Optimization of Phloretin-loaded Nanospanlastics for Targeting of FAS/SREBP1c/AMPK/ OB-Rb Signaling Pathway in HFD-induced Obesity.

OBJECTIVES: Obese patients are at increased risk for CVD, which is the main cause of premature death and has been a major cause of disability and ill health in recent years. PTN, a natural dihydrochalcone flavonoid, has a variety of pharmacological characteristics. This article aimed to prepare PTN-NSLs to evaluate their anti-obesity activity. METHODS: Morphology, Particle size, zeta potential, UV-vis, entrapment efficiency, FT-IR spectra, and an in vitro release study of PTN-NSLs were described. PTN-NSLs were also tested for their anti-obesity properties in obese rats. The LD50 of PTN-NSLs was calculated, as was the 1/20 LD50 prepared for the treatment of obese rats. Also, the level of glycemic, oxidative stress and inflammatory biomarkers were estimated in the obese rat's model. RESULTS: The synthesized PTN-NSLs were uniform, spherically shaped, and well dispersed with no aggregation noted, with a size range of 114.06 ± 8.35 nm. The measured zeta potential value of PTN-NSLs was -32.50.8 mv. Also, the UV spectra of PTN and PTN-NSLs have strong absorption at 225 and 285 nm. Also, the LD50 of PTN-NSLs was found to be 2750 mg/kg.b.w. Moreover, administrating obese rats with PTN-NSLs resulted in improved glycemic features as well as GSH, SOD, GPx, GR, IL10, TBARs, and IL-6 levels, as well as attenuated FAS, SREBP1c, AMPK, ACO, CPT1, and OB-Rb gene expression. CONCLUSIONS: Administration of PTN-NSLs significantly attenuated the levels of glycemic, oxidative stress, and inflammatory biomarkers. The biochemical and PCR findings are aided by histological investigations. Also, the present findings imply that PTN-NSLs might be a promising pharmacological tool for the treatment of obesity-related diseases.

A Novel Chitosan-coated Leciplex Loaded with Ambrisentan as a Possible Pulmonary Nanosystem: Optimization, Characterization, and Pharmacokinetics Assessments.

The purpose of this research was to formulate, optimize, and characterize ambrisentan chitosan-coated LeciPlex (AMS-CTS-LPX) to increase the therapeutic effectiveness and bioavailability of ambrisentan. A central composite design (CCD) was implemented to assess the impact of various factors on the production of AMS-CTS-LPX and to identify the optimum formulation via the use of Design Expert® software. The assembly of AMS-CTS-LPX was conducted using a single-step process. Subsequently, the optimal formulation was chosen and subjected to further assessments. Further, a comparative pharmacokinetic study was carried out using a rat model. The optimized formulation exhibited an entrapment efficiency of 82.39%, with a diameter of 137.53 nm and a surface charge of +43.65 mV. Additionally, it had a sustained cumulative release of 90.41% after 8 h and showed good stability. The safety of AMS-CTS-LPX administered intratracheally was confirmed by in vivo histopathological studies. The pharmacokinetic investigations revealed a 5.6-fold increase in the bioavailability of AMS from the optimal AMS-CTS-LPX formulation compared to the oral AMS solution. Collectively, the results of the current study suggest that CTS-LPX may be beneficial as a pulmonary nanosystem for the administration of AMS.

Nose-to-Brain Targeted Delivery of Donepezil Hydrochloride via Novel Hyaluronic Acid-Doped Nanotransfersomes for Alzheimer's Disease Mitigation.

Alzheimer's disease is the most serious neurodegenerative disorder characterized by cognitive and memorial defects alongside deterioration in behavioral, thinking and social skills. Donepezil hydrochloride (DPZ) is one of the current two FDA-approved cholinesterase inhibitors used for the management of Alzheimer's disease. The current study aimed to formulate hyaluronic acid-coated transfersomes containing DPZ (DPZ-HA-TFS) for brain delivery through the intranasal pathway to surpass its oral-correlated GIT side effects. DPZ-HA-TFS were produced using a thin film hydration method and optimized with a 24 factorial design. The influence of formulation parameters on vesicle diameter, entrapment, cumulative release after 8 h, and ex vivo nasal diffusion after 24 h was studied. The optimal formulation was then evaluated for morphology, stability, histopathology and in vivo biodistribution studies. The optimized DPZ-HA-TFS formulation elicited an acceptable vesicle size (227.5 nm) with 75.83% entrapment efficiency, 37.94% cumulative release after 8 h, 547.49 µg/cm2 permeated through nasal mucosa after 24 h and adequate stability. Histopathological analysis revealed that the formulated DPZ-HA-TFS was nontoxic and tolerable for intranasal delivery. Intranasally administered DPZ-HA-TFS manifested significantly superior values for drug targeting index (5.08), drug targeting efficiency (508.25%) and direct nose-to-brain transport percentage (80.32%). DPZ-HA-TFS might be deemed as a promising intranasal nano-cargo for DPZ cerebral delivery to tackle Alzheimer's disease safely, steadily and in a non-invasive long-term pattern.

