Pectin nanoparticles loaded with nitric oxide donor drug: A potential approach for tissue regeneration.

The process of wound healing and tissue regeneration involves several key mechanisms to ensure the production of new tissues with similar cellular functions. This study investigates the impact of pectin, a natural polysaccharide, and nebivolol hydrochloride (NBV), a nitric oxide (NO) donor drug, on wound healing. Utilizing ionotropic gelation, NBV-loaded pectin nanoparticles were developed following a 2231 full factorial design. The optimized formulation, determined using Design expert® software, exhibited an encapsulation efficiency percentage of 70.68%, zeta potential of -51.4 mV, and a particle size of 572 nm, characterized by a spherical, discrete morphology. An in vivo study was conducted to evaluate the effectiveness of the optimal formulation in wound healing compared to various controls. The results demonstrated the enhanced ability of the optimal formulation to accelerate wound healing. Moreover, histopathological examination further confirmed the formulation's benefits in tissue proliferation and collagen deposition at the wound site 15 days post-injury. This suggests that the developed formulation not only promotes faster healing but does so with minimal side effects, positioning it as a promising agent for effective wound healing and tissue regeneration.

Seasonal metabolic profiling of Valencia orange leaf essential oil using GC coupled with chemometrics, nano-formulation, and insecticidal evaluation: in vivo and in silico.

Mosquitoes and mosquito-borne infectious diseases are a global challenge, especially with increased resistance to synthetic insecticides. The foregoing study aimed to utilize the essential oil of leaves of Citrus sinensis var. Valencia as a cheap, safe, eco-friendly (green), and effective alternative to chemical insecticides. Essential oil samples were collected from fresh and dried leaves across different seasons. They are subjected to hydrodistillation and then GC analysis to be compared. Seventy-seven compounds were detected in all samples where monoterpene hydrocarbons represented the most abundant class of hydrocarbons in fresh leaves (52.6-74.4%) and dried leaves (58.6-66.9%). Sabinene (8.26-29.2%), delta-3-carene (8.23-16.4%), d-limonene (2.50-11.2%), and ß-myrcene (2.40-4.93%) were the major monoterpene hydrocarbons in all seasons. Oxygenated monoterpenes comprising ß-linalool, citronellal, terpinen-4-ol, ß-citral, and α-citral exhibited also appreciable percentages in fresh (21.2-43.4%) and dried leaves (23.4-33.0%). Hierarchical cluster analysis (HCA) and principal component analysis (PCA) effectively segregated all samples into three discriminate clusters where, ß-linalool, terpinen-4-ol, ß-elemene enantiomer, sabinene, and ß-phellandrene constitute the main discriminatory biomarkers. Essential oil of fresh spring leaves (FS) was chosen for nano-formulation adopting the hot emulsification method. Both FS sample and the prepared nano-hexosomal formula were screened against the 3rd instar larvae Culex pipiens L. (common house mosquito). LC50 and LC95 values of FS and oil loaded nano-formula were (48 and 30 552 mg L-1) and (30 and 1830 mg L-1) respectively. α-Citral followed by citronellal showed the best fitting within the binding sites of acetylcholine esterase enzyme utilizing molecular docking. Thus, it can be concluded that Valencia orange leaf as a nano-formulation could serve as an effective and sustainable insecticidal agent.

Hesperidin hexosomal loaded nanodispersion: insights of its antimycobacterial, cytotoxic and anti-HCoV effects.

Fruits of Citrus sinensis L. Osbeck var. Valencia contain hesperidin as a major flavanone glycoside. Hesperidin (H) was isolated from the peels of Valencia orange and formulated as hexosomal nanodispersions (F1) adopting the hot emulsification method. The antimycobacterial activity(anti-TB) was evaluated through a microplate Alamar blue (MABA) assay where F1 showed significant activity with MIC = 0.19 µM. To unravel the potential mechanism of the anti-TB, a molecular docking study of H using the Mycobacterial Dihydrofolate reductase (Mtb. DHFR) enzyme was performed. Hesperidin exhibited significant interactions with Mtb. DHFR active site. Sulforhodamine B assay was applied to evaluate cytotoxic activity against the lung cancer cell line (A-549). F1 showed a cytotoxic effect at IC50= 33 µM. It also has potent antiviral activity against Human Coronavirus 229E with IC50= 258.8 µM utilising crystal violet assay. Peels of Valencia orange could be a source of bioactive metabolites to control significant diseases.

