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Gangliosides (glycosphingolipids) reduce antibody production by inhibiting B-cell receptor (BCR) signaling. We have shown that a copresentation of gangliosides and polyethylene glycol (PEG) on the same liposomes suppresses anti-PEG IgM production in mice. In addition, we recently observed that pDNA incorporated in PEGylated cationic liposomes (PCLs) induces anti-DNA IgM, which could be a hurdle to the development of efficient gene delivery systems. Therefore, the focus of this study was to determine if the copresentation of gangliosides and DNA on the same PCL would suppress antibody production against DNA. PCLs including DNA induced both anti-PEG IgM production and anti-DNA IgM production. The extent of anti-PEG and anti-DNA IgM production was likely dependent on the immunogenicity of the complexed DNA. Treatment of clodronate-containing liposomes, which causes a depletion of phagocytic cells, suppressed anti-PEG IgM production from PCLs that did not include DNA but failed to suppress anti-PEG IgM production from PCLs that complexed DNA (PCLD). Both anti-PEG IgM and anti-DNA IgM was induced in T-cell-deficient nude mice as well as in normal mice following treatment with PCLs and PCLD, respectively. These results indicate that phagocytic cells contribute to anti-PEG IgM production but not to anti-DNA IgM production, while T-cells do not contribute to any form of antibody production. The copresentation of gangliosides and DNA significantly reduced anti-PEG IgM production but unfortunately did not reduce anti-DNA IgM production. It appears that the immunosuppressive effect of gangliosides, presumably via the CD22 signaling pathway, is limited only to anti-PEG immunity.

Polyethylene glycol (PEG) is a versatile polymer that is widely used as an additive in foods and cosmetics, and as a carrier in PEGylated therapeutics. Even though PEG is thought to be less immunogenic, or perhaps even non-immunogenic, with a variety of physicochemical properties, there is mounting evidence that PEG causes immunogenic responses when conjugated with other materials such as proteins and nanocarriers. Under these conditions, PEG with other materials can result in the production of anti-PEG antibodies after administration. The antibodies that are induced seem to have a deleterious impact on the therapeutic efficacy of subsequently administered PEGylated formulations. In addition, hypersensitivity to PEGylated formulations could be a significant barrier to the utility of PEGylated products. Several reports have linked the presence of anti-PEG antibodies to incidences of complement activation-related pseudoallergy (CARPA) following the administration of PEGylated formulations. The use of COVID-19 mRNA vaccines, which are composed mainly of PEGylated lipid nanoparticles (LNPs), has recently gained wide acceptance, although many cases of post-vaccination hypersensitivity have been documented. Therefore, our review focuses not only on the importance of PEGs and its great role in improving the therapeutic efficacy of various medications, but also on the hypersensitivity reactions attributed to the use of PEGylated products that include PEG-based mRNA COVID-19 vaccines.

