Pharmacodynamic Studies of Pravastatin Sodium Nanoemulsion Loaded Transdermal Patch for Treatment of Hyperlipidemia.

Pravastatin sodium (PVS) is a hypolipidemic drug with poor oral bioavailability due to the first-pass effect. Therefore, this study aims to formulate and evaluate transdermal patches containing PVS-loaded nanoemulsions (PVS-NEs) to increase PVS's hypolipidemic and hepatoprotective activities. PVS-NEs were prepared using the aqueous titration method, where oleic acid was chosen as an oil phase, and span 80 and tween 80 were used as surfactant and cosurfactant respectively. Droplet size (DS), polydispersity index (PDI), zeta potential (ZP), clarity, and thermodynamic stability of NEs were all characterized. Also, PVS-NEs (NE2) with 50% oil phase, 40% SC mix 2:1, and 10% water were selected as an optimum formula based on the results of DS (251 ± 16), PDI (0.4 ± 0.16), and ZP (-70 ± 10.4) to be incorporated into a transdermal patch, and PVS-NE2 loaded transdermal patches (PVS-NE2-TDPs) were prepared by solvent evaporation method. F1 patch with HPMC E15 and PVP K30 in a ratio of 3:1 represented satisfactory patch properties with good drug-excipients compatibility. Thus, it was selected as an optimum patch formula. The optimized F1 patch was characterized for thickness, moisture content, weight variation, and drug-excipients incompatibility. Therefore, it was subjected to ex vivo skin permeation and finally pharmacodynamic studies. Ex vivo permeation studies of F1 revealed that the cumulative amount of PVS permeated across rat skin was 271.66 ± 19 µg/cm2 in 72 h, and the pharmacodynamic studies demonstrated that the F1 patch was more effective in treating hyperlipidemia than PVS-TDP (control patch) based on both blood analysis and histopathological examination. .

Spanlastic-laden in situ gel as a promising approach for ocular delivery of Levofloxacin: In-vitro characterization, microbiological assessment, corneal permeability and in-vivo study.

The objective of this study was to encapsulate the antibacterial drug levofloxacin hemihydrate (LF) into spanlastics (SLs) followed by incorporation into gelrite in situ gel to enhance its antibacterial activity and sustain ocular delivery. A combination of Span 60 as main vesicle component and Tweens as an edge activator (EA) was used to prepare SLs using the thin film hydration method. A 32 factorial design was applied to study the effect of formulation variables (ratio of Span 60: EA and type of EA) on SLs characteristics (encapsulation efficiency (EE%), particle size (PS), zeta potential (ZP) and percentage of drug released). In-vitro antimicrobial study was conducted to determine the antibacterial activity of the optimized formula. Finally confocal laser scanning microscopy (CLSM) was applied to monitor SLs corneal penetration. The optimum formulation (F5), contains 240 mg Span 60 and 60 mg Tween 60 as EA. F5 exhibited EE% = 59.7 ± 4.2%, PS = 177.6 ± 1.8 nm, PDI = 0.27 ± 0.022 and ZP = -40.6 ± 0.68 mV. Furthermore, only 39.37 ± 0.72% of LF amount was released after 4 h compared to complete release from drug solution. The apparent permeation coefficient was (14.7 × 10-3 cm/h) compared to (9.7 × 10-3 cm/h) for LF solution. Moreover, F5 exhibited 200% and 100% increase in the antibacterial efficacy against Pseudomonas aeruginosa and Staphylococcus aureus respectively.

Formulation and Evaluation of Pravastatin Sodium-Loaded PLGA Nanoparticles: In vitro-in vivo Studies Assessment.

