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Aims: This study aims at formulating combined delivery of Risedronate sodium (RIS) and Vitamin D3 (VITD3) for augmented therapeutic outcome against osteoporosis (OP) using deep lung targeted PAMAM-G5-NH 2 dendrimers to minimize RIS gastrointestinal side effects and enhance both drugs bioavailability through absorption from the alveoli directly to the blood., Methods: RIS-PAMAM-G5-NH 2 , VITD3-PAMAM-G5-NH 2 , and RIS/VITD3-PAMAM-G5-NH 2 were prepared and evaluated in vitro for particle size (PS), zeta potential (ZP), %loading efficiency (%LE), morphology and FTIR. The efficacy of the RIS/VITD3-PAMAM-G5-NH 2 compared to oral RIS was evaluated in OP-induced rats by comparing serum calcium, phosphorus, and computed bone mineral density (BMD) pre- and post-treatment. Additionally, a comprehensive metabolomics and molecular pathways approach was applied to find serum potential biomarkers for diagnosis and to evaluate the efficacy of inhaled RIS/VITD3-PAMAM-G5-NH 2 ., Key Findings: RIS/VITD3-PAMAM-G5-NH 2 was successfully prepared with a %LE of 92.4 ± 6.7 % (RIS) and 83.2 ± 4.4 % (VIT-D3) and a PS of 252.8 ± 34.1 adequate deep lung delivery. RIS/VITD3-PAMAM-G5-NH 2 inhalation therapy was able to restore serum calcium, phosphorus, and BMD close to normal levels after 21 days of treatment in OP-induced rats. The WNT-signalling pathway and changes in the metabolite levels recovered to approximately normal levels upon treatment. Moreover, histone acetylation of the WNT-1 gene and miR-148a-3p interference proved to play a role in the regulation of the WNT-signalling pathway during OP progression and treatment., Significance: Pulmonary delivery of RIS/VITD3-PAMAM-G5-NH 2 offers superior treatment for OP treatment compared to the oral route. Molecular and Metabolic pathways represents key indicators for OP diagnosis and progression., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Ciclesonide (CIC), an inhaled corticosteroid for bronchial asthma is currently available as metered dose inhaler (CIC-MDI) which possesses a major challenge in the management of the elderly, critically ill patients and children. In this work, nebulized CIC nano-structure lipid particles (CIC-NLPs) were prepared and evaluated for their deep pulmonary delivery and cytotoxicity to provide additional clinical benefits to patients in controlled manner and lower dose. The bio-efficacy following nebulization in ovalbumin (OVA) induced asthma Balb/c mice compared to commercial (CIC-MDI) was also assessed. The developed NLPs of 222.6 nm successfully entrapped CIC (entrapment efficiency 93.3%) and exhibited favorable aerosolization efficiency (mass median aerodynamic diameter (MMAD) 2.03 μm and fine particle fraction (FPF) of 84.51%) at lower impactor stages indicating deep lung deposition without imparting any cytotoxic effect up to a concentration of 100 μg/ml. The nebulization of 40 µg dose of the developed CIC-NLPs revealed significant therapeutic impact in the mitigation of the allergic airways inflammations when compared to 80 µg dose of the commercial CIC-MDI inhaler (Alvesco ® ). Superior anti-inflammatory and antioxidative stress effects characterized by significant decrease ( p < .0001) in inflammatory cytokines IL-4 and 13, serum IgE levels, malondialdehyde (MDA), nitric oxide (NO), TNF-α, and activated nuclear factor-κB (NF-κB) activity were obvious with concomitant increase in superoxide dismutase (SOD) activity. Histological examination with inhibition of inflammatory cell infiltration in the respiratory tract was correlated well with observed biochemical improvement.

Risedronate sodium (RS) is a potent nitrogen-containing bisphosphonate which is known to induce osteoclast apoptosis. As a drug repurposing approach, the current work explored the potential of nebulizable RS-chitosan (CS) microspheres to induce alveolar macrophage apoptosis. RS-CS microspheres were assessed for lung deposition, cytotoxicity, and cellular uptake percentage in Calu-3 cells. The potential of nebulizable microspheres for treating elastase-induced emphysema in rats was investigated, compared to RS marketed oral tablets®, with respect to histopathological, immunohistochemical, and flow cytometric studies. The in vitro lung deposition pattern suggested deep alveolar deposition of RS microspheres, with respect to high FPF% and suitable MMAD (66% and 1.506 μm, respectively, at a flow rate of 28.3 L min -1 ). No apparent cytotoxicity was observed, with a cell viability > 90%. The inhalation of RS-CS microspheres was suggested to inhibit airspace enlargement and lung rarefaction after elastase instillation and reduce the macrophage accumulation in alveolar parenchyma. Immunohistochemical and cytometric analyses revealed significant low expression levels of CD68 and CD11b surface markers, respectively, with significantly (P < 0.05) lower detected numbers of intact alveolar macrophages following inhalation of RS-CS microspheres. The nebulization of RS-CS microspheres could induce apoptosis in alveolar macrophages and be promisingly adopted for attenuation of pulmonary emphysema.