Kariman M AbouElhassan,1,2 Hatem A Sarhan,1 Amal K Hussein,1 Ashraf Taye,3 Yasmin M Ahmed,4 Mohamed A Safwat5 1Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt; 2Faculty of Pharmacy, South Valley University, Qena, 83523, Egypt; 3Department of Pharmacology and Toxicology, Faculty of Pharmacy, South Valley University, Qena, 83523, Egypt; 4Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, 62514, Egypt; 5Department of Pharmaceutics, Faculty of Pharmacy, South Valley University, Qena, 83523, EgyptCorrespondence: Kariman M AbouElhassan, Faculty of Pharmacy, South Valley University, El-Moatakal Street, Qena, Egypt, Tel +20 1008052043, Fax +20 963211279, Email karimanmusalim@yahoo.comBackground: Alzheimer’s disease (AD) is one of the furthermost advanced neurodegenerative disorders resulting in cognitive and behavioral impairment. Citicoline sodium (CIT) boosts the brain’s secretion of acetylcholine, which aids in membrane regeneration and repair. However, it suffers from poor blood–brain barrier (BBB) permeation, which results in lower levels of CIT in the brain.Purpose: This study targeted to encapsulate CIT into novel nano-platform transbilosomes decorated with hyaluronic acid CIT-HA*TBLs to achieve enhanced drug delivery from the nose to the brain.Methods: A method of thin-film hydration was utilized to prepare different formulae of CIT-TBLs using the Box–Behnken design. The optimized formula was then hyuloranated via integration of HA to form the CIT-HA*TBLs formula. Furthermore, AD induction was performed by aluminum chloride (Alcl3), animals were allocated, and brain hippocampus tissue was isolated for ELISA and qRT-PCR analysis of malondialdehyde (MDA), nuclear factor kappa B (NF-kB), and microRNA-137 (miR-137) coupled with immunohistochemical amyloid-beta (Aβ1– 42) expression and histopathological finding.Results: The hyuloranated CIT-HA*TBLs formula, which contained the following ingredients: PL (300 mg), Sp 60 (43.97 mg), and SDC (20 mg). They produced spherical droplets at the nanoscale (178.94 ± 12.4 nm), had a high entrapment efficiency with 74.92± 5.54%, had a sustained release profile of CIT with 81.27 ± 3.8% release, and had ex vivo permeation of CIT with 512.43± 19.58 μg/cm2. In vivo tests showed that CIT-HA*TBL thermogel dramatically reduces the hippocampus expression of miR-137 and (Aβ1– 42) expression, boosting cholinergic neurotransmission and decreasing MDA and NF-kB production. Furthermore, CIT-HA*TBLs thermogel mitigate histopathological damage in compared to the other groups.Conclusion: Succinctly, the innovative loading of CIT-HA*TBLs thermogel is a prospectively invaluable intranasal drug delivery system that can raise the efficacy of CIT in Alzheimer’s management.Keywords: Alzheimer’s disease, transbilosomes, Box–Behnken design, intranasal drug delivery, brain targeting, in vivo study

The aim of the present work was to develop a promising drug delivery system of oxiconazole nitrate-loaded solid lipid nanoparticles (SLNs) topical gel to enhance the drug effectiveness for the treatment of Tinea infection. SLNs were prepared by emulsification-solvent evaporation method. Particle size and entrapment efficiency of the prepared SLNs were investigated. An appropriate formulation was selected and examined for morphology and physicochemical characterization adopting Scanning electron microscope and Differential scanning colorimetry. In-vitro drug release was also investigated. The selected SLNs were loaded into 1% Carbopol 934 gel that was investigated for homogeneity, pH, grittiness, spreadability, viscosity and

Quercetin (QRC) is a bioflavonoid with anti-inflammatory, antioxidant, and anticancer activities, yet QRC poor bioavailability has hampered its clinical implementation. The aim of the current work was to harness novasomes (NOVs), free fatty acid enriched vesicles, as a novel nano-cargo for felicitous QRC delivery with subsequent functionalization with selenium (SeNOVs), to extend the systemic bio-fate of NOVs and potentiate QRC anticancer efficacy through the synergy with selenium. QRC-NOVs were primed embedding oleic acid, Brij 35, and cholesterol adopting thin-film hydration technique according to Box–Behnken design. Employing Design-Expert® software, the impact of formulation variables on NOVs physicochemical characteristics besides the optimum formulation election were explored. Based on the optimal NOVs formulation, QRC-SeNOVs were assembled via electrostatic complexation/in situ reduction method. The MTT cytotoxicity assay of the uncoated, and coated nanovectors versus crude QRC was investigated in human rhabdomyosarcoma (RD) cells. The in vivo pharmacokinetic and biodistribution studies after intravenous administrations of technetium-99m (99mTc)-labeled QRC-NOVs, QRC-SeNOVs, and QRC-solution were scrutinized in Ehrlich tumor-bearing mice. QRC-NOVs and QRC-SeNOVs disclosed entrapment efficiency of 67.21 and 70.85%, vesicle size of 107.29 and 129.16 nm, ζ potential of −34.71 and −43.25 mV, and accumulatively released 43.26 and 31.30% QRC within 24 h, respectively. Additionally, QRC-SeNOVs manifested a far lower IC50 of 5.56 μg/mL on RD cells than that of QRC-NOVs (17.63 μg/mL) and crude QRC (38.71 μg/mL). Moreover, the biodistribution study elicited higher preferential uptake of 99mTc-QRC-SeNOVs within the tumorous tissues by 1.73- and 5.67-fold as compared to 99mTc-QRC-NOVs and 99mTc-QRC-solution, respectively. Furthermore, the relative uptake efficiency of 99mTc-QRC-SeNOVs was 5.78, the concentration efficiency was 4.74 and the drug-targeting efficiency was 3.21. Hence, the engineered QRC-SeNOVs could confer an auspicious hybrid nanoparadigm for QRC delivery with fine-tuned pharmacokinetics, and synergized antitumor traits.

