Assembly of In-Situ Gel Containing Nano-Spanlastics of an Angiotensin II Inhibitor as a Novel Epitome for Hypertension Management: Factorial Design Optimization, In-vitro Gauging, Pharmacokinetics, and Pharmacodynamics Appraisal.

More than 1 billion people worldwide suffer from hypertension; therefore, hypertension management has been categorized as a global health priority. Losartan potassium (LP) is an antihypertensive drug with a limited oral bioavailability of about 33% since it undergoes the initial metabolic cycle. Thus, nasal administration is a unique route to overcome first-pass metabolism. The investigation focused on the potential effects of LP-loaded spanlastic vesicles (SNVs) on LP pharmacodynamics and pharmacokinetic parameters, utilizing a thin-film hydration methodology established on a 3122 full factorial design. Entrapment efficiency (EE%) ranged from 39.8 ± 3.87.8 to 83.8 ± 2.92% for LP-SNVs. Vesicle size (VS) varied from 205.5 ± 6.5.10 to 445.1 ± 13.52 nm, and the percentage of LP released after 8 h (Q8h) ranged from 30.8 ± 3.10 to 68.8 ± 1.45%. LP permeated through the nasal mucosa during 24 h and flocculated from 194.1 ± 4.90 to 435.3 ± 13.53 µg/cm2. After twenty-four hours, the optimal LP-SNVs in-situ gel showed 2.35 times more permeation through the nasal mucosa than the LP solution. It also lowered systolic blood pressure, so it is thought to be better than the reference formulation in terms of pharmacodynamics. The pharmacokinetics studies demonstrated that the intranasal LP-SNVs gel boosted its bioavailability approximately 6.36 times compared to the oral LP solution. Our research showed that intranasal LP-SNVs could be a good nanoplatform because they are well-tolerated and have possible pharmacokinetics and pharmacodynamics.

Clinical Care Team's Guide for Awareness on Risk Assessment of Eltrombopag Complicating Acute Kidney Injury in Relapsed Immune Thrombocytopenic Patients: A Case Report.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder caused by antigen-specific T cells and antiplatelet autoantibodies that inhibit platelet production in the bone marrow or destroy platelets in the spleen. ITP is a form of autoimmunity and is closely associated with inflammation. Corticosteroids are the first-line therapy for ITP, with a total response rate of 53-80%. However, corticosteroid therapy is associated with significant side effects and is often ineffective in patients with corticosteroid-resistant or -intolerant disease. Eltrombopag has been validated as a second-line option in ITP therapy. Despite several studies demonstrating the efficacy and safety of Eltrombopag in immune thrombocytopenia patients, the prevalence of Eltrombopag-induced acute kidney injury has been observed. This case report describes a patient who experienced acute kidney injury during Eltrombopag therapy. A sudden increase in serum creatinine to 6.7 mg/dL and metabolic acidosis occurred after eight weeks of Eltrombopag. The patient's renal failure had worsened, proteinuria was detected, and emergency hemodialysis was initiated. With vigilant kidney function screening and prompt treatment, the patient's renal function improved remarkably following cessation of Eltrombopag and initiation of hemodialysis. This case highlights the importance of comprehensive medication history-taking and vigilant kidney function screening in patients receiving Eltrombopag.

Rosuvastatin calcium-based novel nanocubic vesicles capped with silver nanoparticles-loaded hydrogel for wound healing management: optimization employing Box-Behnken design: in vitro and in vivo assessment.