Repurposing celecoxib for colorectal cancer targeting via pH-triggered ultra-elastic nanovesicles: Pronounced efficacy through up-regulation of Wnt/ß-catenin pathway in DMH-induced tumorigenesis.

Celecoxib (CLX), a selective inhibitor for cyclooxygenase 2 (COX-2), has manifested potential activity against diverse types of cancer. However, low bioavailability and cardiovascular side effects remain the major challenges that limit its exploitation. In this work, we developed ultra-elastic nanovesicles (UENVs) with pH-triggered surface charge reversal traits that could efficiently deliver CLX to colorectal segments for snowballed tumor targeting. CLX-UENVs were fabricated via a thin-film hydration approach. The impact of formulation factors (Span 80, Tween 80, and sonication time) on the nanovesicular features was evaluated using Box-Behnken design, and the optimal formulation was computed. The optimum formulation was positively coated with polyethyleneimine (CLX-PEI-UENVs) and then coated with Eudragit S100 (CLX-ES-PEI-UENVs). The activity of the optimized nano-cargo was explored in 1,2-dimethylhydrazine-induced colorectal cancer in Wistar rats. Levels of COX-2, Wnt-2 and ß-catenin were assessed in rats' colon. The diameter of the optimized CLX-ES-PEI-UENVs formulation was 253.62 nm, with a zeta potential of -23.24 mV, 85.64% entrapment, and 87.20% cumulative release (24 h). ES coating hindered the rapid release of CLX under acidic milieu (stomach and early small intestine) and showed extended release in the colon section. In colonic environments, the ES coating layer was removed due to high pH, and the charge on the nanovesicular corona was shifted from negative to positive. Besides, a pharmacokinetics study revealed that CLX-ES-PEI-UENVs had superior oral bioavailability by 2.13-fold compared with CLX suspension. Collectively, these findings implied that CLX-ES-PEI-UENVs could be a promising colorectal-targeted nanoplatform for effective tumor management through up-regulation of the Wnt/ß-catenin pathway.

An investigation of the acaricidal activity of benzyl alcohol on Rhipicephalus annulatus and Rhipicephalus sanguineus and its synergistic or antagonistic interaction with commonly used acaricides.

The most economically significant ectoparasites in the tropics and subtropics are ixodid ticks, especially Rhipicephalus annulatus and Rhipicephalus sanguineus. Years of extensive use of the readily available acaricides have resulted in widespread resistance development in these ticks, as well as negative environmental consequences. Benzyl alcohol (BA) has been frequently used to treat pediculosis and scabies, and it may be an effective alternative to commonly used acaricides. The main aim of the present study was to evaluate the acaricide activity of BA and its combination with the regularly used chemical acaricides against R. annulatus and R. sanguineus. Different concentrations of BA alone and in combination with deltamethrin, cypermethrin and chlorpyrifos were tested in vitro against adult and larvae of both tick species. The results showed that BA is toxic to R. annulatus and R. sanguineus larvae, with 100% larval mortality at concentrations of ≥50 mL/L, and LC50 and LC90 attained the concentrations of 19.8 and 33.8 mL/L for R. annulatus and 18.8 and 31.8 mL/L for R. sanguineus, respectively. Furthermore, BA in combination with deltamethrin, cypermethrin and chlorpyrifos exhibited synergistic factors of 2.48, 1.26 and 1.68 against R. annulatus larvae and 1.64, 11.1 and 1.14 against R. sanguineus larvae for deltamethrin + BA, cypermethrin + BA and chlorpyrifos + BA, respectively. BA induced 100% mortality in adult R. annulatus at concentrations of ≥250 mL/L with LC50 and LC90 reached the concentrations of 111 and 154 mL/L, respectively. Additionally, BA had ovicidal activity causing complete inhibition of larval hatching at 100 mL/L. The combination of BA with deltamethrin and cypermethrin increased acetylcholinesterase inhibition, whereas the combination of BA with chlorpyrifos decreased glutathione (GSH) activity and malondialdehyde levels. In the field application, the combination of BA 50 mL/L and deltamethrin (DBA) resulted in a significant reduction in the percentage of ticks by 30.9% 28 days post-treatment when compared with groups treated with deltamethrin alone. In conclusion, BA causes mortality in laboratory and field studies alone and in combination with cypermethrin or deltamethrin. BA can be used for control of ticks of different life stages, that is, eggs and larvae, through application to the ground.

