Pharmacokinetics and Histotoxic Profile of a Novel Azithromycin-Loaded Lipid-Based Nanoformulation.

Azithromycin traditional formulations possesses poor oral bioavailability which necessitates development of new formulation with enhanced bioavailability of the drug. The objective of current research was to explore the kinetics and safety profile of the newly developed azithromycin lipid-based nanoformulation (AZM-NF). In the in-vitro study of kinetics profiling, azithromycin (AZM) release was assessed using dialysis membrane enclosing equal quantity of either AZM-NF, oral suspension of azithromycin commercial product (AZM-CP), or azithromycin pure drug (AZM-PD) in simulated intestinal fluid. The ex-vivo study was performed using rabbit intestinal segments in physiological salts solution in a tissue bath. The in-vivo study was investigated by oral administration of AZM to rabbits while taking blood samples at predetermined time-intervals, followed by HPLC analysis. The toxicity study was conducted in rats to observe histopathological changes in rat's internal organs. In the in-vitro study, maximum release was 95.38 ± 4.58% for AZM-NF, 72.79 ± 8.85% for AZM-CP, and 46.13 ± 8.19% for AZM-PD (p < 0.0001). The ex-vivo investigation revealed maximum permeation of 85.68 ± 5.87 for AZM-NF and 64.88 ± 5.87% for AZM-CP (p < 0.001). The in-vivo kinetics showed Cmax 0.738 ± 0.038, and 0.599 ± 0.082 µg/ml with Tmax of 4 and 2 h for AZM-NF and AZM-CP respectively (p < 0.01). Histopathological examination revealed compromised myocardial fibers integrity by AZM-CP only, liver and kidney showed mild aberrations by both formulations, with no remarkable changes in the rest of studied organs. The results showed that AZM-NF exhibited significantly enhanced bioavailability with comparative safer profile to AZM-CP investigated.

Antioxidant, antinociceptive, anti-inflammatory, and hepatoprotective activities of pentacyclic triterpenes isolated from Ziziphus oxyphylla Edgew.

Ziziphus oxyphylla Edgew is in folk use in Pakistan as an analgesic, anti-inflammatory, and liver ailments. Therefore, we have investigated antioxidant, antinociceptive, anti-inflammatory, and hepatoprotective activities of the isolated compounds (ceanothic acid and zizybrenalic acid) from the chloroform fraction of Z. oxyphylla. Ceanothic acid and zizybrenalic acid showed significant DPPH and H2O2 scavenging activity as compared to control. In the acute toxicity study, ceanothic acid and zizybrenalic acid showed no toxic effects upto 200 mg/kg. The antinociceptive activity shown by ceanothic acid and zizybrenalic acid at 50 mg/kg was 64.28% and 65.35% compared to diclofenac sodium (72.3%) at 50 mg/kg. The percent inhibition of xylene-induced ear edema exhibited by ceanothic acid and zizybrenalic acid at 50 mg/kg was 51.33% and 58.66%, respectively, as compared to diclofenac sodium (72.66%). Both the isolated compounds exhibited inhibition of carrageenan-induced paw edema as compared to control. Hepatoprotection exhibited by zizybrenalic acid was more pronounced than ceanothic acid as observed from the decrease in carbon tetrachloride (CCl4)-induced elevation of serum biomarkers, antioxidant enzymes and lipid peroxidation. Furthermore, zizybrenalic acid produced a marked decline in CCl4-induced prolongation of phenobarbital-induced sleeping duration. Zizybrenalic acid exhibited 55.4 ± 1.37% inhibition of hypotonic solution-induced hemolysis compared to sodium salicylate (75.6 ± 2.15%). The histopathological damage caused by CCl4 was also countered by the administration of ceanothic acid and zizybrenalic acid. Ceanothic acid and zizybrenalic acid exhibited antioxidant, antinociceptive, anti-inflammatory, and hepatoprotective activities. Zizybrenalic acid exhibited better antioxidant, antinociceptive, anti-inflammatory, and hepatoprotective activity than ceanothic acid.

Protective effect of the solvent extracts of Portulacca oleracea against acidified ethanol induced gastric ulcer in rabbits.

Portulacca oleracea L. has been used for treatment of different ailments. The aim of this study was to investigate the effectiveness and possible mechanism of action involved in the anti gastric ulcerogenic effect of Portulacca oleracea. Methanolic extract & subsequent fractions (100, 200 and 400 mg/kg) of Portulacca oleracea (P. oleracea) were administered orally to experimental rabbits one hour before oral administration of HCl/ethanol (40:60). Anti gastric ulcerogenic potential of P. oleracea was evaluated by assessment of gastric pH, pepsin, free acidity, ulcer index, mucus content and total acidity. For the investigation of possible mechanism of action malondialdehyde (MDA), histamine, and H + K + ATPase content were determined in the stomach homogenate. Histopathological study of stomach tissue was carried out by H&E dye. Ethyl acetate fraction (EAF) of P. oleracea was the most potent fraction among all fractions that exhibited efficient protection against acidified ethanol mediated gastric-ulcer. The ethyl acetate fraction (EAF) significantly increased the pH of gastric juice, while pepsin and histamine was observed to decrease significantly in comparison to acidified ethanol group (***p ≤ 0.001). The EAF showed moderately H + K + ATPase inhibitory activity. Moreover, it was also observed that EAF decreased the malondialdehyde (MDA) level in the stomach tissue homogenate showing antioxidant effect. Histopathological studies showed that among the tested fractions, EAF significantly prevented acidified ethanol induced gastric mucosal damage. These results showed that mechanism of anti gastric ulcerogenic potential of P. oleracea could be associated with the reduction in histamine level, H + K + ATPase inhibition and reduced MDA level.

