Abdulaziz Mohsen Al-mahallawi

Nano-transfersomal ciprofloxacin loaded vesicles for non-invasive trans-tympanic ototopical delivery: In-vitro optimization, ex-vivo permeation studies, and in-vivo assessment

Ciprofloxacin is a synthetic fluoroquinolone antibiotic that has been used for systemic treatment of otitis media in adults. It was approved for topical treatment of otorrhea in children with tympanostomy tubes. The aim of this work was to enhance the local non-invasive delivery of ciprofloxacin to the middle ear across an intact tympanic membrane (TM) in an attempt to treat acute otitis media (AOM) ototopically. In order to achieve this goal, ciprofloxacin nano-transfersomal vesicles were prepared by thin film hydration (TFH) technique, using several edge activators (EAs) of varying hydrophilic-lipophilic balance (HLB) values. A full factorial design was employed for the optimization of formulation variables using Design-Expert(®) software. The optimal formulation was subjected to stability testing, ex-vivo permeation studies (through ear skin and TM of rabbits), and in-vivo evaluation. Results revealed that the optimal formulation (composed of phospholipid and sodium cholate as an EA at a molar ratio of 5:1) exhibited enhanced ex-vivo drug flux through ear skin and TM when compared with the commercial product (Ciprocin(®) drops). It demonstrated a greater extent of in-vivo drug deposition in the TM of albino rabbits relative to Ciprocin(®). Consequently, transfersomes could be promising for the non-invasive trans-tympanic delivery of ciprofloxacin.

Investigating the potential of employing bilosomes as a novel vesicular carrier for transdermal delivery of tenoxicam.

Bilosomes represent an evolving vesicular carrier that have been explored for oral vaccines delivery based on its ability to resist enzymes and bile salts in the gastrointestinal tract (GIT). Bilosomes vesicles are formed of bilayer membrane of non-ionic surfactant molecules encompassing bile salts. Although, bilosomes have not been proposed for transdermal drug delivery, this carrier seems to have promising potential in this regard. Accordingly, the aim of this investigation was to assess the capability and safety of utilizing bilosomes for transdermal delivery of tenoxicam (TX) as a model drug. A 3(1)2(2) full factorial design was adopted to study the effects of different formulation parameters on bilosomes properties and select the optimal formulation using Design-Expert(®) software. The selected formulation displayed nano-sized spherical vesicles (242.5 ± 6.43nm) with reasonable entrapment efficiency percent (68.33 ± 2.33%). Confocal laser scanning microscopy confirmed the capability of the flourolabeled bilosomes to penetrate deep within the skin. Both, ex vivo permeation and in vivo skin deposition studies confirmed the superiority of bilosomes over drug solution in delivering TX transdermally. In addition, in vivo histopathological study proved the safety of topically applied bilosomes. In summary, the highlighted results confirmed that bilosomes can be further adopted for delivering drugs transdermally.

Fabrication of novel ultradeformable bilosomes for enhanced ocular delivery of terconazole: In vitro characterization, ex vivo permeation and in vivo safety assessment

The objective of this work was to encapsulate terconazole (TCZ), a water insoluble antifungal drug, into novel ultradeformable bilosomes (UBs) for achieving enhanced ocular delivery. In addition to the constituents of the conventional bilosomes; namely, Span 60, cholesterol, and the bile salts, UBs contain an edge activator which imparts extra elasticity to the vesicles and consequently hypothesized to result in improved corneal permeation. In this study, TCZ loaded UBs were prepared utilizing ethanol injection method according to 23 full factorial design. The investigation of the influence of different formulation variables on UBs properties and selection of the optimum formulation was done using Design-Expert® software. The selected UBs formulation (UB1; containing 10mg bile salt and 5mg Cremophor EL as an edge activator) showed nanosized spherical vesicles (273.15±2.90nm) and high entrapment efficiency percent (95.47±2.57%). Results also revealed that the optimum UBs formulation exhibited superior ex vivo drug flux through rabbit cornea when compared with conventional bilosomes, niosomes, and drug suspension. Furthermore, in vivo ocular tolerance and histopathological studies conducted using male albino rabbits proved the safety of the fabricated UBs after topical ocular application. Overall, the obtained results confirmed that UBs could be promising for ocular drug delivery.

