Development and optimization of vildagliptin solid lipid nanoparticles loaded ocuserts for controlled ocular delivery: A promising approach towards treating diabetic retinopathy.

Diabetes mellitus (DM) is the most prevalent cause of diabetic retinopathy (DRP). DRP has been recognized for a long time as a microvascular disease. Many drugs were used to treat DRP, including vildagliptin (VLD). In addition to its hypoglycemic effect, VLD minimizes ocular inflammation and improves retinal blood flow for individuals with type 2 diabetes mellitus. Nevertheless, VLD can cause upper respiratory tract infections, diarrhea, nausea, hypoglycemia, and poor tolerability when taken orally regularly due to its high water solubility and permeability. Effective ocular administration of VLD is achieved using solid lipid nanoparticles (SLNPs), which improve corneal absorption, prolonged retention, and extended drug release. Ocuserts (OCUs) are sterile, long-acting ocular dosage forms that diminish the need for frequent dosing while improving residence time and stability. Therefore, this study intends to develop VLD solid lipid nanoparticle OCUs (VLD-SLNPs-OCUs) to circumvent the issues commonly associated with VLD. SLNPs were prepared using the double-emulsion/melt dispersion technique. The optimal formula has been implemented in OCUs. Optimization and development of VLD-SLNPs-OCUs were performed using a Box-Behnken Design (BBD). VLD-SLNPs-OCUs loading efficiency was 95.28 ± 2.87%, and differential scanning calorimetry data (DSC) showed the full transformation of VLD to an amorphous state and the excellent distribution in the prepared OCUs matrices. The in vivo release of VLD from the optimized OCUs after 24 h was 35.12 ± 2.47%, consistent with in vitro drug release data of 36.89 ± 3.11. The optimized OCUs are safe to use in the eye, as shown by the ocular irritation test. VLD-SLNPs-OCUs provide extended VLD release, an advantageous alternative to conventional oral dose forms, resulting in fewer systemic adverse effects and less variation in plasma drug levels. VLD-SLNPs-OCUs might benefit retinal microvascular blood flow beyond blood glucose control and may be considered a promising approach to treating diabetic retinopathy.

Anti-Tumor Activity of Orally Administered Gefitinib-Loaded Nanosized Cubosomes against Colon Cancer.

Gefitinib (GFT) is a tyrosine kinase inhibitor drug used as a first-line treatment for patients with advanced or metastatic non-small cell lung, colon, and breast cancer. GFT exhibits low solubility and hence low oral bioavailability, which restricts its clinical application. One of the most important trends in overcoming such problems is the use of a vesicular system. Cubosomes are considered one of the most important vesicular systems used to improve solubility and oral bioavailability. In this study, GFT cubosomal nanoparticles (GFT-CNPs) were prepared by the emulsification method. The selected formulation variables were analyzed and optimized by full factorial design and response surface methodology. Drug entrapment efficiency (EE%), transmission electron microscopy, particle size, polydispersity index, in vitro release and its kinetics, and the effect of storage studies were estimated. The chosen GFT-CNPs were subjected to further investigations as gene expression levels of tissue inhibitors of metalloproteinases-1 (TIMP-1) and matrix metalloproteinases-7 (MMP-7), colon biomarkers, and histopathological examination of colon tissues. The prepared GFT-CNPs were semi-cubic in shape, with high EE%, smaller vesicle size, and higher zeta potential values. The in vivo data showed a significant decrease in the serum level of embryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), and gene expression level of TIMP-1 and MMP-7. Histopathological examination showed enhancement in cancer tissue and highly decreased focal infiltration in the lamina propria after treatment with GFT-CNPs.

Tailoring of Rosuvastatin Calcium and Atenolol Bilayer Tablets for the Management of Hyperlipidemia Associated with Hypertension: A Preclinical Study.