Tunable Polymeric Mixed Micellar Nanoassemblies of Lutrol F127/Gelucire 44/14 for Oral Delivery of Praziquantel: A Promising Nanovector against Hymenolepis nana in Experimentally-Infected Rats.

Hymenolepiasis represents a parasitic infection of common prevalence in pediatrics with intimidating impacts, particularly amongst immunocompromised patients. The present work aimed to snowball the curative outcomes of the current mainstay of hymenolepiasis chemotherapy, praziquantel (PRZ), through assembly of polymeric mixed micelles (PMMs). Such innovative nano-cargo could consolidate PRZ hydrosolubility, extend its circulation time and eventually upraise its bioavailability, thus accomplishing a nanoparadigm for hymenolepiasis tackling at lower dose levels. For consummating this goal, PRZ-PMMs were tailored via thin-film hydration technique integrating a binary system of Lutrol F127 and Gelucire 44/14. Box-Behnken design was planned for optimizing the nanoformulation variables employing Design-Expert® software. Also, in Hymenolepis nana-infected rats, the pharmacodynamics of the optimal micellar formulation versus the analogous crude PRZ suspension were scrutinized on the 1st and 3rd days after administration of a single oral dose (12.5 or 25 mg/kg). Moreover, in vitro ovicidal activity of the monitored formulations was estimated utilizing Fuchsin vital stain. Furthermore, the in vivo pharmacokinetics were assessed in rats. The optimum PRZ-PMMs disclosed conciliation between thermodynamic and kinetic stability, high entrapment efficiency (86.29%), spherical nanosized morphology (15.18 nm), and controlled-release characteristics over 24 h (78.22%). 1H NMR studies verified PRZ assimilation within the micellar core. Additionally, the in vivo results highlighted a significant boosted efficacy of PRZ-PMMs manifested by fecal eggs output and worm burden reduction, which was clearly evident at the lesser PRZ dose, besides a reversed effect for the intestinal histological disruptions. At 50 µg/mL, PRZ-PMMs increased the percent of non-viable eggs to 100% versus 47% for crude PRZ, whilst shell destruction and loss of embryo were only clear with the applied nano-cargo. Moreover, superior bioavailability by 3.43-fold with elongated residence time was measured for PRZ-PMMs compared to PRZ suspension. Practically, our results unravel the potential of PRZ-PMMs as an oral promising tolerable lower dose nanoplatform for more competent PRZ mass chemotherapy.

Innovative pulmonary targeting of terbutaline sulfate-laded novasomes for non-invasive tackling of asthma: statistical optimization and comparative in vitro/in vivo evaluation.

Asthma represents a globally serious non-communicable ailment with significant public health outcomes for both pediatrics and adults triggering vast morbidity and fatality in critical cases. The ß2-adrenoceptor agonist, terbutaline sulfate (TBN), is harnessed as a bronchodilator for monitoring asthma noising symptoms. Nevertheless, the hepatic first-pass metabolism correlated with TBN oral administration mitigates its clinical performance. Likewise, the regimens of inhaled TBN dosage forms restrict its exploitation. Consequently, this work is concerned with the assimilation of TBN into a novel non-phospholipid nanovesicular paradigm termed novasomes (NVS) for direct and effective TBN pulmonary targeting. TBN-NVS were tailored based on the thin film hydration method and Box-Behnken design was applied to statistically optimize the formulation variables. Also, the aerodynamic pattern of the optimal TBN-NVS was explored via cascade impaction. Moreover, comparative pharmacokinetic studies were conducted using a rat model. TBN elicited encapsulation efficiency as high as 70%. The optimized TBN-NVS formulation disclosed an average nano-size of 223.89 nm, ζ potential of -31.17 mV and a sustained drug release up to 24 h. Additionally, it manifested snowballed in vitro lung deposition behavior in cascade impactor with a fine particle fraction of 86.44%. In vivo histopathological studies verified safety of intratracheally-administered TBN-NVS. The pharmacokinetic studies divulged 3.88-fold accentuation in TBN bioavailability from the optimum TBN-NVS versus the oral TBN solution. Concisely, the results proposed that NVS are an auspicious nanovector for TBN pulmonary delivery with integral curbing of the disease owing to target specificity.