Risedronate sodium (RS) is a potent inhibitor of bone resorption, having an extreme poor permeability and limited oral bioavailability (0.62%). RS should be orally administered under fasting conditions while keeping in an upright posture for at least 30 min to diminish common gastroesophageal injuries. To surmount such limitations, novel risedronate-chitosan (RS-CS) crosslinker-free nebulizable microspheres were developed adopting the quality by design (QbD) approach and risk assessment (RA) thinking. RS:CS ratio, surfactant (Pluronic® F127) concentration, homogenization duration, speed, and temperature were identified using Ishikawa diagrams as the highest formulation and process risk factors affecting the critical quality attributes (CQAs), average particle size (PS), and entrapment efficiency (EE%). The risk factors were screened using the Plackett-Burman design, and the levels of the most significant factors were optimized using a multilevel factorial design to explore the optimized system with the least PS, maximum EE%, and a prolonged drug release profile. The optimized system (B6) was developed at a RS:CS ratio of 1:7, a surfactant concentration of 2% (w/v), and a homogenization speed of 14,000 rpm. It revealed good correlation with QbD theoretical prediction, where positively charged (47.9 ± 3.39 mV) discrete, spherical microspheres (3.47 ± 0.16 μm) having a high EE% (94.58 ± 0.19%) and prolonged RS release over 12 h (Q 12 h , 89.70 ± 0.64%) were achieved. In vivo lung deposition after intratracheal instillation of B6 confirmed the delivery of high RS percentage to rat lung tissues (87 ± 3.54%) and its persistence for 24 h. This investigation demonstrated the effectiveness of QbD philosophy in developing RS-CS crosslinker-free nebulizable microspheres.

Clopidogrel bisulfate (CB) is a golden antiplatelet treatment, yet its benefits are limited by its low bioavailability (<50%) caused by poor intestinal solubility and absorption. The present study aims to improve CB intestinal solubility and absorption through developing a novel stable dry CB procubosomes tablets ready to disintegrate and re-disperse upon dilution in the GIT forming in situ CB cubosome nanoparticles while simultaneously overcome the poor stability of conventional cubosome dispersion at room temperature. Glyceryl monooleate based CB cubosome dispersion was prepared using Poloxamer 407 as surfactant, freeze dried using different stabilizing excipients (dextrose, mannitol and avicel) then compressed into procubosome tablets. The effect of excipient's physicochemical properties on the flowability, in vitro dissolution and stability at accelerated conditions (40 ± 2 °C/75 ± 5% RH) were evaluated. The prepared procubosomes exhibited an excipient type dependent dissolution profile where Avicel based procubosome tablet CF2 showed the highest in vitro dissolution profile among other excipients used during the freeze drying process. Upon transition to intestinal pH of 6.8 to mimic the drug absorption site, CF2 procubosome Avicel tablet, was able to preserve the enhanced CB release profile (99.6 ± 6.92%) compared to commercial Plavix® where, CB dissolved % dropped dramatically to 79.1 ± 2.45%. After storage for six months, CF2 retained the fresh tablet drug content of 98.5 ± 5.82% and dissolution properties. Moreover, following oral administration in rabbits, CF2 showed higher relative bioavailability (153%) compared to commercial Plavix® with significant higher C max ,shorter t max , as well as enhanced antiplatelet activity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Clopidogrel bisulphate (CB) is a first line antiplatelet drug for treatment of myocardial infarction and stroke. Yet, its efficacy is limited by its poor solubility in intestinal pH, its main site of absorption. The main aim of this study is to enhance the intestinal release of CB by loading in cubosome nanoparticles. Glyceryl monooleate (GMO) based CB loaded cubosomes were prepared using a 3 3 factorial design to study the effect of polyvinyl alcohol (PVA), poloxamer 407 (PL407) concentrations and ratio of CB to the disperse phase on the average particle size, entrapment efficiency (%EE), in vitro release at 15 min (%Q 15 ), and their morphology using transmission electron microscopy (TEM). The release of the optimized formula was compared in buffer transition media (pH 1.2 for 2 h then pH 6.8 for 6 h) to free drug to study the effect of the changing pH in the gastrointestinal tract (GIT) on CB release. The antihaemostatic properties of the optimized formula were compared to the commercial product Plavix ® using bleeding time (BT) model in rabbits. The prepared cubosomes were in the nano range (115±6.47 to 248±4.63 nm) with high %EE (91.22±4.09% to 98.98±3.21%). The optimized formula showed significantly higher (p<0.05) CB release in intestinal pH and preserved the high% released (95.66±1.87%) in buffer transition release study compared to free drug (66.82±4.12%) as well as significantly (p<0.05) higher antihaemostatic properties with longer BT (628.47±6.12 s) compared to Plavix ® (412.43±7.97 s). Thus, cubosomes proved to be a successful platform to enhance the intestinal release of CB and improve its absorption.