Hyperlipidemia is still the leading cause of heart disease in patients with hypertension. The purpose of this study is to make rosuvastatin calcium (ROS) and atenolol (AT) bilayer tablets to treat coexisting dyslipidemia and hypertension with a single product. ROS was chosen for the immediate-release layer of the constructed tablets, whereas AT was chosen for the sustained-release layer. The solid dispersion of ROS with sorbitol (1:3 w/w) was utilized in the immediate-release layer while hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), and sodium bicarbonate were incorporated into the floating sustained-release layer. The concentrations of HPMC and EC were optimized by employing 32 full factorial designs to sustain AT release. The bilayer tablets were prepared by the direct compression method. The immediate-release layer revealed that 92.34 ± 2.27% of ROS was released within 60 min at a pH of 1.2. The second sustained-release layer of the bilayer tablets exhibited delayed release of AT (96.65 ± 3.36% within 12 h) under the same conditions. The release of ROS and AT from the prepared tablets was found to obey the non-Fickian diffusion and mixed models (zero-order, Higuchi and Korsmeyer-Peppas), respectively. Preclinical studies using rabbit models investigated the impact of ROS/AT tablets on lipid profiles and blood pressure. A high-fat diet was used to induce obesity in rabbits. Bilayer ROS/AT tablets had a remarkable effect on decreasing the lipid profiles, slowing weight gain, and lowering blood pressure to normal levels when compared to the control group.

High Rates of Aminoglycoside Methyltransferases Associated with Metallo-Beta-Lactamases in Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa Clinical Isolates from a Tertiary Care Hospital in Egypt.

BACKGROUND: Multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Pseudomonas aeruginosa are the leading cause of healthcare-associated infections worldwide. OBJECTIVE: The aim was to identify the resistant phenotypes among P. aeruginosa and to characterize different aminoglycosides and carbapenem resistance genes as major mechanisms of resistance in these isolates, in Theodor Bilharz Research Institute (TBRI), a tertiary care hospital in Cairo, Egypt. METHODS: During a period of 11 months, 42 P. aeruginosa clinical isolates were collected from the microbiology laboratory by routine culture. Antimicrobial sensitivity testing to the aminoglycosides gentamicin and amikacin, and other classes of antibiotics, was performed by a disk diffusion method. Isolates were tested for aminoglycoside resistance genes, aac(6')-lb, aac-(3)-lla, rmtB, rmtC, armA, rmtD, and rmtF, and carbapenemase resistance genes bla NDM, bla VIM, and bla IMP, using conventional PCR. RESULTS: Thirty-three (78.5%) of the clinical P. aeruginosa isolates showed MDR and XDR phenotypes at 42.4% and 57.65%, respectively, and these were included in the study. Aminoglycoside resistance was found in 97%, whereas carbapenem resistance was found in 81% of the isolates phenotypically. Only 59.4% (19/26) of the aminoglycoside-resistant isolates harbored resistance genes; none of the amikacin-susceptible isolates harbored any of the tested aminoglycoside resistance genes. Aminoglycoside resistance genes rmtB, armA, aac(6')-lb, and rmtF were found at rates of 17/33 (51.5%), 3/33 (9%), 2/33 (6%), and 2/33 (6%), respectively, whereas rmtD, acc(3)-II, and rmtC were not detected. Only 40.7% (11/27) of the carbapenem-resistant isolates harbored resistance genes. Carbapenem resistance genes, bla NDM andbla VIM, were found at rates of 7/33 (21.2%) and 6/33 (18.1%), respectively, and bla IMP was not detected. CONCLUSION: Rates of MDR and XDR P. aeruginosa and resistance to aminoglycosides and carbapenems in our setting are high. Methyltransferases and metallo-beta-lactamases are the main mechanisms of resistance to aminoglycosides and carbapenems, respectively. The presence of bla NDM and rmtF in the strains confirms their rapid dissemination in the Egyptian environment.

Intranasal In Situ Gel of Apixaban-Loaded Nanoethosomes: Preparation, Optimization, and In Vivo Evaluation.