Vilazodone-phospholipid mixed micelles for enhancing oral bioavailability and reducing pharmacokinetic variability between fed and fasted states.

Despite the effectiveness and high tolerability of vilazodone (VLZ) as an antidepressant, its use is still limited due to its poor solubility and food dependent absorption. This study aims to load VLZ-phospholipid complex into self-assembled micelles forming VLZ-PL mixed micelles (VLZ-PL-MM), that can enhance VLZ solubility, improve its bioavailability and reduce the pharmacokinetic variability between the fed and fasting conditions. The effect of surfactant type and concentration was assessed using four different non-ionic surfactants (Brij 58, Tween 80, Labrasol and Pluronic F127) in four different weight ratios between the drug-complex and surfactant (1:0.5, 1:1, 1:2 and 1:3 w/w). Two VLZ-PL-MM formulae prepared using Brij 58 and Labrasol in 1:3 w/w ratio were selected as optimised ones since they have the highest encapsulation efficiency (100.83 and 93.87%, respectively), a particle size below 250 nm (206.73 and 221.33 nm, respectively) and negative zeta potential values (-29.63, -17.20 mV, respectively). Lyophilisation of these formulations using 3% sucrose was successful with no statistical changes in particle size and zeta potential upon rehydration. Both formulations elicited faster and higher in-vitro drug release profiles compared to the pure drug and the marketed tablet. In addition, both selected formulae improved ex-vivo permeation across rabbit intestinal membrane compared to the pure drug and the marketed tablet, with marked superiority of the one prepared using Brij 58. The results of the in-vivo study in male albino rabbits revealed similar AUC0-24 values after the oral administration of the best achieved VLZ-PL-MM system under fed and fasted conditions (769.89 and 741.55 ng.h mL-1, respectively). On the other hand, the marketed product showed significantly lower values of the AUC0-24 relative to the VLZ-PL-MM system and there was a marked enhancement of absorption of drug from the marketed product in presence of food (244.24 and 174.96 ng.h mL-1 under fed and fasted conditions, respectively). In addition, VLZ concentrations in the brain after 24 h obtained from the selected VLZ-PL-MM were significantly higher than those obtained from marketed tablet under fed and fasted conditions. Thus, the phospholipid mixed micelles formulation enhances the oral bioavailability of the poorly soluble drug and reduces the pharmacokinetic variability between fasting and fed conditions.

Dissolution enhancement of olmesartan medoxomil through polymer-based surface solid dispersion and solidified surfactant techniques.

This study aims to formulate Olmesartan medoxomil (OM) into oral fast-dissolving tablets (FDTs) to improve its solubility and bioavailability via two different techniques; The polymer-based surface solid dispersion (SSD) technique and the solidified surfactant (SS) technique. In the first technique, two polymers were used; polyvinylpyrrolidone (PVP K90) and Poloxamer 407 (Pluronic®F127), while in the second technique the liquid Tween 80 was solidified by adsorption onto Aeroperl®300. The pre-compression and post-compression parameters of the obtained formulations were assessed. The best formulations were subjected to a taste masking evaluation and a short-term stability study. The results demonstrated that, in comparison to the pure drug, the proportion of drug released from each of the prepared FDTs considerably increased. Results of the stability studies showed that the chosen drug formulations remained stable throughout the storage period.

Hexosomal Dispersion: A Nano-Based Approach to Boost the Antifungal Potential of Citrus Essential Oils against Plant Fungal Pathogens.