Optimization of Chitosan-Decorated Solid Lipid Nanoparticles for Improved Flurbiprofen Transdermal Delivery.

Transdermal delivery is a potential alternative route to oral administration for drugs associated with stomach discomfort, such as flurbiprofen, a widely nonsteroidal anti-inflammatory drug (NSAID). This study aimed to design solid lipid nanoparticle (SLN) transdermal formulations of flurbiprofen. Chitosan-coated SLNs were prepared by the solvent emulsification method, and their properties and permeation profiles across the excised rat skin were characterized. The particle size of uncoated SLNs was at 695 ± 4.65 nm, which increased to 714 ± 6.13, 847 ± 5.38, and 900 ± 8.65 nm upon coating with 0.05, 0.10, and 0.20% of chitosan, respectively. The drug association efficiency was improved when a higher concentration of chitosan was employed over SLN droplets that endowed a higher affinity of flurbiprofen with chitosan. The drug release was significantly retarded as compared to the uncoated entities and followed non-Fickian anomalous diffusion that was depicted by "n" values of >0.5 and <1. Also, the total permeation of chitosan-coated SLNs (F7-F9) was significantly higher than that of the noncoated formulation (F5). Overall, this study has successfully designed a suitable carrier system of chitosan-coated SLNs that provide insight into the current conventional therapeutic approaches and suggest new directions for the advancements in transdermal drug delivery systems for improved permeation of flurbiprofen.

5-Fluorouracil-Loaded Hyaluronic Acid-Coated Niosomal Vesicles: Fabrication and Ex Vivo Evaluation for Skin Drug Delivery.

5-Fluorouracil (5-FU) is one of the most potent drugs against solid tumors. However, its parenteral administration is associated with systemic toxicity, while its topical application has limited percutaneous absorption. To overcome these limitations, the current study undertakes the formulation of 5-FU as niosomal vesicles that were coated with hyaluronic acid to improve its targeting efficiency for cancer cells. The niosomes were prepared by the thin-film hydration method using cholesterol as physiological lipid and nonionic surfactants (Tween 80 and Span 80) in the ratio of 1:1. The niosomal vesicles were characterized for their size, size distribution, viscosity, surface tension, density, and drug entrapment efficiency. The vesicles were within the particle size range of 337-478 nm with relatively homogeneous particle size distribution (PDI ≤ 0.5). The ζ-potential and drug entrapment efficiency of coated formulations (F2 and F4) were comparatively higher than corresponding noncoated formulations (F1 and F3). The release behavior of 5-FU from niosomal vesicles using a dialysis membrane depicts that initial burst drug release was higher for F1 and F3 due to their smaller particle size in comparison to their coated counterparts. However, the release was more controlled for F4 due to the larger particle size, higher viscosity, and entrapped fraction of the formulation. The permeation of the drug through the rat's skin was comparatively higher in the case of noncoated formulations than their coated counterparts (p ≤ 0.05). This could be attributed to their small particle size and lower surface tension. In the case of coated formulations, the hydrophilic hyaluronic acid hinders the permeation of the drug through the lipid bilayer membrane of the skin. The retention of the drug in the skin was found to be in the range of 20-40%, which is sufficient to achieve optimum drug concentration in the tumorous tissue. Overall, the study successfully designed novel niosomal carrier systems for improved 5-FU delivery after topical application.

Fabrication of Niclosamide loaded solid lipid nanoparticles: in vitro characterization and comparative in vivo evaluation.

Niclosamide (NCS) is an oral anthelminthic drug having low solubility and hence low bioavailability. Current investigation shows an approach to fabricate solid lipid nanoparticles (SLNs) of NCS and evaluated for pharmaceutical, in vitro and in vivo characterization. NFM-3 showed particle size 204.2 ± 2.2 nm, polydispersity index 0.328 ± 0.02 and zeta potential -33.16 ± 2 mV. Entrapment efficiency and drug loading capacity were 84.4 ± 0.02% and 5.27 ± 0.03%, respectively. Scanning electron microscopy image indicated that particles were nanoranged. DSC and P-XRD results showed change in physicochemical properties of NCS. FT-IR spectra confirmed compatibility between NCS and excipients. The drug release profile showed sustained release (93.21%) of NCS in 12 h. Different kinetic models showed zero-order kinetics and Case-II transport mechanism. Study showed maximum stability at refrigerated temperature. In vivo pharmacokinetic study showed 2.15-fold increase in NCS peak plasma concentration as solid lipid nanoparticle formulation (NFM-3) compared to commercial product while relative bioavailability was 11.08. Results including in vitro and in vivo release studies of NCS confirmed that SLNs system is suitable to improve oral delivery of NCS with increased aqueous solubility, permeability and finally bioavailability.