The present study was conducted to formulate ethosomal thermoreversible in situ gel of apixaban, an anticoagulant drug, for nasal delivery. Ethosomes were formed, of lecithin, cholesterol, and ethanol, by using thin-film hydration method. The prepared ethosomes were characterized by Zetasizer, transmission electron microscope, entrapment efficiency, and in vitro study. The selected ethosomal formula (API-ETHO2) was incorporated in gel using P407 and P188 as thermoreversible agents and carbopol 934 as mucoadhesive agent. Box-Behnken design was used to study the effect of independent variables (concentration of P407, P188, and carbopol 934) on gelation temperature, mucoadhesive strength, and in vitro cumulative percent drug released at 12h (response variables). The optimized formulation was subjected to compatibility study, ex vivo permeation, histopathological examination for the nasal mucosa, and in vivo study. API-ETHO2 was spherical with an average size of 145.1±12.3 nm, zeta potential of -20±4 mV, entrapment efficiency of 67.11%±3.26, and in vitro % release of 79.54%±4.1. All gel formulations exhibited an acceptable pH and drug content. The optimum gel offered 32.3°C, 1226.3 dyne/cm2, and 53.50% for gelation temperature, mucoadhesive strength, and in vitro percent released, respectively. Apixaban ethosomal in situ gel evolved higher ex vivo permeation (1.499±0.11 µg/cm2h) through the nasal mucosa than pure apixaban gel. Histopathological study assured that there is no necrosis or tearing of the nasal mucosa happened by ethosomal gel. The pharmacokinetic parameters in rabbit plasma showed that intranasal administration of optimized API-ethosomal in situ gel achieved higher Cmax and AUC0-∞ than unprocessed API nasal gel, nasal suspension, and oral suspension. The ethosomal thermoreversible nasal gel established its potential to improve nasal permeation and prolong anticoagulant effect of apixaban.

Assessment of eugenol inhibitory effect on biofilm formation and biofilm gene expression in methicillin resistant Staphylococcus aureus clinical isolates in Egypt.

Methicillin-resistant Staphylococcus aureus (MRSA) biofilm infection is a major threat in Healthcare facilities. The search for biofilm inhibitors is essential to overcome the antibiotic resistance. Eugenol is a phyto-compound that possesses many biological properties. In this study, the aim was to estimate the effect of eugenol on biofilms of MRSA through quantifying the level of gene expression of three genes (IcaA, IcaD and SarA) involved in biofilm development.. Fifty MRSA biofilm producers collected from the microbiology lab at Theodor Bilharz Research Institute were incubated with different concentrations of eugenol for 24 h. The minimum inhibitory concentration of eugenol (MIC) that eradicates the biofilms growth was detected. mRNA was extracted from all isolates before and after the application of eugenol at 0.5 x MIC, and then subjected to quantitative real-time PCR (qPCR). Results showed that fourteen isolates out of 50 (28%) exhibited intermediate biofilm formation ability, and 36 out of 50 (72%) were strong biofilm producers. The MIC values of eugenol for MRSA ranged from 3.125% to 0.01%. The mean values of MIC in both strong and intermediate biofilm forming MRSA isolates were statistically comparable (p = 0.202). qPCR results revealed that the levels of expression of the studied genes IcaA, IcaD, and SarA were decreased after eugenol treatment when compared with their corresponding values before treatment (p = 0.001). Eugenol inhibited the formation of biofilm of MRSA isolates, indicating it could be used to control infections associated with MRSA biofilms.

Formulation and Characterization of Nanosized Ethosomal Formulations of Antigout Model Drug (Febuxostat) Prepared by Cold Method: In Vitro/Ex Vivo and In Vivo Assessment.