The aim of this study was to prepare triamcinolone acetonide (TA)-loaded poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) and poly(ethylene glycol)-block-poly(lactic acid) (PEG-b-PLA) micelles as a potential treatment of ocular inflammation. The micelles were evaluated for particle size, drug loading capacity and drug release kinetics. Selected micellar formulations were dispersed into chitosan hydrogel and their anti-inflammatory properties were tested in rabbits using a carrageenan-induced ocular inflammatory model. Particle size ranged from 59.44 ± 0.15 to 64.26 ± 0.55 nm for PEG-b-PCL and from 136.10 ± 1.57 to 176.80 ± 2.25 nm for PEG-b-PLA micelles, respectively. The drug loading capacity was in the range of 6–12% and 15–25% for PEG-b-PCL and PEG-b-PLA micelles, respectively and was dependent on the drug/polymer weight ratio. TA aqueous solubility was increased by 5- and 10-fold after loading into PEG-b-PCL and PEG-b-PLA micelles at a polymer concentration as low as 0.5 mg/mL, respectively. PEG-b-PLA micelles suspended in chitosan hydrogel were able to sustain the drug release where only 42.8 ± 1.6% drug was released in one week. TA/PEG-b-PLA micelles suspended in chitosan hydrogel had better anti-inflammatory effects compared with the plain drug hydrogel or the drug micellar solution. Complete disappearance of the corneal inflammatory changes was observed for the micellar hydrogel. These results confirm the potential of PEG-b-PLA micelles suspended in chitosan hydrogel to enhance the anti-inflammatory properties of triamcinolone acetonide.

Niosomes as vesicular frameworks are novel methods of delivering a drug in a sustained manner to enhance its bioavailability and get therapeutic effect over a longer period time. This study conclusively demonstrates the preparation, characterization, and optimization of sustained release ketorolac tromethamine (KT) niosomal organogels to enhance skin permeation and increase drug efficacy. The ether injection method was used to compose 15 formulae of KT niosomes containing adequate concentrations of unbiased variables. Those variables included hydrophilic-lipophilic balance value (HLB), cholesterol ratio in total lipid (Chol. Ratio), and the ratio of total lipid to the drug (L:D Ratio). The response surface technique was used to investigate the impact of those variables on entrapment efficiency percentage (EE %) of KT niosomes (Y1) and cumulative percentage releases after 6 h (% Rel6) (Y2) and 12 h (% Rel12) (Y3), which are selected as dependent variables. The prepared KT niosomes were round in shape and have a diameter of 100–500 nm. No drug/excipient interaction has occurred either in the physical mixture or KT-loaded niosomes. Optimum drug release pattern was obtained at low HLB level, while Chol. Ratio and L: D Ratio should be at high levels. The entrapment efficiency of the optimized formula of KT niosomes was found to be equal to 40.13%, while the cumulative percent release of KT after 6 and 12 h reached 52.3% and 74.5%, respectively. Significant anti-inflammatory effect is shown with niosomal organogel (85% pow edema inhibition) which is in positive correlation with in vitro results. Concisely, the sustained release niosomal organogel of KT could be an effective alternative to oral dosage forms with less systemic side effect and high drug bioavailability.