Chronic wounds are a serious problem that could cause severe morbidity and even death. The ability of statins including rosuvastatin calcium (RVS) to enhance wound healing was well reported. However, RVS is poorly soluble and has low bioavailability. Thus, this study aimed to prepare and evaluate RVS-loaded nanocubics to enhance its skin performance. In addition, silver nanoparticles (AgNPs) exhibited potent antimicrobial activity, thus, the optimum RVS-loaded nanocubics was capped with AgNPs to evaluate its effect in wound management. Box-Behnken design was adopted to prepare RVS nanocubics. The design investigated the effect of lecithin, poloxamer 407 concentrations and hydration time on vesicle size, zeta potential (ZP), entrapment efficiency (EE%) and in vitro drug release%. Optimum formulation capped with AgNPs was incorporated into a gel base and examined for wound healing efficiency using different pharmacological tests in rats. Nanocubics have shown a mean diameter between 167.2 ± 7.8 and 408 ± 18.4 nm, ZP values ranging from -20.9 ± 1.9 to -53.5 ± 4 mV, EE% equivocated between 31.6 ± 1.4 and 94.4 ± 8.6 and drug release after 12 h between 17.9 ± 1.9 and 68.0 ± 4.0%. The histopathological studies and serum tumour necrosis factor alpha (TNF-α) and interleukin-1ß (IL-1ß) levels confirmed the greater efficacy of RVS nanocubics capped with AgNPs gel in wound healing when compared with gentamicin ointment. RVS-loaded nanocubic vesicles and AgNPs-loaded hydrogel could be considered as a promising platform to enhance the wound healing and tissue repair processes.

Development and Greenness Assessment of HPLC Method for Studying the Pharmacokinetics of Co-Administered Metformin and Papaya Extract.

Foods with medical value have been proven to be beneficial, and they are extensively employed since they integrate two essential elements: food and medication. Accordingly, diabetic patients can benefit from papaya because the fruit is low in sugar and high in antioxidants. An RP-HPLC method was designed for studying the pharmacokinetics of metformin (MET) when concurrently administered with papaya extract. A mobile phase of 0.5 mM of KH2PO4 solution and methanol (65:35, v/v), pH = 5 ± 0.2 using aqueous phosphoric acid and NaOH, and guaifenesin (GUF) were used as an internal standard. To perform non-compartmental pharmacokinetic analysis, the Pharmacokinetic program (PK Solver) was used. The method's greenness was analyzed using two tools: the Analytical GREEnness calculator and the RGB additive color model. Taking papaya with MET improved the rate of absorption substantially (time for reaching maximum concentration (Tmax) significantly decreased by 75% while maximum plasma concentration (Cmax) increased by 7.33%). The extent of absorption reduced by 22.90%. Furthermore, the amount of medication distributed increased (30.83 L for MET concurrently used with papaya extract versus 24.25 L for MET used alone) and the clearance rate rose by roughly 13.50%. The results of the greenness assessment indicated that the method is environmentally friendly. Taking papaya with MET changed the pharmacokinetics of the drug dramatically. Hence, this combination will be particularly effective in maintaining quick blood glucose control.

Emergence of High Antimicrobial Resistance among Critically Ill Patients with Hospital-Acquired Infections in a Tertiary Care Hospital.

Background and Objectives: Inappropriate antibiotic usage in hospitalized patients contributes to microbial resistance. Our study aimed to examine the incidence of clinical bacterial isolates and their antibiotic resistance burden among critically ill patients in different hospital units. Materials and Methods: A single-centered cross-sectional study was conducted in a 120-bed tertiary care hospital that included 221 critically ill patients with hospital-acquired infections. Bacterial cultures and sensitivity reports were obtained and followed by a formal analysis of the antibiogram results to explore recovered isolates' prevalence and antibiotic susceptibility patterns. Results: Gram-negative bacteria were the most predominant pathogens among recovered isolates from the various hospital units (71%). Klebsiella sp. was the most prevalent microbe, followed by Acinetobacter sp., with an incidence level of 28% and 16.2%, respectively. Among the Gram-positive organisms, the coagulase-negative Staphylococci were the most predominant organism (11.3%), while (6.3%) methicillin-resistant Staphylococcus aureus (MRSA) isolates were recovered from different hospital units. Antibiotic sensitivity testing showed that polymyxin B was the most effective antibiotic against Gram-negative bacteria, whereas vancomycin and linezolid were the most active antibiotics against Gram-positive pathogens. Moreover, 7% of the Gram-negative bacteria isolated from different units showed positive production of extended-spectrum beta-lactamase (ESBL). Conclusions: The current study describes the high antibiotic resistance patterns in various hospital units that need extra legislation to prevent healthcare providers from misprescription and overuse of antibiotics.