Long-circulating lipoprotein-mimic nanoparticles for smart intravenous delivery of a practically-insoluble antineoplastic drug: Development, preliminary safety evaluations and preclinical pharmacokinetic studies.

Chlorambucil (CHL) is a water-insoluble antineoplastic drug having a short elimination half-life. It suffers from remarkable differences in pharmacokinetics following oral administration. The current work aimed to assess safety and pharmacokinetics of CHL-loaded, lipoprotein-mimic, nanoparticles (NPs) following intravenous administration. The design of NPs was based on complexation between egg yolk lecithin (EYL) and bovine serum albumin (BSA). The NPs were preliminary evaluated via FT-IR, DSC and P-XRD. The NPs were characterized for particle size, zeta potential, morphology and drug entrapment efficiency (EE%). The best achieved NP dispersion (LP6) and CHL solution were challenged for in vitro hemolytic potential, in vivo vascular irritation studies in rabbits and in vivo pharmacokinetics following intravenous administration in rats. The results confirmed that NPs were stabilized by hydrophobic-attractions and hydrogen-bondings between CHL, BSA and EYL. The amorphous dispersion of CHL within NPs was revealed. LP6 dispersion displayed monodispersed nano-spherical particles (144.33 ± 2.17 nm). It possessed the highest negative zeta potential (-30.55 ± 0.24 mV) and the largest EE% (86.35 ± 2.33%). The significantly (P < 0.05) prolonged MRT(0-∞), longer elimination t50% and reduced plasma clearance highlighted the long-circulating characteristics of LP6. The preliminary safety evaluations and the seven-fold increase in bioavailability elucidated potentiality for smart intravenous delivery of CHL.

Preparation, optimization, and in vitro simulated inhalation delivery of carvedilol nanoparticles loaded on a coarse carrier intended for pulmonary administration

Carvedilol (CAR) is a potent antihypertensive drug but has poor oral bioavailability (24%). A nanosuspension suitable for pulmonary delivery to enhance bioavailability and bypass first-pass metabolism of CAR could be advantageous. Accordingly, the aim of this work was to prepare CAR nanosuspensions and to use artificial neural networks associated with genetic algorithm to model and optimize the formulations. The optimized nanosuspension was lyophilized to obtain dry powder suitable for inhalation. However, respirable particles must have a diameter of 1–5 µm in order to deposit in the lungs. Hence, mannitol was used during lyophilization for cryoprotection and to act as a coarse carrier for nanoparticles in order to deliver them into their desired destination. The bottom-up technique was adopted for nanosuspension formulation using Pluronic stabilizers (F127, F68, and P123) combined with sodium deoxycholate at 1:1 weight ratio, at three levels with two drug loads and two aqueous to organic phase volume ratios. The drug crystallinity was studied using differential scanning calorimetry and powder X-ray diffractometry. The in vitro emitted doses of CAR were evaluated using a dry powder inhaler sampling apparatus and the aerodynamic characteristics were evaluated using an Andersen MKII cascade impactor. The artificial neural networks results showed that Pluronic F127 was the optimum stabilizer based on the desired particle size, polydispersity index, and zeta potential. Results of differential scanning calorimetry combined with powder X-ray diffractometry showed that CAR crystallinity was observed in the lyophilized nanosuspension. The aerodynamic characteristics of the optimized lyophilized nanosuspension demonstrated significantly higher percentage of total emitted dose (89.70%) and smaller mass median aerodynamic diameter (2.80 µm) compared with coarse drug powder (73.60% and 4.20 µm, respectively). In summary, the above strategy confirmed the applicability of formulating CAR in the form of nanoparticles loaded on a coarse carrier suitable for inhalation delivery.