The aim the study was to design, formulate, and evaluate self-nanoemulsifying drug delivery systems (SNEDDS) of itraconazole for improving the topical antifungal properties of the drug by adopting the nanoemulsion intermediate gel of the optimized system. Solubility study was conducted to select the most appropriate oils and surfactants for formulation. Different possible systems were created. Ternary phase diagrams were constructed to select the most promising system for further study. The nanoemulsion intermediate gel of the selected system was evaluated for stability, dilution effect, viscosity, pH, antifungal activity, droplet size, PDI, and zeta potential. In vitro release of the drug from the selected intermediate gel was investigated, and the kinetic model of drug release was determined. Ex vivo permeation of itraconazole was studied, and the amount of drug accumulated in the skin was calculated. Solubility and phase diagrams revealed that the system consisting of 60% cotton seed oil and 40% span 80 provided the nanoemulsion intermediate gel with the highest drug concentration. The selected system had a droplet size of about 236 nm and zeta potential of - 59.8. The viscosity of the corresponding intermediate gel was 1583.47 cp. The system exhibited high stability at 4°C and 25°C for 12 months and improved antifungal activity. In vitro release study showed complete release of itraconazole within 4 h, while the ex vivo permeation study revealed accumulation of the majority of the drug within the skin layers (72.5%).

Mohamed M Ibrahim,1 Abdulla M Abuelmatty,2 Gehan H Mohamed,3 Mohsen A Nasr,4 Amal K Hussein,5 Mohy El Deen Ebaed,6 Hatem A Sarhan5 1Department of Clinical Pharmacy, Faculty of Pharmacy, Minia University, Minia, Egypt; 2Department of Pharmacy, Jahra Hospital, Jahra, Kuwait; 3Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt; 4Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 5Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia, Egypt; 6Department of Biochemistry, Egyptian Ministry of Interior, Cairo, Egypt Background: The intensive care unit (ICU) is a center of multidrug-resistant (MDR) pathogens. This is due to overuse of antibiotics in the treatment of critically ill patients. Tigecycline is a broad-spectrum antibiotic that belongs to the glycylcycline group. Tigecycline has been indicated in treatment of complicated intra-abdominal infections (cIAIs) and complicated skin and soft-tissue infections (cSSTIs).Objective: This study was done to discover the best dose regimen of tigecycline in treatment of cSSTIs and cIAIs, especially in patients who are critically ill and obese, for clinical outcomes and safety.Setting: The study was conducted in an adult ICU that consists of 25 beds in a general hospital and was conducted within 2 years. A total of 954 patients were screened in this study.Methods: This was a retrospective cohort study that compared the clinical outcomes of patients: mortality, ICU stay, and safety of using two different dose regimens of tigecycline between patients with different body weight who were treated for infections caused by MDR pathogens in the ICU. The study was conducted within 2 years. All results were collected from patients’ files and were analyzed with SPSS version 20.Main outcome: The study was implemented to figure out the best dose regimen of tigecycline to achieve a reduction in mortality, ICU stay, treatment duration, and secondary septic-shock incidence with minimum side effects in treatment of cSSTIs and cIAIs in patients with different body weight.Results: There was a significant improvement in mortality, ICU stay, recurrent infection by the same organism, duration of tigecycline treatment, number of patients who had first negative culture after starting treatment, secondary bacteremia, and secondary septic shock with patients who used high-dose regimens of tigecycline in different subgroups of body weight, with no significant difference in side effects.Conclusion: The use of high-dose tigecycline resulted in a significant enhancement in all clinical outcomes, especially mortality and ICU stay when used in treatment of overweight and obese patients with cSSTIs and cIAIs. Keywords: tigecycline, obese patients, intensive care unit, complicated intra-abdominal infections, complicated skin and soft-tissue infections&nbsp