Treatment of breast cancer with engineered novel pH-sensitive triaryl-(Z)-olefin niosomes containing hydrogel: an in vitro and in vivo study.

Triaryl-(Z)-olefin (TZO) was synthesized as a Tamoxifen (TMX) analogue for breast cancer treatment to avoid developing the resistance and toxicity of TMX. TZO was synthesized using McMurry olefination reaction and has anti-cancer activity better than TMX by two folds. In this paper, in situ pH-sensitive TZO-loaded noisome hydrogel was prepared for delivering and targeting TZO to its site of activity. Equi-molar of cholesterol and span 60 was used to prepare TZO-loaded niosomes using the Hand Shaking Method. The central composite experimental design was used to prepare differently in situ pH-sensitive TZO-loaded niosomes formulae. The formulae were done by incorporated TZO-loaded niosomes into different concentrations of chitosan and Glyceryl monooleate (GCM). Increasing the chitosan and GCM concentrations resulted in significantly increasing the viscosity and significantly decreasing the release of TZO from different formulae. The formula composed of (0.61% w/v) of chitosan and (0.23% w/v) of GCM was chosen as an optimum formula to evaluate the efficacy of TZO using Ehrlich carcinoma mice model. A significant anti-tumour effect was shown in comparison with TMX. Briefly, in situ pH-sensitive TZO-loaded niosomes could be an effective treatment for breast cancer.

Proniosomal Microcarriers: Impact of Constituents on the Physicochemical Properties of Proniosomes as a New Approach to Enhance Inhalation Efficiency of Dry Powder Inhalers.

Proniosomes are free-flowing systems with coating carriers, which developed as a method for improving the drug flow and pulmonary delivery. Extensive research on proniosomes was done to enhance the dry powder inhalers (DPI)'s inhalation performance. This research aimed at studying the impact of lactose-mannitol mixture additives on the proniosome's physicochemical properties as a method for improving the inhalation efficiency of DPI. Vismodegib has been employed as a compound model. Box-Behnken design has been employed to prepare different proniosomes formulae by incorporating various (A) span 60 concentrations, (B) lactose concentrations and (C) mannitol: total carrier mixture. The measured responses were vesicle size (R1), %release (R2), Carr's index (R3) and %recovery (R4). The results displayed that R1 and R4 were significantly antagonistic to C and significantly synergistic to both A and B while R2 and R3 were significantly synergistic to C and significantly antagonistic to both A and B. The optimal formula was selected for its aerodynamic behaviour, cytotoxic activity and bioavailability assessment. The optimal formula resulted in better Vismodegib lung deposition, cytotoxic activity and relative bioavailability. This novel formula could be a promising carrier for sustained delivery of drugs via the pulmonary route.

Novel Enhanced Therapeutic Efficacy of Dapoxetine HCl by Nano-Vesicle Transdermal Gel for Treatment of Carrageenan-Induced Rat Paw Edema.

The aim of this was to develop a well-balanced, replaceable, and patient non-infringing innovative transdermal drug delivery system "nano-vesicle transdermal gel" (NVTG) approaches for inhibiting inflammation. To consummate this objective, we developed a skin permeation nanogel system containing surface active agent along with ethanol. Carbopol 971p, hydroxypropyl methyl cellulose (HPMC K15M), and chitosan were used to fabricate the nanogels. The nanogel system was evaluated for pH, content uniformity, spreadability, rheological studies, in vitro skin permeation, and drug release. Carbapol 971p with the desired in vitro skin permeation was utilized to investigate skin irritation test and effects on inflammation using acute inflammatory paw edema models. Moreover, in vivo pharmacokinetic study was assessed. pH of this nanogels was found within the range of 6.1-7.2, whereas the viscosity was found 310.13 to 6361 cps. The ex vivo skin permeation gels showed permeation flux range, 5.9 ± 0.80 to 17.92 ± 1.13 µg/cm2 h. The highest permeation flux (17.92 ± 1.13 µg/cm2 h) was observed, which was 3.14-folds higher than that of the plain DH gel (10.72 ± 0.84 µg/cm2 h. Additionally, from toxicological study, no obvious signs of toxicity such as skin irritation (of laboratory rats) were identified. The in vivo anti-inflammatory behavior in carrageenan-induced rats showed comparatively higher inhibition of rat paw edema swelling by the prepared nanogel compared to that of the plain DH gel and marketed ibuprofen over 6 h. The amount of drug accumulated in the skin after topical application was much higher than oral application. In conclusion, developed NVTG formulation loaded with dapoxetine HCl (DH) offers new opportunities for creating novel therapeutic modality for inflammation patients with fewer adverse effects.