Tailoring of Selenium-Plated Novasomes for Fine-Tuning Pharmacokinetic and Tumor Uptake of Quercetin: In Vitro Optimization and In Vivo Radiobiodistribution Assessment in Ehrlich Tumor-Bearing Mice.

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.

Harnessing of Doxylamine Succinate/Pyridoxine Hydrochloride-Dual Laden Bilosomes as a Novel Combinatorial Nanoparadigm for Intranasal Delivery: In Vitro Optimization and In Vivo Pharmacokinetic Appraisal.

The present work is concerned with tailoring and appraisal of a novel nano-cargo; bilosomes (BLS) dual laded with doxylamine succinate (DAS) and pyridoxine hydrochloride (PDH), the first treatment option against gestational nausea and vomiting, for intranasal delivery. This bifunctional horizon could surmount constraints of orally-commercialized platforms both in dosage regimen and pharmacokinetic profile. For accomplishing this purpose, DAS/PDH-BLS were elaborated integrating phospholipid, sodium cholate and cholesterol applying thin-film hydration method based on Box-Behnken design. Utilizing Design-Expert® software, the effect of formulation variables on BLS physicochemical features alongside the optimal formulation selection were investigated. Then, the optimum DAS/PDH-BLS formulation was incorporated into a thermally-triggered in situ gelling base. The in vivo pharmacokinetic studies were explored in rats for intranasal DAS/PDH-BLS in situ gel compared with analogous intranasal free in situ gel and oral solution. The optimized BLS disclosed vesicle size of 243.23 nm, ζ potential of -31.33 mV, entrapment efficiency of 59.18 and 41.63%, accumulative % release within 8 h of 63.30 and 85.52% and accumulative permeated amount over 24 h of 347.92 and 195.4 µg/cm2 for DAS/PDH, respectively. Following intranasal administration of the inspected BLS in situ gel, pharmacokinetic studies revealed a 1.64- and 2.3-fold increment in the relative bioavailability of DAS and a 1.7- and 3.73-fold increase for PDH compared to the intranasal free in situ gel and oral solution, respectively besides significantly extended mean residence times for both drugs. Thus, the intranasally exploited DAS/PDH-BLS could be deemed as a promising hybrid nanoplatform with fruitful pharmacokinetics and tolerability traits.

Intratracheally Inhalable Nifedipine-Loaded Chitosan-PLGA Nanocomposites as a Promising Nanoplatform for Lung Targeting: Snowballed Protection via Regulation of TGF-ß/ß-Catenin Pathway in Bleomycin-Induced Pulmonary Fibrosis.

Pulmonary fibrosis is a serious ailment that may progress to lung remodeling and demolition, where the key participants in its incidence are fibroblasts responding to growth factors and cellular calcium swinging. Calcium channel blockers, like nifedipine (NFD), may represent auspicious agents in pulmonary fibrosis treatment. Unfortunately, NFD bears complicated pharmacodynamics and a diminished systemic bioavailability. Thus, the current study aimed to develop a novel, non-invasive nanoplatform for NFD for direct/effective pulmonary targeting via intratracheal instillation. A modified solvent emulsification-evaporation method was adopted for the fabrication of NFD-nanocomposites, integrating poly(D,L-lactide-co-glycolide) (PLGA), chitosan (CTS), and polyvinyl alcohol, and optimized for different physiochemical properties according to the 32 full factorial design. Additionally, the aerodynamic behavior of the nanocomposites was scrutinized through cascade impaction. Moreover, the pharmacokinetic investigations were conducted in rats. Furthermore, the optimum formulation was tested in bleomycin-induced pulmonary fibrosis in rats, wherein fibrotic and oxidative stress parameters were measured. The optimum nanocomposites disclosed a nanosized spherical morphology (226.46 nm), a high entrapment efficiency (61.81%) and a sustained release profile over 24 h (50.4%). As well, it displayed a boosted in vitro lung deposition performance with a mass median aerodynamic diameter of 1.12 µm. Pharmacokinetic studies manifested snowballed bioavailability of the optimal nanocomposites by 3.68- and 2.36-fold compared to both the oral and intratracheal suspensions, respectively. The intratracheal nanocomposites revealed a significant reduction in lung fibrotic and oxidative stress markers notably analogous to normal control besides repairing abnormality in TGF-ß/ß-catenin pathway. Our results conferred a compelling proof-of-principle that NFD-CTS-PLGA nanocomposites can function as a promising nanoparadigm for pulmonary fibrosis management.