Samar Genedy,1 Ahmed Khames,2,3 Amal Hussein,4 Hatem Sarhan4 1Department of Clinical Pharmacy, Faculty of Pharmacy, Minia University, Minia, Egypt; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt; 3Department of Pharmaceutics and Pharmacy Technology, College of Pharmacy, Taif University, Taif, Kingdom of Saudi Arabia; 4Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Minia University, Minia, Egypt Background: Hypertensive disorders are the most common complication in pregnancy which can even lead to maternal mortality. Hydralazine hydrochloride (HHC), a direct-acting vasodilator, is intravenously used as the first-line therapy in controlling hypertension in pregnancy (preeclampsia). It suffers poor oral bioavailability (26%–50%) due to first-pass metabolism.Objective: This work aims for the preparation of HHC rapidly disintegrating sublingual tablets of higher absorption rate, short onset of action, and higher bioavailability for rapid control on blood pressure (BP) in hypertensive emergencies especially preeclampsia.Methods: HHC sublingual tablet mixtures were prepared using starch sodium glycolate and Pharmaburst as super disintegrants at three different levels by direct compression and were subjected to full in vitro evaluation; the drug bioavailability from the optimized sublingual tablet formula was assessed in comparison to conventional oral tablets in rabbits, and the clinical efficacy on controlling BP in induced preeclampsia like mouse model was also studied.Results: The results indicated compatibility of the prepared tablet mixtures, good flow, and acceptable mechanical strength. Sublingual tablet formula containing Pharmaburst (7%) that showed fastest disintegration (21 seconds) and 100% drug release within 5 minutes was selected for further bioavailability and pharmacodynamic studies. The drug bioavailability was significantly increased with Cmax = 28.2767±4.61 µg/mL, AUC(0–α) = 52.85±3.18 µg.h/mL, and Tmax = 0.33±0.011 hour in comparison to 18.0633±23.2 µg/mL, 33.18±5.18 µg.h/mL, and 0.75±0.025 hour for conventional oral tablets. Results of pharmacodynamic studies proved significant rapid control on both systolic and diastolic BP to normal values within only 30 minutes without any significant difference from intravenous data.Conclusion: These results confirm the suitability of the prepared HHC sublingual tablets for use in rapid control on hypertensive crisis especially in pregnant women as an alternate to parenteral administration.Keywords: pre-eclampsia like mouse model, absorption from buccal cavity, preeclampsia, sublingual tablets, hypertension, L-NAME

Acne vulgaris is a common inflammatory skin disorder. It affects the pilosebaceous units followed by an overgrowth by Propionibacterium acne bacteria. Dapsone is a sulfone antibiotic with an anti-inflammatory effect, which is considered to be accountable for its effectiveness in the treatment of acne vulgaris. The present study aims to prepare and evaluate the effectiveness of dapsone niosomes for topical application with an objective to control and prolong the release of the drug with improved skin penetration as a novel formulation for healing of mild to moderate acne vulgaris. Niosomes were formulated by thin film hydration method using different ratios of surfactants (various spans 20, 40, 60 and 80) and cholesterol and were investigated with respect to its shape, size, entrapment efficiency, Fourier transform infrared spectroscopy (FTIR) and in vitro release. Fifteen patients with mild to moderate acne vulgaris were selected and treated with dapsone niosomes as a single topical treatment for their acne lesions. Clinical assessment was done before and after 2 and 8 weeks of treatment. Niosomes containing span 60 showed a higher percentage of drug release after 24 h and greater entrapment efficiency as compared to other formulations. The clinical improvement was noticeable after 2 weeks of treatment with highly significant improvement of acne lesions after 8 weeks of treatment (P < 0.001). Dapsone niosomes is a promising topical formulation for safe, tolerable and effective drug delivery system with minimal side effects apart from mild erythema and post-inflammatory hyperpigmentation. Key words: Dapsone, acne vulgaris, niosomes, topical, clinical application.

We have previously reported the utility of folate-polyethylene glycol-appended dendrimer conjugate with glucuronylglucosyl-β-cyclodextrin (Fol-PEG-GUG-β-CDE) (generation 3) as a tumor-selective carrier for siRNA against polo-like kinase 1 (siPLK1) in vitro. In the present study, we evaluated the potential of Fol-PEG-GUG-β-CDE as a carrier for the low-molecular antitumor drug doxorubicin (DOX). Further, to fabricate advanced antitumor agents, we have prepared a ternary complex of Fol-PEG-GUG-β-CDE/DOX/siPLK1 and evaluated its antitumor activity both in vitro and in vivo. Fol-PEG-GUG-β-CDE released DOX in an acidic pH and enhanced the cellular accumulation and cytotoxic activity of DOX in folate receptor-α (FR-α)-overexpressing KB cells. Importantly, the Fol-PEG-GUG-β-CDE/DOX/siPLK1 ternary complex exhibited higher cytotoxic activity than a binary complex of Fol-PEG-GUG-β-CDE with DOX or siPLK1 in KB cells. In addition, the cytotoxic activity of the ternary complex was reduced by the addition of folic acid, a competitor against FR-α. Furthermore, the ternary complex showed a significant antitumor activity after intravenous administration to the tumor-bearing mice. These results suggest that Fol-PEG-GUG-β-CDE has the potential of a tumor-selective co-delivery carrier for DOX and siPLK1.