The demand for natural fungicides to replace synthetic ones has surged since toxic residues persist in soils, causing environmental contamination and posing a serious threat to worldwide public health. In the context of crop protection and enhancing the efficiency and safety of fungicides, nanotechnology is an eco-friendly strategy in managing fungal pathogens. In the present study, essential oils were isolated from the peels of four citrus fruits (Citrus lemon, Citrus aurantifolia, Citrus maxima, and Citrus sinensis) and were investigated using gas chromatography-mass spectrometric analysis. Monoterpene hydrocarbon was the most predominant group and limonene was the most abundant in the four oils. The antifungal potential of the oils was investigated, and the most active oil (Citrus lemon) was loaded into hexosomal dispersion, and its antifungal potential was retested against the same fungi. The structurally unique nano-based formulation showed great potency for fungal control. To the best of our knowledge, it is the first time the oil of Citrus lemon in nano-hexosomes has been formulated and its fungicidal activity examined. The data collected suggest that citrus essential oils (CEOs), especially when nano-formulated, could be successfully used in integrated fungus management programs.

Metformin dampens cisplatin cytotoxicity on leukemia cells after incorporation into cubosomal nanoformulation.

Acute lymphoblastic leukemia (ALL) is one of the most common type of leukemia in children. It is caused by abnormal cell division of the lymphoid progenitor cells in the bone marrow. In the past decade, metformin has gained increased attention for its anti-leukemic potential. Moreover, other chemotherapeutic agents were investigated for the possible superior efficacy over the existing treatments in treating ALL. Several studies examined the effect of cisplatin as a potential candidate for therapy. Here, we investigate the anti-leukemic effect of metformin and cisplatin on 697 cells. Both compounds revealed significant cytotoxic effects. Specifically designed lipid-based cubosomal nanoformulations were used as drug carriers to facilitate compound entry in low doses. Our results indicate that the use of the carrier did not affect cytotoxicity significantly. In addition, combining the drugs in different carriers demonstrated an antagonistic effect through damping the efficacy of both drugs. This was evident from experiments investigating cellular viability, annexin V/PI staining, mitochondrial membrane potential and caspase-3 activity. Taken together, it appears that metformin does not represent a suitable option for sensitizing leukemia cells to cisplatin.

Norfloxacin loaded nano-cubosomes for enhanced management of otitis externa: In vitro and in vivo evaluation.

The research's goal is to design and formulate nano-structured cubosomes loaded with norfloxacin (NFX)formanagement of otitis externa. In this study, glyceryl monooleate (GMO) as lipid phase, Cremophor EL as surfactant and either Pluronic F108 or Pluronic F127 as stabilizer were the used ingredients. The nano-cubosomal formulation "CUB 1" (its dispersed phase is composed of GMO (95%), Cremophor EL (2.5%) and Pluronic F108 (2.5%)) was the best achieved one. It had small particles size (216.75 ± 2.47 nm), good polydispersity index (0.339 ± 0.012) and acceptable zeta potential (-41.2 ± 2.262 mV). Images obtained after transmission electron microscopy examination ensured nearly cubic shape of formed nanoparticles with excellent dispersibility. Moreover, micrographs of rabbit ear skin specimens examined by confocal laser microscopy ensured good permeation capability of nano-structured cubosomes.In addition, in vivoskin deposition results revealed that higher amount of NFX was deposited in the rabbit ear skin throughout the study period (10 h) compared to drug suspension. Additionally, histopathological results proved that NFX loaded cubosomes can be safely applied topically on ear skin without any signs of inflammation nor skin irritation. Accordingly, these results anticipated the nano-structured cubosomal capabilities as a favorable nano-carrier for dermal NFX delivery to external ear skin for enhancing the management of otitis externa.

Chemical composition and potentiation of insecticidal and fungicidal activities of Citrus trifoliata L. fruits essential oil against Spodoptera littoralis, Fusarium oxysporum and Fusarium solani via nano-cubosomes.