Response Surface Optimization of Ultra-Elastic Nanovesicles Loaded with Deflazacort Tailored for Transdermal Delivery: Accentuated Bioavailability and Anti-Inflammatory Efficacy.

PURPOSE: The aim of the present study was to develop deflazacort (DFZ) ultra-elastic nanovesicles (UENVs) loaded gel for topical administration to evade gastrointestinal adverse impacts accompanying DFZ oral therapy. METHODS: UENVs were elaborated according to D-optimal mixture design employing different edge activators as Span-60, Tween-85 and sodium cholate which were incorporated into the nanovesicles to improve the deformability of vesicles bilayer. DFZ-UENVs were formulated by thin-film hydration technique followed by characterization for different parameters including entrapment efficiency (%EE), particle size, in vitro release and ex vivo permeation studies. The composition of the optimized DFZ-UENV formulation was found to be DFZ (10 mg), Span-60 (30 mg), Tween-85 (30 mg), sodium cholate (3.93 mg), L-α phosphatidylcholine (60 mg) and cholesterol (30 mg). The optimum formulation was incorporated into hydrogel base then characterized in terms of physical parameters, in vitro drug release, ex vivo permeation study and pharmacodynamics evaluation. Finally, pharmacokinetic study in rabbits was performed via transdermal application of UENVs gel in comparison to oral drug. RESULTS: The optimum UENVs formulation exhibited %EE of 74.77±1.33, vesicle diameter of 219.64±2.52 nm, 68.88±1.64% of DFZ released after 12 h and zeta potential of -55.57±1.04 mV. The current work divulged successful augmentation of the bioavailability of DFZ optimum formulation by about 1.37-fold and drug release retardation compared to oral drug tablets besides significant depression of edema, cellular inflammation and capillary congestion in carrageenan-induced rat paw edema model. CONCLUSION: The transdermal DFZ-UENVs can achieve boosted bioavailability and may be suggested as an auspicious non-invasive alternative platform for oral route.

Preparation and appraisal of self-assembled valsartan-loaded amalgamated Pluronic F127/Tween 80 polymeric micelles: Boosted cardioprotection via regulation of Mhrt/Nrf2 and Trx1 pathways in cisplatin-induced cardiotoxicity.

This study aimed to develop valsartan (VAL)-loaded mixed micelles and investigate their cardioprotective potential and molecular mechanisms through Mhrt/Nrf2 and Trx1 pathways. VAL-loaded mixed micelles have not been elaborated and their impact on Mhrt/Nrf2 and Trx1 pathways has not been yet inspected. VAL-loaded mixed micelles were prepared, incorporating Pluronic F127 and Tween 80, adopting thin-film hydration method. The micelles were evaluated for drug entrapment efficiency, loading characteristics, particle size, morphology, in vitro drug release and micelles storage stability. The pharmacokinetic studies were explored in rats. Also, VAL suspension and mixed micelles were tested in cisplatin-induced cardiotoxicity in rats either pre to or simultaneously with cisplatin. RNA expression of lnc Mhrt and protein expression of Nrf2, Trx1, Ask1, AMPK and caspase 3, oxidative stress and cardiac injury markers besides tailed DNA% by comet assay were assessed. Pharmacokinetic studies evoked a 3.75-fold increase in oral bioavailability as compared with VAL suspension. Overall, treatment with VAL-loaded mixed micelles was superior to VAL suspension in decreasing oxidative stress and cardiac injury markers and restoring the abnormalities occurred in Mhrt/Nrf2 and Trx1 pathways. Thus, mixed micelles would be promising nanocarrier for the engineering of VAL with reinforced pharmacokinetics and cardioprotection characteristics.

A novel nanogel loaded with chitosan decorated bilosomes for transdermal delivery of terbutaline sulfate: artificial neural network optimization, in vitro characterization and in vivo evaluation.