Fatma M Mady,1,2 Hanaa Essa,2 Tarek El-Ammawi,3 Hamdy Abdelkader,2 Amal K Hussein2 1Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Taibah University, Medina, Saudi Arabia; 2Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia, Egypt; 3Department of Dermatology, STDs, and Andrology, Minia University Hospital, Minia, Egypt Abstract: Silymarin is a naturally occurring flavonoid drug; evidence from recent research has highlighted its use as a potential treatment for atopic dermatitis (AD). Both poor water solubility and drug permeability have hindered the percutaneous absorption of silymarin. Formulation of silymarin into pluronic-lecithin organogel (PLO) basis for topical skin delivery is the main aim of this work. Six different PLO formulations were prepared containing various pluronic to lecithin ratios using two cosolvent systems of ethyl alcohol and dimethyl sulfoxide. Formulation 2 (20% pluronic and 3% lecithin) was found to be the optimal base for topical delivery of silymarin as it showed optimum pH, viscosity, drug content, and satisfactory in vitro silymarin permeation. The silymarin PLO formulation significantly relieved inflammatory symptoms of AD such as redness, swelling, and inflammation. These findings warrant the ability for application of these novel silymarin PLO formulations as a novel treatment for AD. Keywords: silymarin, pluronic lecithin organogel, atopic dermatitis, skin penetration&nbsp

This study aimed to use the biocompatibility features of the biodegradable polymers to prepare depot injectable finasteride (FIN) microspheres for the treatment of benign prostatic hyperplasia. FIN microspheres were prepared utilising an emulsion-solvent evaporation/extraction technique. The Box-Behnken experimental design was adopted to optimise the preparation process. FIN plasma levels in albino rabbits were determined after injection with optimised FIN microspheres formula and compared with oral FIN suspension. Results revealed that the optimum microspheres displayed an amended sustained release pattern with lower initial burst. The cumulative FIN % released after 25 days was in the range 27.83-73.18% for F4 and F1, respectively. The optimised formula, with 50.0% (X1), and 22.316% (X2) and 1.38% (X3) showed 6.503 μm, 93.213%, 14.574%, and 64.838% for Y1, Y2, Y3, and Y4, respectively. In vivo studies displayed a sustained release pattern with minimal initial burst release when injected into rabbits.

Mohamed M Ibrahim,1 Tarek Fouad Tammam,2 Mohy El Deen Ebaed,3 Hatem A Sarhan,4 Gamal F Gad,5 Amal K Hussein4 1Department of Clinical Pharmacy, Faculty of Pharmacy, Minia University, Minia, Egypt; 2Department of Anesthesia and Intensive Care, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; 3Department of Biochemistry, Egyptian Ministry of Interior, Cairo, Egypt; 4Department of Pharmaceutics, 5Department of Microbiology and Immunology, Faculty of Pharmacy, Minia University, Minia, Egypt Background: Mechanical ventilation support can be the main source of ventilator-associated pneumonia (VAP). VAP is a serious infection that may be associated with dangerous gram-negative bacteria mainly, and it leads to an increase in the mortality in the intensive care unit (ICU). Imipenem is one of the strongest antibiotics now available for treating VAP which is associated with gram-negative and gram-positive bacteria, and it belongs to beta-lactam antibiotic group (carbapenem).Objective: This study tried to investigate the efficacy of imipenem against VAP when it was infused within 180 min versus the efficacy when it was infused within 30–60 min.Setting: This study was conducted in main ICU in general hospital which consists of surgical and medical beds within 2years. One hundred and eighty-seven patients were enrolled on it.Method: This study is a retrospective cohort which was conducted within 2 years. The efficacy of imipenem which was administered by intermittent infusion (30–60 min) within first year was compared with the efficacy of imipenem which was administered by extended infusion (180min) within second year in the field of VAP curing and cost reduction. All data were collected retrospectively from patient medical files and were statistically analyzed by SPSS version 20.Main outcome: The study was designed to measure clinical and cost reduction outcomes, mortality and hospital stay.Results: The results indicated that there is a significant decrease in mortality, number of recurrent infection, and ICU stay length, and the number of mechanical ventilator days was associated with extended imipenem infusion during the second year of the study.Conclusion: The use of imipenem with extended infusion over 3 hours enhances its clinical outcomes in the treatment of VAP. Keywords: carbapenem, imipenem, VAP, extended infusion, intermittent infusion

