Nanocarriers significantly augment the absorption of ocular-delivered drugs: A comparative meta-analysis study.

This study presents a meta-analysis that compiles information collected from several studies aiming to prove, by evidence, that nanocarriers out-perform conventional formulations in augmenting the bioavailability of ocular topically administered drugs. Data was further categorized into two subgroups; polymeric-based nanocarriers versus their lipid-based counterparts, as well as, naturally-driven carriers versus synthetically-fabricated ones. After normalization, the pharmacokinetic factor, area under the curve (AUC), was denoted as the "effect" in the conducted study, and the corresponding Forest plots were obtained. Our meta-analysis study confirmed the absorption enhancement effect of loading drugs into nanocarriers as compared to conventional topical ocular dosage forms. Interestingly, no significant differences were recorded between the polymeric and lipidic nanocarriers included in the study, while naturally-driven nanoplatforms were proven superior to the synthetic alternatives.

Design and evaluation of chrysin-loaded nanoemulsion against lithium/pilocarpine-induced status epilepticus in rats; emphasis on formulation, neuronal excitotoxicity, oxidative stress, microglia polarization, and AMPK/SIRT-1/PGC-1α pathway.

OBJECTIVES: The present study aims to formulate and evaluate the efficacy of chrysin-loaded nanoemulsion (CH NE) against lithium/pilocarpine-induced epilepsy in rats, as well as, elucidate its effect on main epilepsy pathogenesis cornerstones; neuronal hyperactivity, oxidative stress, and neuroinflammation. METHODS: NEs were characterized by droplet size, zeta potential, pH, in vitro release, accelerated and long-term stability studies. Anti-convulsant efficacy of the optimized formula and underlying mechanisms involved were assessed and compared to that from CH suspension given orally at a 30 folds higher dose. RESULTS: Optimized formula displayed a droplet size of 48.09 ± 0.83 nm, PDI 0.25 ± 0.011, sustained release, and good stability. CH treatment reduced seizures scoring, corrected behavioral and histological changes induced by Li/Pilo. Moreover, CH restored neurotransmitters balance and oxidative stress markers levels. Besides, CH induced microglia polarization from M1 to M2 hindering inflammation induced by Li/Pilo. Also, CH restored energy metabolism homeostasis via regulating protein expression of AMPK/SIRT-1/PGC-1α pathway markers. CH NE formulation was found to significantly enhance drug delivery to rats' hippocampus compared to CH suspension. CONCLUSION: Our findings prove the therapeutic efficacy of CH NE at a lower dose which could be a potential brain targeting platform to combat epilepsy.

Nanostructured Lipid Carriers for Oral Delivery of a Corticosteroid: Role of Formulation on Biopharmaceutical Performance.

Corticosteroids are potent anti-inflammatory and immunosuppressive drugs widely used world-wide for treatment of diverse conditions. However, their use is restricted by their poor bioavailability and high risk-benefit ratio. Therefore, the aim of this study was to develop nanostructred lipid carriers (NLC) of prednisolone acetate (PA) to improve the drug's therapeutic outcome by altering its pharmacokinetic profile and/or allow preferential targeting to inflammatory tissues. PA-loaded NLCs were formulated by solvent injection method using Compritol (solid lipid), oleic acid (liquid lipid) and Tween 80 or Pluronic F68 (surfactant). Formulation conditions, such as liquid lipid concentration, total lipids, drug:lipid ratio and surfactant type were optimized based on particle size (PS), polydispersity index (PDI), and encapsulation efficiency (EE%) results. Optimized formulation was further characterized for its surface morphology, thermal properties, storage stability and anti-inflammatory activity in an animal acute inflammation model. Selected NLCs displayed PS of 170.7 nm, EE% of 67.4%, sustained release over 72 h and good stability for 30 days at refrigeration conditions. PA NLCs displayed superior anti-inflammatory activity of 83.9 ± 4.46% compared to PA suspension (40.5 ± 7.03%) and drug-free NLCs (54.7 ± 6.12%). The current work delineates the potential of NLCs for distinctly improved biopharmaceutical performance of PA.

"Spanlastic nanovesicles for enhanced ocular delivery of vanillic acid: design, in vitro characterization, and in vivo anti-inflammatory evaluation".