Treatment of Basal Cell Carcinoma Via Binary Ethosomes of Vismodegib: In Vitro and In Vivo Studies.

Vismodegib (VMD) is a hedgehog inhibitor which indicated for basal cell skin cancer (BCC). This work focuses on investigating the influence of isopropyl alcohol additive for topical delivering and targeting of VMD-loaded binary ethosomes for BCC treatment. Different binary ethosome formulae were prepared based on Box-Behnken design using different concentrations of phospholipid (A), cholesterol (B) and isopropyl alcohol/total alcohol ratio (C). The prepared formulae were characterized for %entrapment efficiency (R1), vesicle size (R2), %release (R3) and steady-state flux (R4). Increasing A, B and C resulted in significant increase of R1 and R2 and significant decrease of R3 and R4. The optimization was achieved and the optimum formula was selected to investigate its anti-tumour efficacy in vivo. The optimum formula showed a localized VMD and consequently a significant anti-tumour activity compared with oral VMD. Briefly, VMD-loaded binary ethosome gel could be an effective treatment of BCC with lower side effects. Graphical abstract.

Treatment of Brucellosis in Guinea Pigs via a Combination of Engineered Novel pH-Responsive Curcumin Niosome Hydrogel and Doxycycline-Loaded Chitosan-Sodium Alginate Nanoparticles: an In Vitro and In Vivo Study.

Brucellosis is a common zoonotic infection, particularly in the developing world. The recommended treatment regimens for brucellosis involve the use of two medications such as doxycycline and curcumin in order to avoid relapses and prolonged use of these drugs. Doxycycline has excellent activity in the acidic phagolysosomal environment, while curcumin modulates the immune system function and macrophage activity. Due to the intracellular existence of Brucellae and the different anti-immune mechanisms of Brucella, the treatment of Brucella infection faces many limitations. The design of nanosystems is a promising treatment approach for brucellosis. The objective of this study was to design and evaluate the efficacy of in situ pH-responsive curcumin-loaded niosome hydrogel and doxycycline-loaded chitosan-sodium alginate nanoparticles as chemotherapeutic agents against brucellosis. The prepared formulae showed a spherical nano shape with a slow drug release pattern and small particle size. The prepared formulae were evaluated in vivo using Guinea pigs experimentally infected with Brucella melitensis biovar3. The prepared formula combination gave a significant high reduction rate of Brucella spleen viable count compared with that of untreated controls at p < 0.05. The results showed that the treatment schemes were not fully successful in eliminating Brucella infection in Guinea pigs; however, they significantly (p < 0.05) reduced the viable Brucella count in a shorter time and sub-therapeutic doses. Collectively the novel prepared formulae could be a successful therapy for the effective treatment of brucellosis infection at the recommended therapeutic doses. Graphical abstract.

Formulation development of self-nanoemulsifying drug delivery system of celecoxib for the management of oral cavity inflammation.