Purpose: Pravastatin sodium (PVS) is a hypolipidemic drug which suffers from extensive first-pass metabolism and short half-life. Poly(d,l-lactide-co-glycolide) (PLGA) is considered a promising carrier to improve its hypolipidemic and hepatoprotective activities. Methods: PVS-loaded PLGA nanoparticles (PVS-PLGA-NPs) were prepared by double emulsion method using a full 32 factorial design. The in vitro release and the physical stability studies of the optimized PVS-PLGA-NPs (F5) were performed. Finally, both hypolipidemic and hepatoprotective activities of the optimized F5 NPs were studied and compared to PVS solution. Results: All the studied physical parameters of the prepared NPs were found in the accepted range. The particle size (PS) ranged from 90 ± 0.125 nm to 179.33 ± 4.509 nm, the poly dispersity index (PDI) ranged from 0.121 ± 0.018 to 0.158 ± 0.014. The optimized NPs (F5) have the highest entrapment efficiency (EE%) (51.7 ± 5%), reasonable PS (168.4 ± 2.506 nm) as well as reasonable zeta potential (ZP) (-28.3 ± 1.18mv). Solid-state characterization indicated that PVS is well entrapped into NPs. All NPs have distinct spherical shape with smooth surface. The prepared NPs showed a controlled release profile. F5 showed good stability at 4 ± 2°C during the whole storage period of 3 months. In vivo study and histopathological examination indicated that F5 NPs showed significant increase in PVS hypolipidemic as well as hepatoprotective activity compared to PVS solution. Conclusion: The PVS-PLGA-NPs could be considered a promising model to evade the first-pass effect and showed improvement in the hypolipidemic and hepatoprotective activities compared to PVS solution.

Formulation and Pathohistological Study of Mizolastine-Solid Lipid Nanoparticles-Loaded Ocular Hydrogels.

BACKGROUND: Mizolastine (MZL) is a dual-action nonsedating topical antihistamine anti-inflammatory agent that is used to relieve allergic conditions, such as rhinitis and conjunctivitis. Solid lipid nanoparticles (SLNs) are advanced delivery system in ophthalmology, with the merits of increasing the corneal drug absorption and hence improved bioavailability with the objective of ocular drug targeting. METHODS: First, MZL was formulated as MZL-SLNs by hot homogenization/ultrasonication adopting a 32 full factorial design. Solid-state characterization, in vitro release, and stability studies have been performed. Then, the optimized MZL-SLNs formula has been incorporated into ocular hydrogels using 1.5% w/v Na alginate and 5% w/v polyvinylpyrrolidone K90. The gels were evaluated via in vitro release as well as in vivo studies by applying allergic conjunctivitis congestion in a rabbit-eye model. RESULTS: The optimized formula (F4) was characterized by the highest entrapment efficiency (86.5±1.47%), the smallest mean particle size (202.3±13.59 nm), and reasonable zeta potential (-22.03±3.65 mV). Solid-state characterization of the encapsulation of MZL in SLNs was undertaken. In vitro results showed a sustained release profile from MZL-SLNs up to 30 hours with a non-Fickian Higuchi kinetic model. Stability studies confirmed immutability of freeze-dried MZL-SLNs (F4) upon storage for 6 months. Finally, hydrogel formulations containing MZL-SLNs, proved ocular congestion disappearance with completely repaired conjunctiva after 24 hours. Moreover, pretreatment with MZL-SLNs-loaded hydrogel imparted markedly decreased TNF-α and VEGF-expression levels in rabbits conjunctivae compared with post-treatment with the same formula. CONCLUSION: MZL-SLNs could be considered a promising stable sustained-release nanoparticulate system for preparing ocular hydrogel as effective antiallergy ocular delivery systems.

Ocular Inserts of Voriconazole-Loaded Proniosomal Gels: Formulation, Evaluation and Microbiological Studies.

BACKGROUND: Voriconazole (VRC) is a triazole broad spectrum antifungal drug, used in the management of versatile fungal infections, particularly fungal keratitis. The obligatory use of niosomal delivery of VRC may reduce the frequency of dosing intervals resulting from its short biological half time and consequently improve patient compliance. METHODS: VRC loaded proniosomes (VRC-PNs) were set by the coacervation technique and completely characterized. The developed formula was comprehensively assessed concerning in- vitro release behavior, kinetic investigation, and its conflict against refrigerated and room temperature conditions. A selected noisomal formula was incorporated into ocusert (VRC-PNs Ocu) formulated by 1% w/w hydroxypropyl methyl cellulose HPMC and 0.1% w/w carbopol 940. Eventually, in vitro antifungal activity against Candida albicans and Aspergillus nidulans was assessed by the cup diffusion method. RESULTS: The optimized VRC-PNs (Pluronic F127: cholesterol weight ratio 1:1 w/w) exhibited the highest entrapment efficiency (87.4±2.55%) with a spherical shape, proper size in nano range and a suitable Zeta potential of 209.7±8.13 nm and -33.5±1.85 mV, respectively. Assurance of drug encapsulation in nanovesicles was accomplished by several means such as attenuated total reflection Fourier-transform infrared spectroscopy, differential scanning calorimetry in addition to powder X-ray diffraction investigations. It displayed a biphasic in vitro release pattern and after 6 months of storage at a refrigerated temperature, the optimized formula preserved its stability. VRC-PNs Ocu proved a very highly significant antifungal activity matched with the free drug or nanosuspension which was extra assured by comparing its mean inhibition zone with that of 5% natamycin market eye drops. CONCLUSION: In conclusion, VRC-PNs Ocu could be considered as a promising stable sustained release topical ocular nanoparticulate system for the management of fungal infections.