The objective of the present work was to formulate, optimize, and evaluate transdermal terbutaline sulfate (TBN)-loaded bilosomes (BLS) in gel, compared to conventional oral TBN solution and transdermal gel loaded with free TBN, aiming at evading the hepatic first-pass metabolism. A face-centered central composite design was adopted to observe the effects of different formulation variables on TBN-BLS, and artificial neural network (ANN) modeling was employed to optimize TBN-BLS. TBN-BLS were prepared by a thin film hydration method integrating soybean phosphatidylcholine and cholesterol as a lipid phase and sodium deoxycholate (SDC) as a surfactant with or without the coating of chitosan (CTS). After being subjected to physicochemical characterization, TBN-BLS were enrolled in a histopathological study and pharmacokinetic investigation in a rat model. The optimized TBN chitosan-coated bilosomes (TBN-CTS-BLS) were spherical vesicles (245.13 ± 10.23 nm) with adequate entrapment efficiency (65.25 ± 5.51%) and good permeation characteristics (340.11 ± 22.34 µg/cm2). The TBN-CTS-BLS gel formulation was well-tolerated with no inflammatory signs manifested upon histopathological evaluation. The pharmacokinetic study revealed that the optimized TBN-CTS-BLS formulation successively enhanced the bioavailability of TBN by about 2.33-fold and increased t1/2 to about 6.21 ± 0.24 h as compared to the oral solution. These findings support the prospect use of BLS as active and safe transdermal carrier for TBN in the treatment of asthma. Graphical Abstract.

Surface modified niosomes of olanzapine for brain targeting via nasal route; preparation, optimization, and in vivo evaluation.

Olanzapine (OL) is an atypical antipsychotic drug which suffers from an extensive hepatic metabolism and poor bioavailability. In addition, it has low brain permeability due to efflux by P-glycoproteins. In the current investigation, surface modified niosomes containing OL were prepared for brain targeting of the drug through nasal route. Spans were mixed with cholesterol at ratios of 1:1, 1:2, 1:3, and 1:4 of cholesterol to surfactant, respectively to prepare niosomes. Chitosan (CS) coated vesicles were prepared by mixing optimum niosomal formula with CS solution (0.6%). Physicochemical and stability parameters and confocal laser scanning microscopy (CLSM) of developed vesicles were determined. Also, the brain targeting properties of the optimized formula were measured in rats. Niosomes had entrapment efficiency more than 90% and particle size ranging from 201.3 ± 2.4 nm to 1446 ± 9 nm. TEM photomicrographs of developed vesicles showed a clear shell surrounding the coated vesicles. The produced vesicles exhibited 2.46 folds increase in the amount of drug that permeated nasal mucosa and prolonged OL release compared to drug solution. Coated niosomes further improved drug permeation. CLSM of coated optimum formula showed high permeation across the nasal mucosa. Stability studies revealed non-significant changes in the physicochemical parameters of optimum formula over the storage period. The optimized nasal CS-coated niosomes showed a three-fold increase in OL concentration in the brain compared to the intranasal solution of the drug. In conclusion, the developed vesicles were efficient in nasal delivery of OL into the brain.

Transdermal delivery of fluvastatin sodium via tailored spanlastic nanovesicles: mitigated Freund's adjuvant-induced rheumatoid arthritis in rats through suppressing p38 MAPK signaling pathway.

The current study aimed to encapsulate fluvastatin sodium (FVS), a member of the statins family possessing pleiotropic effects in rheumatoid arthritis (RA), into spanlastic nanovesicles (SNVs) for transdermal delivery. This novel delivery could surmount FVS associated oral encumbrances such as apparent first-pass effect, poor bioavailability and short elimination half-life, hence, accomplishing platform for management of RA. To consummate this objective, FVS-loaded SNVs were elaborated by thin film hydration method, utilizing either Span 60 or Span 80, together with Tween 80 or Brij 35 as an edge activator according to full factorial design (24). Applying Design-Expert® software, the influence of formulation variables on SNVs physicochemical properties and the optimized formulation selection were explored. Additionally, the pharmacokinetic studies were scrutinized in rats. Furthermore, in Freund's adjuvant-induced arthritis, rheumatoid markers, TNF-α, IL-10, p38 MAPK, and antioxidant parameters were measured. The optimum SNVs were nano-scaled spherical vesicles (201.54 ± 9.16 nm), having reasonable entrapment efficiency (71.28 ± 2.05%), appropriate release over 8 h (89.45 ± 3.64%) and adequate permeation characteristics across the skin (402.55 ± 27.48 µg/cm2). The pharmacokinetic study disclosed ameliorated bioavailability of the optimum SNVs gel by 2.79- and 4.59-fold as compared to the oral solution as well as the traditional gel, respectively. Moreover, it elicited a significant suppression of p38 MAPK expression and also significant improvement of all other measured biomarkers. Concisely, the foregoing findings proposed that SNVs can be auspicious for augmenting FVS transdermal delivery for management of RA.

Novel in situ gelling vaginal sponges of sildenafil citrate-based cubosomes for uterine targeting.