The oral administration of celecoxib (CLX) is a real problem because of its low aqueous solubility that results in high variability in absorption and its severe adverse effect such as cardiotoxic effects and gastrointestinal toxicity. Self-nanoemulsifying drug delivery systems (SNEDDS) can enhance the poor dissolution and erratic absorption of poorly water-soluble drugs such as CLX. This study was conducted to investigate the potential of SNEDDS to enhance the efficacy of CLX on inflamed mucous tissue and reduce systemic adverse effects by increasing its poor dissolution properties. A pseudo-ternary phase diagram was derived from the results of CLX solubility experiments in various excipients. These studies revealed the use of Labrafil M 2515 CS as oil, tween 80 as a surfactant, and polyethylene glycol 400 as a co-surfactant for the optimization of SNEDDS formulations. Eight formulations were formulated and characterized by their particle size, polydispersity index, viscosity, globular shape, drug solubility, self-emulsification efficiency, in vitro drug release, and permeation. The anti-inflammatory effect of CLX-SNEDDS was evaluated by carrageenan-induced cheek oedema in rats. The cheeks were treated with CLX-SNEDDS before oedema induction and then noticed for narrow periods (2 h) followed by histopathological studies to determine the efficacy of treatment. The selected formulations (F3 and F5) showed spherical morphologies under transmission electron microscopy, mean droplet sizes of 116.9 ± 1.78 and 124 ± 1.87 nm, respectively, complete in vitro drug release, and high cumulative amounts of drug permeation in 8 h. They also showed significant remarkable cheek oedema inhibition in comparison with the control groups (p < 0.05). CLX-SNEDDS was found to achieve effective local therapeutic concentration and intended to reduce cheek oedema, congestive capillary, inflammatory cells, and side effects due to lower dose size.

Progesterone-loaded nanosized transethosomes for vaginal permeation enhancement: formulation, statistical optimization, and clinical evaluation in anovulatory polycystic ovary syndrome.

Bio-identical progesterone (PRG) is an exogenous female steroidal hormone which is used for treatment of polycystic ovary syndrome (PCOS). However, it suffers from poor bioavailability due to hepatic metabolism and poor solubility. The target of this work was to evaluate and statistically optimize PRG-loaded nanovesicle transethosomes (NVTEs) based in mucoadhesive gel for transvaginal delivery of PRG as potential luteal-phase support. A 24 full factorial design was used to explore the effect of phosphatidylcholine (PC), Tween 80, cetyltrimethyl ammonium bromide and ethanol concentration on particle size, entrapment efficiency (EE%), % in vitro PRG release after 24 h and transvaginal flux. PRG-loaded NVTEs were prepared by injection sonication method. The results revealed that the mean particle sizes ranged from 133.3 ± 3.42 to 349.5 ± 1.24 nm, zeta potential ranged from -23.5 ± 3.84 to +74.6 ± 4.97 mV, EE% ranged from 87.93 ± 3.58 to 97.05 ± 2.61%, % PRG release ranged from 50.9 ± 2.75 to 90.69 ± 2.07 and transvaginal flux ranged from 0.274 ± 0.03 to 0.531 ± 0.04 mg/cm2/h. The optimized formulation was subjected to transmission electron microscope for morphological examination and then incorporated in the mucoadhesive vaginal gel using Carbopol 974, hydroxyl propyl methylcellulose and sodium alginate. The optimized formulation was clinically studied in anovulatory PCOS and showed a significant increase in the serum PRG, endometrial thickness, echogenicity degree and the pregnancy rate. Briefly, PRG-loaded NVTEs vaginal gel might be a promising formulation for luteal phase support and increase pregnancy rate in anovulatory PCOS.

Nanosized nasal emulgel of resveratrol: preparation, optimization, in vitro evaluation and in vivo pharmacokinetic study.

Nano-emulgel has become one of the most significant controlled release systems, which has the advantages of both gels and nano-emulsions. This work aims at the formulation of nasal nano-emulgel for resveratrol, employing carbopol 934 and poloxamer 407 as the gelling agents. The optimum nano-emulsion was determined through further characterization of the selected system. The nasal nano-emulgel was prepared and tested for the in vitro release, the release kinetics, FTIR, ex vivo permeation, nasal mucosa toxicity, and in vivo pharmacokinetic study. The optimum nano-emulsion consisted of Tween 20, Capryol 90, and Transcutol at a ratio of (54.26: 23.81: 21.93%v/v), and it exhibited transmittance of 100%, resveratrol solubility of 159.9 ± 6.4 mg/mL, globule size of 30.65 nm. The in vitro resveratrol released from nano-emulsion and nasal nano-emulgel was 96.17 ± 4.43% and 78.53 ± 4.7%, respectively. Ex vivo permeation was sustained during 12 h up to 63.95 ± 4.7%. The histopathological study demonstrated that the formula is safe and tolerable to the nasal mucosa. Cmax and AUC (0-∞) of resveratrol obtained after nasal administration of nasal nano-emulgel was 2.23 and 8.05 times, respectively. Similarly, Tmax was increased up to 3.67 ± 0.82 h. The optimized nasal nano-emulgel established intranasal safety and bioavailability enhancement so it is considered as a well-designed system to target the brain.