Spanlastics are novel surfactant-based, elastic vesicular nanocarriers composed of spans and edge activators. The present work aims to exploit their special penetration enhancing properties to enhance the ophthalmic delivery of the versatile nutraceutical vanillic acid (VA), for treatment of ocular inflammation. VA-loaded spanlastics were formulated by ethanol injection method using Tween 80, sodium deoxy cholate or Tween 60 as edge activators (EA) at various Span 60: EA mass ratios. Vesicles were characterized for their particle size (PS), polydispersity index (PDI), zeta potential, entrapment efficiency (EE%), surface morphology, in vitro release profile, thermal properties and long-term stability, in addition to in vivo anti-inflammatory efficacy of the selected formula in an endotoxin-induced uveitis model. Selected formulation composed of Span 60: Tween 80 at a mass ratio of 70:30 displayed smallest PS of 299.8 ± 9.97 nm, PDI of 0.386 ± 0.047, an acceptable EE%, as well as good physical stability for 3 months. According to clinical scoring, inflammatory mediators levels and histopathological examination, VA-loaded spanlastic formulation resulted in significant alleviation of inflammation compared to drug suspension (p < 0.05). Formulation of VA into spanlastic nanoformulation is a promising approach to improve its ocular permeability, absorption and anti-inflammatory activity providing a safer alternative to current regimens.

Nose-to-brain delivery of chrysin transfersomal and composite vesicles in doxorubicin-induced cognitive impairment in rats: Insights on formulation, oxidative stress and TLR4/NF-kB/NLRP3 pathways.

Many cancer survivors suffer from chemotherapy-induced cognitive impairment known as 'Chemobrain'. Doxorubicin -topoisomerase II inhibitor- is widely used in breast cancer, hematological cancers and other neoplasms. However, it is reported to precipitate cognitive impairment in cancer patients via inducing oxidative stress and inflammatory response. Chrysin -5,7 dihydroxyflavone- has promising antioxidant, anti-inflammatory and anticancer properties, but suffers low bioavailability owing to its poor solubility and extensive metabolism. In the present study, chrysin was successfully formulated as transfersomal lipid vesicles and chitosan composite vesicles (CCV) exhibiting a nanometric size range, high drug entrapment efficiency, and controlled release over a 72h period. Intranasal administration of optimized chrysin formulations at a reduced dose of 0.5 mg/kg improved doxorubicin-induced memory impairment in rats evidenced by behavioral testing, inhibition of acetylcholinesterase activity and oxidative stress markers; catalase, reduced glutathione, lipid peroxidation and hydrogen peroxide. This could reduce caspase-3 expression inhibiting apoptosis. Moreover, chrysin formulations were able to inhibit doxorubicin-induced Tol-like receptor 4 (TLR4) and p65 subunit of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) protein expression which in turn, reduced procaspase-1, Cysteinyl Aspartate Protease-1 (caspase-1) and Interleukin-1ß (IL-1ß) protein expression via inhibiting Nod-like receptor pyrin containing 3 (NLRP3) inflammasome. Collectively, our findings suggest the enhanced therapeutic potential of chrysin when formulated as transfersomes and CCV against chemotherapy-induced chemobrain via hindering acetylcholinesterase, oxidative stress and TLR4-NF-kB(p65)-NLRP3 pathways.

The Role of Surface Active Agents in Ophthalmic Drug Delivery: A Comprehensive Review.

With the significant advances made in nanotechnology, research efforts focused on developing novel drug delivery platforms that can overcome the multitude of challenges encountered in ophthalmic drug delivery. Surface active agents (SAAs) have been extensively used for the formulation of many of the dosage forms targeting ocular tissues. Novel ophthalmic carriers utilizing SAAs were broadly classified into particulate, vesicular, and controlled release drug delivery systems. Depending on their physicochemical properties, SAAs can perform a variety of roles ranging from wetting agents, emulsifiers, stabilizers, charge inducers, solubilizers, antimicrobial agents, corneal permeation enhancers, and gelling agents. Nevertheless, their use is limited by their potential toxicity and possible interactions with other formulation ingredients. This review provides a comprehensive analysis of the different functional roles of SAAs in novel ophthalmic drug delivery platforms, their mechanism of action, and limitations that need to be considered during formulation to maximize their potential benefit. Understanding the mechanisms by which they perform their different roles and the possible interactions between SAAs and other formulation ingredients can help orientate the choice of formulators toward the SAA most suitable for the intended ocular application at a concentration that is both safe and effective.

