporated into SNESNS to increase the solubilization power of the in-situ formed nanoemulsion and facilitate the dispersion of the in-situ formed nanosized drug particles. P-SNESNS was evaluated for particle size, Polydispersity index, in vitro dissolution and transmission electron microscopy (TEM). The drug amount dissolved after water dilution of LSD p-SNESNS was ~2 folds that dissolved after dilution of non-phospholipid SNESNS. The self-nanosuspension obtained by aqueous dilution of p-SNESNS kept the cubic morphology of LSD macroparticles. The high in vitro dissolution of LSD in the non-sink dissolution media (water and Phosphate buffer pH6.8) indicated that the p-SNESNS formulation had successfully increased the drug solubility irrespective of pH of the medium. The pharmacokinetics parameters of LSD p-SNESNS in humans were the same in both the fasted and fed states and were similar to those of LSD capsules in the fed state. Our results propose that p-SNESNS could be promising to increase patient compliance and drug efficiency of BCS class II antipsychotics by diminishing the food effect on their oral absorption and preventing the necessity to administer them with food., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Nimodipine (NM) is the only FDA-approved drug for treating subarachnoid hemorrhage induced vasospasm. NM has poor oral bioavailability (5-13%) due to its low aqueous solubility, and extensive first pass metabolism. The objective of this study is to develop radiolabeled NM-loaded LPM and to test its ability prolong its circulation time, reduce its frequency of administration and eventually target it to the brain tissue. NM was radiolabeled with 99m Tc by direct labeling method using sodium dithionite. Different reaction conditions that affect the radiolabeling yield were studied. The in vivo pharmacokinetic behavior of the optimum NM-loaded LPM formulation in blood, heart, and brain tissue was compared with NM solution, after intravenous and intranasal administration. Results show that the radioactivity percentage (%ID/g) in the heart of mice following administration of 99m Tc-NM loaded LPM were lower compared with that following administration of 99m Tc-NM solution, which is greatly beneficial to minimize the cardiovascular side effects. Results also show that the %ID/g in the blood, and brain following intravenous administration of 99m Tc-NM-loaded LPM were higher at all sampling intervals compared with that following intravenous administration of 99m Tc-NM solution. This would be greatly beneficial for the treatment of neurovascular diseases. The drug-targeting efficiency of NM to the brain after intranasal administration was calculated to be 1872.82%. The significant increase in drug solubility, enhanced drug absorption and the long circulation time of the NM-loaded LPM could be promising to improve nasal and parenteral delivery of NM.

Bosentan is an endothelin receptor antagonist (ERA) prescribed for patients with pulmonary arterial hypertension (PAH). The oral delivery of bosentan possesses several drawbacks such as low bioavailability (about 50%), short duration of action, frequent administration, hepatotoxicity and systemic hypotension. The pulmonary administration would circumvent the pre-systemic metabolism thus improving the bioavailability and avoids the systemic adverse effects of oral bosentan. However, the short duration of action and the frequent administration are the major drawbacks of inhalation therapy. Thus, the aim of this work is to explore the potential of respirable controlled release polymeric colloid (RCRPC) for effective, safe and sustained pulmonary delivery of bosentan. Central composite design was adopted to study the influence of formulation and process variables on nanoparticles properties. The particle size, polydispersity index (PDI), entrapment efficiency (EE) and in vitro bosentan released were selected as dependent variables. The optimized RCRPC showed particle size of 420 nm, PDI of 0.39, EE of 60.5% and sustained release pattern where only 31.0% was released after 16 h. The in vitro nebulization of RCRPC indicated that PLGA nanoparticles could be incorporated into respirable nebulized droplets better than drug solution. Pharmacokinetics and histopathological examination were determined after intratracheal administration of the developed RCRPC to male albino rats compared to the oral bosentan suspension. Results revealed the great improvement of bioavailability (12.71 folds) and sustained vasodilation effect on the pulmonary blood vessels (more than 12 h). Bosentan-loaded RCRPC administered via the pulmonary route may therefore constitute an advance in the management of PAH.

Twenty diclofenac sodium buccoadhesive discs containing Cp974p, polycarbophil, PEO, SCMC-medium viscosity (SCMC-MV), SCMC-ultrahigh viscosity (SCMC-UHV) or their combinations were prepared. These buccoadhesive discs were evaluated for release pattern, swelling capacity, surface pH, mucoadhesion performance, and in vitro permeation of diclofenac sodium through buccal membranes. In vivo testing of mucoadhesion time, strength of adhesion, irritation, bitterness due to drug swallowing and disc disintegration in the buccal cavity were also performed. Drug bioavailability of a selected diclofenac sodium buccoadhesive product was then compared with that of Voltarin 100 SR tablet. The percentage relative bioavailability of diclofenac sodium from the selected buccoadhesive disc 50 mg was found to be 141.31%., (copyright 2004 Elsevier B.V.)