This study was aimed at preparing, characterising and evaluating in situ gel formulations based on a blend of two hydrophilic polymers i.e. poloxamer 407 (P407) and poloxamer 188 (P188) for a sustained ocular delivery of ketorolac tromethamine (KT). Drug-polymer interaction studies were performed using {DSC} and FT-IR. The gelation temperature (Tsol-gel), gelation time, rheological behaviour, mucoadhesive characteristics of these gels, transcorneal permeation and ocular irritation as well as toxicity was investigated. {DSC} and FT-IR studies revealed that there may be electrostatic interactions between the drug and the polymers used. {P188} modified the Tsol/gel of {P407} bringing it close to eye temperature (35°C) compared with the formulation containing {P407} alone. Moreover, gels that comprised {P407} and {P188} exhibited a pseudoplastic behaviour at different concentrations. Furthermore, mucoadhesion study using mucin discs showed that in situ gel formulations have good mucoadhesive characteristics upon increasing the concentration of P407. When comparing formulations {PP11} and PP12, the work of adhesion decreased significantly (P < 0.001) from 377.9 ± 7.79 mN.mm to 272.3 ± 6.11 mN.mm. In vitro release and ex vivo permeation experiments indicated that the in situ gels were able to prolong and control {KT} release as only 48 of the {KT} released within 12 h. In addition, the HET-CAM and {BCOP} tests confirmed the non-irritancy of {KT} loaded in situ gels, and HET-CAM test demonstrated the ability of ocular protection against strongly irritant substances. {MTT} assay on primary corneal epithelial cells revealed that in situ gel formulations loaded with {KT} showed reasonable and acceptable percent cell viability compared with control samples.

The present work aimed to prolong the contact time of flurbiprofen (FBP) in the ocular tissue to improve the drug anti-inflammatory activity. Different niosome systems were fabricated adopting thin-film hydration technique and using the nonionic surfactant Span 60. The morphology of the prepared niosomes was characterized by scanning electron microscopy (SEM). Physical characterization by differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy were conducted for the optimized formula (F5) that was selected on the basis of percent entrapment efficiency, vesicular size and total lipid content. F5 was formulated as 1% w/w Carpobol 934 gel. Pharmacokinetic parameters of FBP were investigated following ocular administration of F5-loaded gel system, F5 niosome dispersion or the corresponding FBP ocular drops to albino rabbits dispersion. Anti-inflamatory effect of F5-loaded carbopol gel was investigated by histopathological examination of the corneal tissue before and after the treatment of inflamed rabbit eye with the system. Results showed that cholesterol content, surfactant type. and total lipid contents had an apparent impact on the vesicle size of the formulated niosomes. Physical characterization revealed reduced drug crystallinity and incidence of interaction with other niosome contents. F5-loaded gel showed higher Cmax, area under the curve (AUC0-12), and thus higher ocular bioavailability than those of the corresponding FBP ocular solution. F5-loaded gel showed a promising rapid anti-inflammatory effect in the inflamed rabbit eye. These findings will eradicate the necessity for frequent ocular drug instillation and thus, improve patient compliance.

The aim of this work was to formulate chitosan (CS)-based nanoparticles (NPs) loaded with ketorolac tromethamine (KT) intended for topical ocular delivery. NPs were prepared using ionic gelation method incorporating tri-polyphosphate (TPP) as cross-linker. Following the preparation, the composition of the system was optimized in terms of their particle size, zeta potential, entrapment efficiency (EE) and morphology, as well as performing structural characterization studies using Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). The data suggested that the size of the NPs was affected by CS/TPP ratio where the diameter of the NPs ranged from 108.0 ± 2.4 nm to 257.2 ± 18.6 nm. A correlation between drug EE and the corresponding drug concentration added to the formulation was observed, where the EE of the NPs increased with increasing drug concentration, for up to 10 mg/mL. FT-IR and DSC revealed that KT was dispersed within the NPs where the phosphate groups of TPP were associated with the ammonium groups of CS. The in vitro release profile of KT from CS NPs showed significant differences (p < 0.05) compared to KT solution. Furthermore, mucoadhesion studies revealed adhesive properties of the formulated NPs. The KT-loaded NPs were found to be stable when stored at different storage conditions for a period of 3 months. The ex vivo corneal permeation studies performed on excised porcine eye balls confirmed the ability of NPs in retaining the drug on the eye surface for a relatively longer time. These results demonstrate the potential of CS-based NPs for the ocular delivery of KT.