Nanosized Transferosome-Based Intranasal In Situ Gel for Brain Targeting of Resveratrol: Formulation, Optimization, In Vitro Evaluation, and In Vivo Pharmacokinetic Study.

Resveratrol (RES) is a potent antioxidant used for the management of several central nervous system diseases. RES bioavailability is less than 1 owing to its low solubility and extensive intestinal and hepatic metabolism. The aim of the study was to enhance RES bioavailability through developing intranasal transferosomal mucoadhesive gel. Reverse evaporation-vortexing sonication method was employed to prepare RES-loaded transferosomes. Transferosomes were developed via 34 definitive screening design, using soya lecithin, permeation enhancers, and surfactants. The optimized formula displayed spherical shape with vesicle size of 83.79 ± 2.54 nm and entrapment efficiency (EE%) of 72.58 ± 4.51%. Mucoadhesive gels were prepared and evaluated, then optimized RES transferosomes were incorporated into the selected gel and characterized using FTIR spectroscopy, in vitro release, and ex vivo permeation study. Histopathological examination of nasal mucosa and in vivo pharmacokinetic study were conducted. In vitro drug release from transferosomal gel was 65.87 ± 2.12% and ex vivo permeation was 75.95 ± 3.19%. Histopathological study confirmed the safety of the optimized formula. The Cmax of RES in the optimized RES trans-gel was 2.15 times higher than the oral RES suspension and AUC(0-∞) increased by 22.5 times. The optimized RES trans-gel developed intranasal safety and bioavailability enhancement through passing hepatic and intestinal metabolism.

Development, Optimization, and In Vitro/In Vivo Characterization of Enhanced Lipid Nanoparticles for Ocular Delivery of Ofloxacin: the Influence of Pegylation and Chitosan Coating.

This study aims to investigate whether modification of solid lipid nanoparticles (SLNs) with chitosan (CTS) and polyethylene glycol (PEG) coatings enhances corneal retention time and transcorneal bioavailability. Ofloxacin (OFLOX) was selected as the model drug because of its potential benefits for the treatment of local eye infections. The OFLOX-CTS-PEG-SLN was prepared by a modified emulsion/solvent evaporation technique. A central composite design was implemented to investigate the influence of total lipid/drug ratio, surfactant concentration, PEG stearate concentration in the lipid mixture, and CTS concentration on size, entrapment, transcorneal permeation, and adhesion to the corneal mucosal membrane. The optimized OFLOX-CTS-PEG-SLN was characterized for OFLOX cumulative percentage released in simulated tear fluid and permeated across the excised bovine corneal membrane. Moreover, nanoparticle morphology, eye irritation via histopathological analysis, and OFLOX concentration in the ocular fluids and tissues were determined. A total lipid/drug ratio of 19:1, Tween 80 of 2%, PEG stearate concentration in the lipid mixture (% w/w) of 2.6%, and CTS concentration (% w/v) of 0.23% produced 132.9 nm particles entrapping 74.8% of the total drug added. The particles detached from the corneal membrane at a force of 3700 dyne/cm2. The %OFLOX released from the optimized nanoparticles was 63.3, and 66% of the drug permeated after 24 h. Compared to Oflox® drops, the optimized OFLOX-CTS-PEG-SLN exhibited similar tolerability but two- to threefold higher concentrations in the eyes of rabbits. Coating of SLN with chitosan and PEG augments the ocular bioavailability of OFLOX by increasing transcorneal permeation and enhancing mucoadhesion strength.

Preparation and optimization of tablets containing a self-nano-emulsifying drug delivery system loaded with rosuvastatin.