Polysaccharides-based nanocomplexes for the prolonged delivery of enoxaparin: In-vitro and in-vivo evaluation.

Thromboprophylaxis and anticoagulant therapy face serious medical challenges in terms of how crucial it is to maintain therapeutic activity of the anticoagulant agent over the required period of time. Failure to do so will lead to an increased risk of clot propagation if a subtherapeutic drug level is reached. On the other hand, higher-than intended anticoagulation levels might lead to an enhanced risk of hemorrhagic complications. Nanocomplexes (NCs) for the controlled delivery of the antithrombotic Enoxaparin (Enox) with dextran sulfate (DS) and chitosan (CS) were formulated, in an attempt to circumvent therapeutic and compliance challenges associated with the prolonged administration of the current dosage form. Using polyelectrolyte complexation method, various fabrication and formulation parameters were tested. Assessment of ex-vivo stability of selected formulae in rat serum was done prior to determination of their pharmacokinetic profile. High EE% was achieved in all systems prepared. In absence of DS, target size was obtained when 0.54mg/mL CS at an initial pH of 5 and Enox to CS mass ratio of 1:2.5 were employed at room temperature. These parameters were shifted to new optima upon introduction of DS. The anticoagulant activity of NCs (in absence/presence of DS) was significantly sustained compared to the market product (135 and >144h versus 5h, respectively).

Passive targeting and lung tolerability of enoxaparin microspheres for a sustained antithrombotic activity in rats.

Pulmonary bed can retain microparticles (MP) larger than their capillaries' diameter, hence we offer a promising way for lung passive targeting following intravenous (IV) administration. In this study, enoxaparin (Enox)-albumin microspheres (Enox-Alb MS) were, optimally, developed as lung targeted sustained release MP for IV use. Lung tolerability and targeting efficiency of Enox-Alb MS were tested, and the pharmacokinetic profile following IV administration to albino rats was constructed. In vivo studies confirmed high lung targeting efficiency of Enox-Alb MS with lack of potential tissue toxicity. The anticoagulant activity of the selected Alb MS was significantly sustained for up to 38 h compared to 5 h for the market product. Alb MS are promising delivery carriers for controlled and targeted delivery of Enox to the lungs for prophylaxis and treatment of pulmonary embolism.

Low molecular weight heparins for current and future uses: approaches for micro- and nano-particulate delivery.

Low molecular weight heparins (LMWHs), the anticoagulant drug of choice in many indications, had been suggested as novel drug treatment for a range of diseases. Their superior pharmacokinetic properties compared to unfractionated heparin (UFH), motivated scientists to explore new delivery systems for improved therapeutic outcomes. Micro- and nano-carriers, with the versatile nature and characteristics of materials used for their fabrication, are able to surmount the challenges opposed by their native structures. The present review discusses the recent perspectives on the development of micro- and nano-particulate vectors for the delivery of LMWHs through various routes. Special focus on the application of the suggested systems, their characterization and the achieved improved bioavailability will be given throughout the review.

Comparative effects of different cosurfactants on sterile prednisolone acetate ocular submicron emulsions stability and release.

Pluronic F68 is a nonionic, thermogelling block copolymer showing a high dehydration resistance during autoclaving due to its high cloud point (>100 degrees C). Tween 80 (with cloud point of 72.5 degrees C), is a polyoxyethylene-based cosurfactant, susceptible to temperature because of a decrease in its solubility by temperature increase. This study was done to explore whether or not, when compared with Tween 80, Pluronic F68 could be used blindly as a suitable cosurfactant for the preparation of terminally sterilized ocular submicron emulsions containing a lipid soluble drug, prednisolone acetate (PA). Various oils of variable viscosities were also tried. The results proved that no prediction can be made based on previously known physico-chemical properties alone and that emulsion stability depends on the contribution of the various emulsion components including: oil, surfactant and cosurfactant, in addition to the drug properties.