Formulation and Evaluation of Atorvastatin Calcium-Poly-ε-Caprolactone Nanoparticles Loaded Ocular Inserts for Sustained Release and Antiinflammatory Efficacy.

PURPOSE: The work was performed to investigate the feasibility of preparing ocular inserts loaded with Poly-ε-Caprolactone (PCL) nanoparticles as a sustained ocular delivery system. METHODS: First, Atorvastatin Calcium-Poly-ε-Caprolactone (ATC-PCL) nanoparticles were prepared and characterized. Then, the optimized nanoparticles were loaded within inserts formulated with Methylcellulose (MC) and Polyvinyl Alcohol (PVA) by a solvent casting technique and evaluated physically, for in-vitro drug release profile. Finally, an in-vivo study was performed on the selected formulation to prove non-irritability and sustained ocular anti-inflammatory efficacy compared with free drug-loaded ocuserts. RESULTS: The results revealed (ATC-PCL) nanoparticles prepared with 0.5% pluronic F127 were optimized with 181.72±3.6 nm particle size, 0.12±0.02 (PDI) analysis, -27.4± 0.69 mV zeta potential and 62.41%±4.7% entrapment efficiency. Nanoparticles loaded ocuserts manifested compatibility between drug and formulation polymers. Moreover, formulations complied with average weight 0.055±0.002 to 0.143±0.023 mg, and accepted pH. ATC-PCL nanoparticles loaded inserts prepared by 5% MC showed more sustained, prolonged in-vitro release over 24h. In-vivo study emphasized non-irritability, ocular anti-inflammatory effectiveness represented by smaller lid closure scores, and statistically significant lowering in PMN count after 3h. CONCLUSION: These findings proposed a possibly simple, new and affordable price technique to prepare promising (ATC-PCL) nanoparticles loaded inserts to achieve sustained release with prolonged antiinflammatory efficacy.

Chitosan-Coated PLGA Nanoparticles for Enhanced Ocular Anti-Inflammatory Efficacy of Atorvastatin Calcium.

BACKGROUND: Atorvastatin calcium (AT) is an ocular anti-inflammatory with limited bioavailability when taken orally due to its low solubility in low pH and extensive first-pass effect. To overcome these problems, AT was entrapped in polymeric nanoparticles (NPs) to improve surface properties and sustained release, in addition to achieving site-specific action. METHODS: AT was entrapped in chitosan (CS)-coated polylactic-co-glycolic acid (PLGA) NPs to form AT-PLGA-CS-NPs (F1). F1 and free AT were embedded in thermosensitive Pluronic®127-hydroxypropyl methylcellulose (HPMC) to form thermosensitive gels (F2) and (F3) while F4 is AT suspension in water. F1 was assessed for size, surface charge, polydispersity index (PDI), and morphology. F2 and F3 were examined for gelation temperature, gel strength, pH, and viscosity. In vitro release of the four formulations was also investigated. The ocular irritancy and anti-inflammatory efficacy of formulations against prostaglandin E1-(PGE1) induced ocular inflammation in rabbits were investigated by counting the polymorphonuclear leukocytes (PMNs) and protein migrated in tears. RESULTS: Oval F1 of 80.0-190.0±21.6 nm exhibited a PDI of 0.331 and zeta potential of 17.4±5.62 mV with a positive surface charge. F2 and F3 gelation temperatures were 35.17±0.22°C and 36.93±0.31°C, viscosity 12,243±0.64 and 9759±0.22 cP, gel strength 15.56±0.6 and 12.45±0.1 s, and pHs of 7.4±0.02 and 7.4±0.1, respectively. In vitro release of F1, F2, F3, and F4 were 48.21±0.31, 26.48±0.5, 84.76±0.11, and 100% after 24 hrs, respectively. All formulations were non-irritant. F2 significantly inhibited lid closure up to 3 h, PMN counts and proteins in tear fluids up to 5 h compared to other formulations. CONCLUSION: AT-PLGA-CS-NP thermosensitive gels proved to be successful ocular anti-inflammatory drug delivery systems.