BACKGROUND: Rosuvastatin (ROS) calcium is the latest synthetic drug in the statin group that has an anti-hyperlipidemic activity. It is available as tablets, and its poor aqueous solubility, slow dissolution rate and low-absorption extent result in less than 20% bioavailability and about 80% being excreted unchanged in the feces without absorption. OBJECTIVE: To utilize nanotechnology to reformulate ROS as a self-nano-emulsifying drug delivery system (SNEDDS), and utilizing design optimization to fabricate the SNEDDS as a tablet. METHODS: The solubility of ROS in different oils, surfactants and co-surfactants was tested. Pseudo-ternary phase diagrams were developed and various SNEDDS formulations were prepared and evaluated regarding globule size, self-emulsification, viscosity and transmittance. The optimized system was examined using transmission electron microscopy. The self-nano-emulsifying tablets were prepared using two types of nano-silica and different percentages of Avicel as a binder and Ac-Di-Sol as a disintegrant. The prepared tablets were evaluated for their physicochemical properties. Bioavailability in human volunteers was assessed. RESULTS: A SNEDDS system was successfully developed with a droplet size range of 15 nm and a composition of 10% Labrafac, 80% Cremophore RH40 and 10% Propylene glycol. The optimized tablet formula contained: hydrophilic nano-silica, 3% Ac-Di-Sol and 30% Avicel. The pharmacokinetic study revealed that the bioavailability was enhanced by more than 2.4-fold compared with the commercially available tablet. CONCLUSIONS: Tablets containing SNEDDS loaded with ROS represent a promising novel formula that has higher gastrointestinal absorption and enhanced systemic bioavailability.

Formulation design and optimization of novel soft glycerosomes for enhanced topical delivery of celecoxib and cupferron by Box-Behnken statistical design.

BACKGROUND: The present study describes glycerosomes (vesicles composed of phospholipids, glycerol and water) as a novel drug delivery system for topical application of celecoxib (CLX) and cupferron (CUP) compound. AIM: The goal of this research was to design topical soft innovative vesicles loaded with CLX or CUP for enhancing the efficacy and avoiding systemic toxicity of CLX and CUP. METHODS: CLX and CUP loaded glycerosomes were prepared by hydrating phospholipid-cholesterol films with glycerol aqueous solutions (20-40%, v/v). Box-Behnken design, using Design-Expert® software, was the optimum choice to statistically optimize formulation variables. Three independent variables were evaluated: phospholipid concentration (X1), glycerol percent (X2) and tween 80 concentration (X3). The glycerosomes particle size (Y1), encapsulation efficiency percent (Y2: EE %) and drug release (Y3) were selected as dependent variables. The anti-inflammatory effect of CLX and CUP glycerosomal gel was evaluated by carrageenan-induced rat paw edema method followed by histopathological studies. RESULTS: The optimized formulations (CLX2* and CUP1*) showed spherical morphology under transmission electron microscopy, optimum particle size of 195.4 ± 3.67 nm, 301.2 ± 1.75 nm, high EE of 89.66 ± 1.73%, 93.56 ± 2.87%, high drug release of 47.08 ± 3.37%, 37.60 ± 1.89% and high cumulative amount of drug permeated in 8 h of 900.18 ± 50.24, 527.99 ± 34.90 µg.cm-2 through hairless rat skin, respectively. They also achieved significant remarkable paw edema inhibition in comparison with the control group (p < .05). CONCLUSION: Finally, the administration of CLX2* and CUP1* loaded glycerosomal gel onto the skin resulted in marked reduction of edema, congestive capillary and inflammatory cells and this approach may be of value in the treatment of different inflammatory disorders.

Mucoadhesive niosomal in situ gel for ocular tissue targeting: in vitro and in vivo evaluation of lomefloxacin hydrochloride.