Enhanced non invasive trans-tympanic delivery of ciprofloxacin through encapsulation into nano-spanlastic vesicles: Fabrication, in-vitro characterization, and comparative ex-vivo permeation studies

The aim of this research was to encapsulate ciprofloxacin, a broad spectrum fluoroquinolone antibiotic, into Span 60 based nano-elastic vesicles, nano-spanlastics, for accomplishing improved non invasive trans-tympanic delivery, providing means for ototopical treatment of acute otitis media (AOM). To achieve this purpose, ciprofloxacin-loaded nano-spanlastics were prepared by thin film hydration (TFH) technique, using several non-ionic edge activators (EAs) according to full factorial design (32). The investigation of the effect of formulation variables on nano-spanlastic characteristics and selection of the optimum formula were performed using Design-Expert® software. The selected formulation was also subjected to comparative ex-vivo permeation studies through tympanic membrane (TM) of rabbits. Results revealed that the optimal nano-spanlastic formulation (S-2; containing 20% Brij 35 as an EA) exhibited nano-sized spherical vesicles (287.55±9.97nm), relatively high entrapment efficiency percent (51.81±1.57%), and good physical stability after six months of storage at 4-8°C. Ex-vivo TM permeation studies demonstrated the superiority of the optimal nano-spanlastic formulation over the commercial Ciprocin® drops. However, when compared to lipid-based elastic vesicles, nano-transfersomes, nano-spanlastics exhibited lower drug permeation through the TM. Concisely, the obtained results suggested that nano-spanlastics can be promising for improving trans-tympanic delivery of ciprofloxacin.

Comparative study on radiolabeling and biodistribution of core-shell silver/polymeric nanoparticles-based theranostics for tumor targeting

A simple and rapid method for radiolabeling of three types of Ag NPs has been performed using 125I isotope, with high labeling yields, >90% without disturbing the optical properties. All the factors affecting labeling yield were studied. In order to monitor the in-vivo tissue uptake of radiolabeled Ag NPs using γ-rays, Ag-based radioiodo-NPs with a maximum labeling yield were intravenously injected in normal and solid tumor bearing mice. The preliminary biodistribution study revealed that this new radioiodo-NPs have a high affinity to be localized in the tumor site for a long period of time. The reported highly efficient method provides new radiolabeled Ag-based NPs as tumor-specific agents for both diagnostic and therapeutic applications.

Preparation of novel phospholipid-based sonocomplexes for improved intestinal permeability of rosuvastatin: In vitro characterization, dynamic simulation, Caco-2 cell line permeation and in vivo assessment studies

ABSTRACT The study aimed to fabricate innovative drug‐phospholipid complexes termed “sonocomplexes” adopting ultrasound irradiation to increase the liposolubility and to enhance the intestinal absorption of rosuvastatin as a model drug for BCS class III active pharmaceutical ingredients (APIs). A 22 full factorial design was fashioned to investigate the influence of phosphatidylcholine content in the phospholipid (˜30 and 60%) and molar ratio of phospholipid to rosuvastatin (1:1 and 2:1) on physicochemical properties of sonocomplexes. In comparison to pure drug, sonocomplexes showed a minimum of about 2 folds and a maximum of about 15 folds increase in lipophilicity (expressed in terms of partition coefficient, P). Results of molecular docking, dynamic simulations, Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) confirmed the strong interactions between rosuvastatin and the phospholipid via hydrogen bonding interaction, van der Waals forces and hydrophobic interaction. The complexation efficiency reached around 99% and transmission electron microscopy (TEM) of the aqueous dispersion of the optimal sonocomplex showed spherical nanosized vesicles. The optimal sonocomplex showed significantly superior Caco‐2 cells permeability and markedly better oral bioavailability compared to the pure drug. In summary, sonocomplexes can be considered as effective approach for enhancing the liposolubility and consequently the intestinal permeability of BCS class III drugs.