Sildenafil citrate (SIL), a type 5-specific phosphodiesterase inhibitor, demonstrates valuable results in the management of infertility in women; however, the absence of vaginal dosage form in addition to the associated oral adverse effects minimize its clinical performance. The present study is concerned with SIL uterine targeting following intravaginal administration via optimization of cubosomal in situ gelling sponges (CIS). An emulsification method was employed for preparation of cubosomal dispersions incorporating glyceryl monooleate as a lipid phase and poloxamer 407 as a surfactant with or without polyvinyl alcohol as a stabilizer. Cubosomes were estimated regarding entrapment efficiency (EE%), particle size, and in vitro drug release. Chitosan (2% w/w) was incorporated into the optimum formulation and then lyophilized into small sponges. For the CIS, in vivo histopathological and pharmacokinetic studies were conducted on female Wistar rats and compared with intravaginal free SIL sponges (FIS) and oral SIL solution. SIL-loaded cubosomes showed EE% ranging between 32.15 and 72.01%, particle size in the range of 150.81-446.02 nm and sustained drug release over 8 h. Histopathological study revealed a significant enlargement in endometrial thickness with congestion and dilatation of endometrial blood vessels in intravaginal CIS compared to intravaginal FIS and oral-treated groups. The pharmacokinetic study demonstrated higher AUC0-∞ and Cmax with oral administration compared to intravaginal CIS or intravaginal FIS indicating potential involvement of first uterine pass effect after intravaginal administration. Finally, intravaginal CIS could be considered as a promising platform for SIL uterine targeting with minimized systemic exposure and side effects.

Transdermal delivery of atorvastatin calcium from novel nanovesicular systems using polyethylene glycol fatty acid esters: Ameliorated effect without liver toxicity in poloxamer 407-induced hyperlipidemic rats.

CONTEXT: Atorvastatin calcium (ATV), a cholesterol-lowering agent, suffers from poor systemic availability (14%) after oral administration in addition to other side effects on the gastrointestinal tract, liver and muscle. OBJECTIVE: The goal of the present investigation was to improve ATV bioavailability and overcome complications attendant with peroral administration by developing a new nanovesicular system encapsulating ATV for its delivery via the transdermal route. METHODS: The vesicular systems were prepared by incorporating different polyethylene glycol fatty acid esters such as Labrasol, Cremophor EL, Gelucire 44/14 and Tween 80 as edge activators (EAs) in the lipid bilayer. The effect of the phosphatidylcholine (PC):EA molar ratio on the physicochemical properties of the vesicles was investigated. The pharmacokinetic studies of the optimized formulation were evaluated in rats. The optimized formulation was tested in poloxamer 407-induced hyperlipidemic rats. The plasma lipid profile, activity of liver enzymes, and oxidative stress parameters were measured using commercially available kits. RESULTS: The results revealed high ATV entrapment efficiency (EE%) ranging from 55.62 to 83.91%. The formulations that contained Labrasol showed the highest EE%. The mean diameter of the vesicles was in the range of 186-583nm. T8 containing Gelucire 44/14 as an EA in the molar ratio of 15:1 (PC:EA) gave the smallest size and exhibited the best permeation parameters across the skin. The pharmacokinetic studies revealed that about three times statistically significant (p<0.05) improvement in bioavailability, after transdermal administration of nanotransfersomal ATV gel compared to oral ATV suspension. The transdermal vesicular system exhibited a significant decrease in plasma total cholesterol, triglycerides and LDL cholesterol comparable to oral ATV. Additionally, it lowered the malondialdehyde levels in plasma and abolished the increase in liver enzyme activity. CONCLUSION: The results obtained suggest that the proposed transdermal vesicular system can serve as a promising alternative means for delivery of ATV.

Transbuccal delivery of betahistine dihydrochloride from mucoadhesive tablets with a unidirectional drug flow: in vitro, ex vivo and in vivo evaluation.