Development of natural nano-based plant-protection formulations represents an emerging phenomenon that has been widely improved for crops protection and for enhancing the efficiency and safety of pesticides. In the present study we isolated the essential oil from the fruits of Citrus trifoliata L. and investigated it using gas chromatography-mass spectrometry analysis. Limonene (78.46%) was the major component followed by ß-Myrcene (7.94%) and Caryophyllene (4.20%). Citrus trifoliata essential oil (CTEO) loaded nano-cubosomes were successfully prepared by the emulsification technique. The insecticidal and fungicidal activities of formulated CTEO nano-cubosomes and unformulated CTEO were tested. While both of them exhibited substantial activities, CTEO nano-cubosomes were more effective than unformulated oil. It is the first time to formulate CTEO in nano-cubosomes and examine their insecticidal and fungicidal activities. In light of the current study, CTEO as it is or as nano-cubosomes is recommended as a promising candidate for pest and fungal pathogens control.Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2019.1675063.

Investigating the Potential of Phosphatidylcholine-Based Nano-Sized Carriers in Boosting the Oto-Topical Delivery of Caroverine: in vitro Characterization, Stability Assessment and ex vivo Transport Studies.

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/cm2) compared to the EVs (250 ± 45 µg/cm2) 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.

Development and optimization of osmotically controlled drug delivery system for poorly aqueous soluble diacerein to improve its bioavailability.

In an attempt to improve the low oral bioavailability of Diacerein (DCN), the combination of a ternary solid dispersion and an asymmetric osmotic pump system had been designed to enhance solubility and to control DCN delivery. Ternary DCN solid dispersion was prepared by melting fusion method using surfactant polymers, and carrier (Pluronic® PF127, Solutol® HS15, and PEG 35 K) and this DCN solid dispersion powder with the proper amount of excipients were compressed and coated with Opadry®CA to develop a Semi-Permeable and Asymmetric Osmotic Pump tablets. The ternary DCN solid dispersion by using surfactant polymers (Pluronic® F127 and Solutol® HS 15) with a ratio of 1:1 was displayed market significant improvement in saturated solubility (70.2 ± 4.14 µg/ml) and fast dissolution rate (Q60min = 79.28 ± 3.1% and IDR5 min = 5.25 ± 0.19 ml/min) in comparison to pure DCN. Moreover, the optimized asymmetric osmotic pump tablet with following parameters; 3% w/v Opadry® CA coat concentration, 1% w/w HPMC E15 gelling polymer and 35.8%w/w NaCl Osmogen concentration, was displayed control release of DCN at zero-order kinetic (R2 = 0.977) for up to 24 h(s). The in-vivo study conducted on rabbits was revealed a significant enhancement in the bioavailability of the optimized osmotic pump (28.84 ± 3.32 ng.hr/ml) compared to DCN dispersion (10.39 ± 1.45 ng.hr/ml). In conclusion, the approach of enhancing solubility and wet-ability in accompany with optimized asymmetric osmotic pump system could serve as a promising delivery system and a way to improve the bioavailability of poorly aqueous soluble drugs.

Enhancing Tumor Targeting Efficiency of Radiolabeled Uridine (via) Incorporation into Nanocubosomal Dispersions.

Background: Several nanosystems are currently being utilized to enhance the targeting efficiency of several cancer chemotherapeutic agents. This study was designed to improve tumor accumulation of iodine-125 (125I)-uridine via incorporation into a nanocubosomal preparation. Materials and Methods: Nanocubosomes were prepared with the aid of Glycerol mono-oleate and Pluronic F127. Each prepared nanocubosomal preparation was adequately characterized by testing their particle size, polydispersity index (PDI), ζ potential (ZP), and transmission electron microscopy. The radiolabeling of uridine with 125I was attempted using several oxidizing agents to achieve a high radiochemical yield, and the factors affecting the reaction yield were studied in detail. A comparative biodistribution study of free 125I-uridine and 125I-uridine loaded nanocubosomes was performed in normal and tumor bearing mice. The biodistribution was evaluated by intravenous injection of the sterile test solution, and animals were anesthetized and dissected at different time intervals postinjection (p.i.). Results: 125I-uridine was obtained in a high radiochemical yield (92.5% ± 0.8%). Afterward, 125I uridine was incorporated in a selected nanocubosome formulation, which showed nanosized cubic particles (178.6 ± 0.90 nm) with PDI (0.301 ± 0.04) and a ZP (34.35 ± 0.4). The biodistribution studies revealed that 125I-uridine nanocubosomes showed higher tumor localization (3.1 ± 0.4%IA/g at 2 h p.i. and a tumor/muscle ratio of 6.2) compared with the free 125I-uridine (2.7% ± 0.4%IA/g at 2 h p.i. and a tumor/muscle ratio of 3.3). Conclusion: The results of this study confirmed that 125I-uridine loaded nanocubosome had better efficiency in targeting the tumor site, which makes it an adequate targeting agent for tumor imaging.