Febuxostat (FXT) is a xanthine oxidase (XO) drug which indicated for the treatment of gout. FXT loaded nanosized ethosomes were prepared using cold method with varied concentrations of ethyl alcohol and soya lecithin (SL). The prepared ethosomes were characterized by size, entrapment efficiency (DEE), FT-IR, in vitro release, kinetic studies of in vitro release profile, in vitro skin permeation and deposition, and stability study. The selected ethosomal formulation was incorporated in HPMC gel and characterized for drug content, ex vivo diffusion study through rat skin, and in vivo study and determination of pharmacokinetic parameters using HPLC technique. The results of size analysis showed that minimum size was 124.2 ± 16.77 nm with PDI values between 0.2 and 0.6. The zeta potential was from - 43.5 ± 3.0 to - 20.6 ± 1.42 mV. DEE ranged from 48 to 86%. The results of in vitro skin permeation showed that the amount FXT permeated ranged from 43.33 ± 5.3 to 82.14 ± 5.8%, flux ranged from 14.85 to 28.02. The results of ex vivo study showed that the amount of FXT permeated from unprocessed FXT gel was 49.42 ± 3.29% which was lesser than from FXT ethosomal gel. The results of in vivo study showed that Cmax and tmax were significantly different and higher for transdermal administration of FXT than oral administration. The developed FXT nanosized selected ethosome-based transdermal drug delivery gel system would provide a promising method for better management of gout.

Neuro-Analogical Gate Tuning of Trajectory Data Fusion for a Mecanum-Wheeled Special Needs Chair.

Trajectory tracking of mobile wheeled chairs using internal shaft encoder and inertia measurement unit(IMU), exhibits several complications and accumulated errors in the tracking process due to wheel slippage, offset drift and integration approximations. These errors can be realized when comparing localization results from such sensors with a camera tracking system. In long trajectory tracking, such errors can accumulate and result in significant deviations which make data from these sensors unreliable for tracking. Meanwhile the utilization of an external camera tracking system is not always a feasible solution depending on the implementation environment. This paper presents a novel sensor fusion method that combines the measurements of internal sensors to accurately predict the location of the wheeled chair in an environment. The method introduces a new analogical OR gate structured with tuned parameters using multi-layer feedforward neural network denoted as "Neuro-Analogical Gate" (NAG). The resulting system minimize any deviation error caused by the sensors, thus accurately tracking the wheeled chair location without the requirement of an external camera tracking system. The fusion methodology has been tested with a prototype Mecanum wheel-based chair, and significant improvement over tracking response, error and performance has been observed.

Torsemide Fast Dissolving Tablets: Development, Optimization Using Box-Bhenken Design and Response Surface Methodology, In Vitro Characterization, and Pharmacokinetic Assessment.

The present study planed to develop new fast dissolving tablets (FDTs) of torsemide. Solid dispersions (SDs) of torsemide and sorbitol (3:1) or polyvinylpyrrolidone (PVP) k25 were prepared. The prepared SDs were evaluated for in-vitro dissolution. Fourier transform infrared spectroscopy and differential scanning calorimetry for SDs revealed no drug/excipient interactions and transformation of torsemide to the amorphous form. Torsemide/sorbitol SD was selected for formulation of torsemide FDTs by direct compression method. Box-Bhenken factorial design was employed to design 15 formulations using croscarmellose sodium and crospovidone at different concentrations. The response surface methodology was used to analyze the effect of changing these concentrations (independent variables) on disintegration time (Y1), percentage friability (Y2), and amount torsemide released at 10 min. The physical mixtures of torsemide and the used excipients were evaluated for angle of repose, Hausner's ratio, and Carr's index. The prepared FDTs tablets were evaluated for wetting and disintegration time, weight variation, drug content, percentage friability, thickness, hardness, and in vitro release. Based on the in-vitro results and factorial design characterization, F10 and F7 were selected for bioavailability studies following administration to Albino New Zealand rabbits. They showed significantly higher C max and (AUC0-12) and shorter T max than those obtained after administration of the corresponding ordinary commercial Torseretic ® tablets. Stability study was conducted for F10 that showed good stability upon storage at 30°C/75% RH and 40°C/75% RH for 3 months.