Ocular topically applied Vancomycin (VCM) suffers poor bioavailability due to its high molecular weight and hydrophilicity. In the present investigation, VCM-loaded polymeric nanoparticles (PNPs) were developed aiming to enhance its ocular bioavailability through prolonging its release pattern and ophthalmic residence. PNPs were prepared utilizing double emulsion (W/O/O), solvent evaporation technique. 2 3 ×4 1 full factorial design was applied to evaluate individual and combined influences of polymer type, Eudragit® RS100, sonication time, and Span®80 concentration on PNPs particle size, encapsulation efficiency, and zeta potential. Further, the optimized formulae were incorporated in 1% Carbopol®-based gel. In-vivo evaluation of the optimized formulae was performed via Draize test followed by microbiological susceptibility testing on albino rabbits. Results revealed successful formulation of VCM-loaded PNPs was achieved with particle sizes reaching 155nm and up to 88% encapsulation. Draize test confirmed the optimized formulae as non-irritating and safe for ophthalmic administration. Microbiological susceptibility testing confirmed prolonged residence, higher C max. with more than two folds increment in the AUC (0.25-24) of VCM-PNPs over control groups. Thus, VCM-loaded PNPs represent promising carriers with superior achievements for enhanced Vancomycin ophthalmic delivery over the traditional use of commercially available VCM parenteral powder after constitution into a solution by the ophthalmologists., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Context: A microbiological multidistrict-based survey from different Egyptian governorates was conducted to determine the most prevalent causative agents of ocular infections in the Egyptian population. Antibiotic sensitivity testing was then performed to identify the most potent antimicrobial agent. Vancomycin (VCM) proved the highest activity against gram-positive Staphylococcus bacteria, which are the most commonly isolated causative agents of ocular infection. However, topically applied VCM suffers from poor ocular bioavailability because of its high molecular weight and hydrophilicity., Objective: The aim of the present study was to develop VCM-loaded solid lipid nanoparticles (SLNs) using water-in-oil-in-water (W/O/W) double emulsion, solvent evaporation technique to enhance ocular penetration and prolong ophthalmic residence of VCM., Method: Two consecutive full factorial designs (2(4) followed by 3(2)) were adopted to study the effect of different formulation and process parameters on SLN formulation. The lipid type and structure, polyvinyl alcohol (PVA) molecular weight and concentration, sonication time, as well as lipid:drug ratio were studied as independent variables. The formulated SLN formulae were evaluated for encapsulation efficiency (EE%), particle size (PS), and zeta potential as dependent variables., Results: The statistically-optimized SLN formula (1:1 ratio of glyceryltripalmitate:VCM with 1% low molecular weight PVA and 1 min sonication time) had average PS of 277.25 nm, zeta potential of -20.45, and 19.99% drug encapsulation. Scanning and transmission electron micrographs showed well-defined, spherical, homogenously distributed particles., Conclusion: The present study suggests that VCM incorporation into SLNs is successfully achievable; however, further studies with different nanoencapsulation materials and techniques would be valuable for improving VCM encapsulation.

The application of self-nanoemulsified drug delivery system (SNEDDS) to improve bioavailability of diacerein (D) has been hampered by its large dose and limited solubility. This work aimed to prepare diacerein loaded self nanoemulsifying self nanosuspension (D-SNESNS) containing high drug load. D-SNESNS was prepared by homogenizing D into Maisine™-based SNEDDS that gave the highest drug solubility. D-SNESNS was evaluated for particle size, zeta potential and in vitro dissolution. Significant increase of D solubility was observed from D-SNESNS (∼ 309 μg/mL) than traditional SNEDDS (∼162μg/mL) due to the spontaneous simultaneous formation of nanoemulsion and nanosuspension (top-down approach). When exposed to water with mild agitation, the drug microparticles in D-SNESNS are temporarily surrounded by unsaturated aqueous layer (containing optimum concentrations of surfactant and co-solvent) that facilitates the erosion of the suspended drug particles into nanosized ones. Nanoemulsion-based nanosuspension (NENS) was confirmed using transmission electron microscopy and particle size analysis. D-SNESNS equivalent to 50mg D exhibited complete and very rapid dissolution after 15 min in phosphate buffer pH 6.8 due to the existence of D as solubilized molecules inside nanoemulsion globules and nanosized suspended drug particles forming D-NENS. The relative bioavailabilities of rhein from D-SNESNS in rats with normal and blocked chylomicron flow were about 210% and 164%, respectively in comparison to aqueous D suspension. The significant increase in the dissolution, portal absorption and lymphatic delivery of D propose that SNESNS could be promising to improve oral bioavailability of poorly water soluble drugs that have limited drug load in SNEDDS., (Copyright © 2015 Elsevier B.V. All rights reserved.)