Skin delivery of Meloxicam (MX) offers several advantages over the oral route which is associated with potential side effects.The aim of this study was to develop transdermal MX in niosomes.Vesicles prepared by thin film hydration method were characterized and the acute anti-inflammatory activity of 0.5% MX niosomal hydrogel was evaluated using carrageenan induced rat paw edema method.The results revealed that niosomes prepared from span 60 and cholesterol at 6:4 molar ratio using 20 mg of MX were of the highest entrapment efficiency (55%) and with particle size (187.3 nm). There was a marked increase in the percentage inhibition of edema in animals treated with MX vesicular gel compared to those treated with free MX and piroxicam gels.There was an inverse proportionality between vesicle size and cholesterol content. With increased cholesterol molar ratio the bilayer stability increased and permeability decreased leading to efficiently trapping the MX. In contrast, higher amounts of cholesterol may compete with the drug for packing space within the bilayer. The inhibitory effect of MX niosomal gel may be attributed to its superior skin permeation.The results suggest that niosomes may be promising vehicles for transdermal delivery of MX.

In this study, we newly synthesized the polyamidoamine STARBURST dendrimer (dendrimer, generation 3: G3) conjugates with 6-O-α-(4-O-α-D-glucuronyl)-D-glucosyl-β-cyclodextrin [GUG-β-CDE (G3)] having the various degrees of substitution (DS) of GUG-β-cyclodextrin of 1.6, 3.0, 3.7, 5.0 and 8.6, and evaluated them as a siRNA transfer carrier. GUG-β-CDEs (G3) formed the positively charged and nano-order complexes with siRNA. Of the siRNA complexes with five GUG-β-CDEs (G3), the complex with GUG-β-CDE (G3, DS 3.7) showed the highest RNAi effect and cellular uptake with negligible cytotoxicity in KB cells at a charge ratio of 20. In addition, the RNAi effect and cellular uptake of the complex with GUG-β-CDE (G3, DS 3.7) were higher than those of α-CDE (G3, DS 2.4) and comparable to those of Lipofectamine™ 2000. Furthermore, the complex with GUG-β-CDE (G3, DS 3.7) possessed the endosomal escaping ability, the releasing property of siRNA in the cytoplasm and serum resistance. These results suggest that GUG-β-CDE (G3, DS 3.7) has the potential as a novel siRNA carrier.

This study aimed at combining the hen's egg test-chorioallantoic membrane (HET-CAM), bovine corneal opacity and permeability (BCOP) test and histological examination of excised corneas to evaluate the conjunctival and corneal toxicity of niosomes and their ingredients. Various surfactant/lipid combinations and concentrations (1-10%, w/v) were investigated for the ocular delivery of an ambitious drug (naltrexone hydrochloride) for treatment of diabetic keratopathy. Four niosomal formulations were investigated and found to be non irritant to the 10 days old HET-CAMs (an acceptable conjunctival model). Only one of the tested ingredients (sodium cholate - CH) showed moderate irritation, however such an effect was diminished when incorporated into niosomes. Corneal opacity and fluorescein permeability scores for the test substances correlated well with the HET-CAM test results. Corneal erosion and stromal thickness were found to be in agreement with the HET-CAM and BCOP results, which discriminated well between moderately and mildly irritant test substances. Corneal histological examination revealed toxicity signs included epithelial erosion, stromal condensation and stromal vacuolisation, which allowed better discrimination between strong and moderate irritants. It is concluded that the prepared niosomes possess good ocular tolerability and minimal ocular tissue irritation. They can be further investigated as ocular delivery systems using appropriate animal models.