Formulation and in vivo assessment of terconazole-loaded polymeric mixed micelles enriched with Cremophor EL as dual functioning mediator for augmenting physical stability and skin delivery

Abstract The aim of the current study was to formulate terconazole (TCZ) loaded polymeric mixed micelles (PMMs) incorporating Cremophor EL as a stabilizer and a penetration enhancer. A 23 full factorial design was performed using Design-Expert® software for the optimization of the PMMs which were formulated using Pluronic P123 and Pluronic F127 together with Cremophor EL. To confirm the role of Cremophor EL, PMMs formulation lacking Cremophor EL was prepared for the purpose of comparison. Results showed that the optimal PMMs formulation (F7, where the ratio of total Pluronics to drug was 40:1, the weight ratio of Pluronic P123 to Pluronic F127 was 4:1, and the percentage of Cremophor EL in aqueous phase was 5%) had a high micellar incorporation efficiency (92.98 ± 0.40%) and a very small micellar size (33.23 ± 8.00 nm). Transmission electron microscopy revealed that PMMs possess spherical shape and good dispersibility. The optimal PMMs exhibited superior physical stability when compared with the PMMs formulation of the same composition but lacking Cremophor EL. Ex vivo studies demonstrated that the optimal PMMs formula markedly improved the dermal TCZ delivery compared to PMMs lacking Cremophor EL and TCZ suspension. In addition, it was found that the optimal PMMs exhibited a greater extent of TCZ deposition in the rat dorsal skin relative to TCZ suspension. Moreover, histopathological studies revealed the safety of the optimal PMMs upon topical application to rats. Consequently, PMMs enriched with Cremophor EL, as a stable nano-system, could be promising for the skin delivery of TCZ.

Targeting colorectal cancer cell metabolism through development of cisplatin and metformin nano-cubosomes

BackgroundColorectal cancer (CRC) remains a leading cause of death worldwide. Utilizing cisplatin in CRC is correlated with severe adverse effects and drug-resistance. Combined anticancer drug-treatment, along with, their enhanced delivery, can effectively kill cancer through multiple pathways. Nano-cubosomes are emerging as nanocarriers for anticancer therapies, hence, we constructed nano-cubosomes bearing cisplatin and cisplatin-metformin combination for investigation on HCT-116 cells.MethodsNano-cubosomes bearing either cisplatin alone or cisplatin-metformin combination were formulated using emulsification technique. The loaded nano-cubosomes were characterized in vitro and the optimized formulation was selected. Their cytotoxic effects were investigated by Sulphorhodamine-B (SRB) assay. The AMPK/mTOR metabolic pathway as well as the Akt/mTOR pathway were analyzed using ELISA technique. Colorimetry was used in NADPH oxidase, LDH and caspase-3 activity determination.Resultsnano-cubosomal formulations exhibited superior cytotoxic effect compared to unformulated cisplatin. This cytotoxic effect was profound upon incorporation of metformin, an indirect mTOR inhibitor, in cisplatin nano-cubosomes. The induced CRC cell apoptosis was through inhibition of several metabolic pathways, namely, AMPK/mTOR and Akt/mTOR. Drug-loaded nano-cubosomes ensued depletion in glucose and energy levels that led to AMPK activation and thus mTOR inhibition. mTOR was additionally inhibited via suppression of p-Akt (Ser473) levels after nano-cubosomal treatment. Moreover, drug-loaded nano-cubosomes produced a notable escalation in ROS levels, evident as an increase in NADPH oxidase, inhibition of LDH and a consequential upsurge in caspase-3.ConclusionThese results demonstrated the influence exerted by cisplatin-loaded nano-cubosomes on CRC cell survival and enhancement of their cytotoxicity upon metformin addition.