Eradication of ophthalmic infections depends on increasing transcorneal permeation and localizing antibiotics at ocular surface. This study aimed at formulating lomefloxacin HCl (LF) in the form of niosomes and evaluating the in vivo performance of best formula in rabbits' eyes. Vesicles were developed by mixing three surfactants at three molar ratios of 1:1, 1:2 and 1:3 of surfactant to cholesterol. Size, zeta potential, release percentage, transcorneal permeation parameters, stability studies, cytotoxicity and antibacterial activity of niosomes were determined. Niosomes showed encapsulation efficiency of more than 78%, particle size below 500 nm and zeta potential below -43.6. The produced vesicles showed significantly higher amounts of drug permeated across cornea (166%) compared to LF solution. The in vivo study showed 2-5 folds increase in drug concentration in ocular fluids and tissues following administration of niosomes compared to marketed formula (from 3.75 to 10.31 mcg/mL in the cornea). Microbiological studies showed 35 folds increase in the antibacterial activity of LF niosomes compared to free drug; where MBC decreased from 31.25 mcg/mL in case of LF solution to 0.97 mcg/mL for niosomal gel. The formulated niosomes enhanced the ocular bioavailability of LF through increasing transcorneal permeation and localizing drug at site of action.

In vitro/in vivo correlation and modeling of emitted dose and lung deposition of inhaled salbutamol from metered dose inhalers with different types of spacers in noninvasively ventilated patients.

Substituting spacer by another in noninvasive ventilation (NIV) involves many variables, e.g. total emitted dose (TED), mass median aerodynamic diameter (MMAD), type of spacer, total lung deposition and total systemic absorption, which must be adjusted to ensure patient optimum therapy. Data mining based on artificial neural networks and genetic algorithms were used to model in vitro inhalation process, predict and optimize bioavailability from inhaled doses delivered by metered dose inhaler (MDI) using different spacers in NIV. Modeling of data indicated that in vitro performance of MDI-spacer systems was dependent mainly on fine particle dose (FPD), fine particle fraction (FPF), MMAD and to lesser extent on spacer type. Ex vivo model indicated that amount of salbutamol collected on facemask filter was directly affected by FPF. In vivo model (24hQ) depended directly on spacer type, FPF and TED. Female patients showed higher 0.5hQ and 24hQ values than males. AeroChamber VC spacer demonstrated higher TED and 24hQ in vivo values. Results indicated suitability of MDI-spacer systems in achieving appropriate in vitro inhalation performance. The possibility of modeling and predicting both ex vivo and in vivo capabilities of MDI-spacer systems from knowledge of in vitro attributes enabled detailed focus on important variables required to deliver safe and accurate doses of salbutamol to ventilated patients.

Edge activators and a polycationic polymer enhance the formulation of porous voriconazole nanoagglomerate for the use as a dry powder inhaler.

PURPOSE: Voriconazole has both low aqueous solubility and stability. We hypothesize that designing voriconazole in the form of a nano powder inhaler at a geometric diameter within 1-5 µm will enhance its stability and solubility. Therefore, we prepared nanoagglomerates of voriconazole which will collapse in the lungs to reform the nanoparticles. METHOD: The nanoparticles were formulated using both stearic acid and sodium deoxycholate as edge activators. Osmogenic polycation polyethyleneimine (PEI) was used to form agglomerates of controllable size. RESULTS: Voriconazole nanoparticles and agglomerates showed a significant higher cumulative drug release than the pure powder (p < 0.05) with R(2 )=( )0.95. Small-sized particles were formed (353 nm), while their zeta potential was -30.7 mV. The agglomerates were 2.7 µm in size and their zeta potential was -20.9 mV. The formation of porous agglomerates was confirmed using a transmission electron microscope. Cascade impactor was used to evaluate the aerodynamic properties of the nanoparticles and the agglomerates. The aerodynamic characterization of the nanoparticles and the agglomerates resulted in a significant smaller mass median aerodynamic diameter (MMAD) (p < 0.05) and higher fine particle dose (FPD) (p < 0.01), fine particle fraction (FPF) (p < 0.01), and total emitted dose (TED) (p < 0.01) than the pure powder. CONCLUSION: The results suggest that using the combination of edge activators and diluted polycationic polymer solution provides porous voriconazole nanoagglomerates in a respirable range, which is proved successful in enhancing both the deposition and the dissolution of water insoluble-drugs in the lung.