Enhanced Permeation of Methotrexate via Loading into Ultra-permeable Niosomal Vesicles: Fabrication, Statistical Optimization, Ex Vivo Studies, and In Vivo Skin Deposition and Tolerability.

The aim of this study was to incorporate methotrexate (MTX) into ultra-permeable niosomal vesicles, containing cremophor RH40 as an edge activator (EA) and polyvinyl alcohol (PVA) as a stabilizer to enhance the drug permeation. Formulae were prepared by ethanol injection method following a Box-Behnken design in order to optimize the formulation variables (EA%, stabilizer %, and sonication time). To investigate the role of both cremophor RH40 and PVA, conventional MTX niosomes and MTX niosomes containing PVA only were fabricated. Drug entrapment efficiency percent (EE%), particle size (PS) analysis, zeta potential (ZP) measurements, and transmission electron microscopy (TEM) were conducted to characterize the vesicles. Cell viability studies and ex vivo permeation experiments of the optimized formula were conducted. Lastly, in vivo skin deposition of MTX from both the optimized formula and MTX solution was performed in rats. Besides, histopathological changes in rat skin were assessed. The optimized MTX ultra-permeable niosomal formula demonstrated spherical morphology, with an EE% of 65.16% and a PS of 453.6 nm. The optimized formula showed better physical stability in comparison with that of the same composition but lacking PVA. The cell viability studies verified the superior cytotoxicity of the optimized formula, and the ex vivo permeation studies revealed its ability to improve the drug permeation. The optimized formula demonstrated a significant deposition of MTX in rat dorsal skin, and histopathological evaluation confirmed the tolerability of the optimized formula in rats upon topical application. Accordingly, ultra-permeable noisomes, as a stable nanosystem, could be promising for effective delivery of MTX.

Fabrication of levofloxacin polyethylene glycol decorated nanoliposomes for enhanced management of acute otitis media: Statistical optimization, trans-tympanic permeation and in vivo evaluation.

Acute otitis media (AOM), an infection in the middle ear, is usually treated through systemic administration of antibiotics because the stratum corneum of the intact tympanic-membrane (TM) possesses low permeability that holds against the ototopical antibiotics use. Therefore, the objective of this work was to encapsulate levofloxacin (LFX) into polyethylene glycol 400 (PEG 400) decorated nanoliposomes (PNLs) as an approach for drug delivery through the intact tympanic-membrane. LFX loaded-PNLs were primed by ethanol injection technique. A 23 full factorial design, using Design-Expert® software, was developed to optimize formulation variables. Particle size, polydispersity index, zeta potential and entrapment efficiency percent of the formulae were determined. The optimal formulation (F7, prepared using 30:1 phospholipid to drug weight ratio, 30 mg cholesterol and 125 mg PEG 400) exhibited improved ex vivo trans-tympanic permeation compared to nanoliposomes lacking PEG 400 and drug solution. In addition, F7 showed greater extent of in vivo deposition of LFX in the intact TM compared to drug solution. Furthermore, in vivo histopathological examination proved the tolerability of the PNLs after ototopical application. Overall, the obtained results revealed that PNLs could be promising for LFX delivery through intact TM providing means for the ototopical drug application for treatment of acute middle ear infections.

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

BACKGROUND: Colorectal 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. METHODS: Nano-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. RESULTS: nano-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. CONCLUSION: These results demonstrated the influence exerted by cisplatin-loaded nano-cubosomes on CRC cell survival and enhancement of their cytotoxicity upon metformin addition.

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.

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.

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.

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.

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.

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.