OBJECTIVE: Betahistine dihydrochloride (BH.2HCl), an anti-vertigo histamine analog used in the treatment of Ménière's disease, undergoes extensive first-pass metabolism and suffers from short biological half-life. The aim of the present work was to develop and estimate controlled release mucoadhesive buccal tablets of BH.2HCl with a unidirectional drug flow to overcome this encumbrance. METHODS: A direct compression method was adopted for preparation of the tablets using mucoadhesive polymers like guar gum, hydroxypropyl methyl cellulose K4M, sodium carboxymethyl cellulose and their combinations. The tablets were coated from all surfaces except one surface with a solution of 5% (w/v) cellulose acetate and 1% (w/v) dibutyl phthalate. Different permeation enhancers like 2% sodium deoxycholate, 2% sodium cholate hydrate (SCH) and 5% menthol were tested. Swelling index, ex vivo residence time, mucoadhesion strength, in vivo testing of mucoadhesion time, in vitro dissolution and ex vivo permeation were carried out. Furthermore, compatibility and accelerated stability studies were performed for the drug excipients. Finally, drug bioavailability of the BH.2HCl-optimized buccal mucoadhesive formulation was compared with that of the orally administered Betaserc® 24 mg tablet in six healthy male volunteers. RESULTS: Formulation F10, which contained a combination of 35% guar gum and 5% sodium carboxymethyl cellulose, exhibited long adhesion time, high adhesion strength and diminished irritation to volunteers and showed zero-order release kinetics. SCH produced a significant enhancement in permeation of BH.2HCl across buccal mucosa. BH.2HCl-optimized buccal mucoadhesive formulation showed percentage relative bioavailability of 177%. CONCLUSION: The developed mucoadhesive tablets represent a promising alternative for the buccal delivery of BH.2HCl.

Development, Optimization, and Evaluation of Carvedilol-Loaded Solid Lipid Nanoparticles for Intranasal Drug Delivery.

Carvedilol, a beta-adrenergic blocker, suffers from poor systemic availability (25%) due to first-pass metabolism. The aim of this work was to improve carvedilol bioavailability through developing carvedilol-loaded solid lipid nanoparticles (SLNs) for nasal administration. SLNs were prepared by emulsion/solvent evaporation method. A 23 factorial design was employed with lipid type (Compritol or Precirol), surfactant (1 or 2% w/v poloxamer 188), and co-surfactant (0.25 or 0.5% w/v lecithin) concentrations as independent variables, while entrapment efficiency (EE%), particle size, and amount of carvedilol permeated/unit area in 24 h (Q 24) were the dependent variables. Regression analysis was performed to identify the optimum formulation conditions. The in vivo behavior was evaluated in rabbits comparing the bioavailability of carvedilol after intravenous, nasal, and oral administration. The results revealed high drug EE% ranging from 68 to 87.62%. Carvedilol-loaded SLNs showed a spherical shape with an enriched core drug loading pattern having a particle size in the range of 66 to 352 nm. The developed SLNs exhibited significant high amounts of carvedilol permeated through the nasal mucosa as confirmed by confocal laser scanning microscopy. The in vivo pharmacokinetic study revealed that the absolute bioavailability of the optimized intranasal SLNs (50.63%) was significantly higher than oral carvedilol formulation (24.11%). Hence, we conclude that our developed SLNs represent a promising carrier for the nasal delivery of carvedilol.

Nanotransfersomes of carvedilol for intranasal delivery: formulation, characterization and in vivo evaluation.

CONTEXT: Development of carvedilol-loaded transfersomes for intranasal administration to overcome poor nasal permeability and hepatic first pass effect so as to enhance its bioavailability. OBJECTIVE: The purpose of this study was to develop carvedilol-loaded transfersomes containing different edge activators (EAs) then evaluating the in vivo behavior of the optimized formula in rabbits. METHODS: The vesicles were prepared by incorporating different EAs including Span 20, Span 60, Tween 20, Tween 80, and sodium deoxycholate (SDC) in the lipid bilayer and each EA was used in three different ratios with respect to phosphatidylcholine (PC) including 95:5%, 85:15%, and 75:25% w/w (PC:EA). Evaluation of transfersomes was carried out in terms of shape, size, entrapment efficiency (EE), in vitro release, ex vivo permeation, confocal laser scanning microscopy (CLSM), and stability studies. The pharmacokinetic study of the optimized formula was conducted in rabbits. RESULTS: The mean diameter of the vesicles was in the range of 295-443 nm. Transfersomes prepared with 95:5% (w/w) (PC:EA) ratio showed highest EE% where Span 60 gave the highest values. Whereas those prepared using 85:15% w/w ratio showed highest percentages of drug release where SDC was superior to other EAs. The developed transfersomes exhibited significantly higher amounts of carvedilol permeated through nasal mucosa. CLSM of formula T14 containing SDC with 85:15% (w/w) (PC:EA) ratio revealed high permeation across the nasal mucosa. CONCLUSION: The nanotransfersomal vesicles were significantly more efficient in nasal delivery of carvedilol with absolute bioavailability of 63.4%.