Novel composite fatty acid vesicles-in-Pluronic lecithin organogels for enhanced magnolol delivery in skin cancer treatment.

A novel composite carrier composed of Pluronic lecithin organogels and fatty acid vesicles was used to enhance the stability and facilitate the topical delivery of a natural bioactive drug, magnolol (Mag), for treatment of skin cancer. Jojoba oil was incorporated in the organogel (OG) base to provide a synergistic effect in treatment of skin cancer. The organoleptic properties, rheological behavior, morphology, and drug content of the OG formulations were investigated with emphasis on the impact of vesicle loading on the OG characteristics. The effect of OG on Mag release and ex-vivo permeation studies were evaluated and compared to free Mag in OG. The biological anti-tumor activity of the OG formulae was assessed using a skin cancer model in mice. All OG formulations exhibited uniform drug distribution with drug content ranging from 92.22 ± 0.91 to 100.45 ± 0.77 %. Rheological studies confirmed the OG shear-thinning flow behavior. Ex-vivo permeation studies demonstrated that the permeation of Mag from all OG formulations surpassed that obtained with free Mag in the OG. The anti-tumor activity studies revealed the superior efficacy of 10-hydroxy-decanoic acid (HDA)-based vesicles incorporated in OG formulations in mitigating 7,12- dimethylbenz(a)anthracene (DMBA)-induced skin cancer, thereby offering a promising platform for the local delivery of Mag.

WITHDRAWN: Resveratrol-based Delivery Systems as Contemporary Nominees for Combating Pulmonary Diseases: A Comprehensive Review

Since the authors are not responding to the editor's requests to fulfill the editorial requirement, therefore, the article has been withdrawn of the journal "Current Drug Delivery".Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused.The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php BENTHAM SCIENCE DISCLAIMER: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Do the chitosan nanoparticles really augment the drugs' transdermal fluxes: ending the debate using meta-analysis.

INTRODUCTION: Transdermal delivery has been extensively investigated as a successful alternative to the oral and parenteral routes of administration. The use of polymeric nanoparticles as drug delivery systems through this route has always been controversial. The use of meta-analyses is a useful quantitative means to decide upon the efficiency of this type of vehicles transporting drugs through the skin. AREAS COVERED: In this meta-analysis study, polymeric nanoparticles were quantitatively compared to conventional formulations in order to investigate the feasibility of using these particles in transdermal delivery. Natural versus synthetic polymeric sub-groups were also contrasted to determine the most efficient class for transdermal drug enhancement. EXPERT OPINION: Meta-analyses are gaining ground in the drug delivery field as they can exploit the mines of the literature and pick up by statistical evidence the superior formulations administered through several routes of administration. This is the first study that utilized the transdermal fluxes as the meta-analysis study effect and could prove the superiority of natural polymeric nanoparticles in transdermal delivery. In our opinion, there is paucity in research work regarding this type of nanocarriers, specifically on chitosan nanoparticles. More studies are warranted for full exploitation of its benefits.

Engineering a novel water-in-oil biocompatible microemulsion system for the ocular delivery of dexamethasone sodium phosphate in the treatment of acute uveitis.

Due to their unique characteristics, microemulsions (ME) represent one of the most promising delivery systems which can conquer poor ocular drug bioavailability providing long residence time. Development of a ME system, relying on the use of a safe and non-irritant surfactant combination derived from sustainable resources and which can consolidate the small ME droplets, is the goal of this work. Herein, we report the design and characterization of a novel biocompatible, eco-friendly ME system loaded with the hydrophilic dexamethasone sodium phosphate (DEXP) using a novel surfactant mixture composed of D-α-tocopherol polyethylene glycol succinate (TPGS) and Plantacare® (coco-Glycosides). Capryol™ PGMC and double-distilled water were used as the respective oil and aqueous phases and the MEs were prepared by the water titration method, suitable for scaling up. Optimization of ME formulae was conducted by varying Plantacare® grades, TPGS to Plantacare® mass ratios and drug loading. The formulae were characterized in terms of physical appearance, droplet size (PS), size distribution (PDI), zeta potential (ZP), and stability. The optimized DEXP-loaded ME formula attained acceptable PS, PDI, and ZP values of 43 ± 5 nm, 0.35 ± 0.07, -12 ± 4 mV, respectively. TEM images confirmed a small PS ≤ 100 nm. The in vivo safety of ME was proved by the Draize test. The ME formula prompted excellent mucoadhesion and transcorneal permeation. The confocal studies showed deep penetration into the rabbits' corneas. In vivo studies using endotoxin-induced uveitis showed high ocular efficacy and a significant reduction in inflammatory cells, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The obtained results elect the novel engineered ME system as a promising tool for the ocular delivery of hydrophilic moieties in the management of various ophthalmic diseases.

Glycerospanlastics: State-of-the-art two-in-one nano-vesicles for boosting ear drug delivery in otitis media treatment.

The purpose of this research was to design innovative nanovesicles for ototopical conveyance of triamcinolone acetonide (TA) for otitis media (OM) treatment via incorporating glycerol into nanospanlastics to be termed "Glycerospanlastics". The glycerospanlastics were formulated employing ethanol injection procedure, and central composite design (CCD) was harnessed for optimization of the vesicles. Various attributes of the nanovesicles, viz. particle size distribution, surface charge, TA entrapment efficiency, morphology as well as ex-vivo permeation across the tympanic membrane (TM) were characterized. In vivo implementation of the optimized glycerospanlastics loaded with TA was appraised in OM-induced rats via histopathological and biochemical measurements of the tumor necrosis factor-α (TNF-α) and Interleukin-1ß (IL-1ß) levels in ear homogenates. The safety and tolerability of optimized TA glycerospanlastics was also investigated in non-OM induced animals. The results demonstrated that the optimized TA-glycerospanlastics were in a nanometer range (around 200 nm) with negative charges, high TA entrapment (>85%), good storage properties and better TM permeation relative to TA suspension. More importantly, TA-glycerospanlastics performed better than marketed drug suspension in OM treatment as manifested by restoration of histopathological alterations in TM and lowered values of IL-1ß and TNF-α. Glycerospanlastics could be promising safe ototopical nanoplatforms for OM treatment and other middle ear disorders.

Customizable resveratrol spray-dried micro-composites for inhalation as a promising contender for treatment of idiopathic pulmonary fibrosis.

The past decades have witnessed tremendous expansion in utilization of plant-derived medicines as resveratrol (RES) in treating several diseases like idiopathic pulmonary fibrosis (IPF). RES can exhibit its role in treating IPF via its outstanding antioxidant and anti-inflammatory activities. The goal of this work was to formulate RES-loaded spray-dried composite microparticles (SDCMs) suitable for pulmonary delivery via dry powder inhaler (DPI). They were prepared by spray drying of a previously prepared RES-loaded bovine serum albumin nanoparticles (BSA NPs) dispersion using different carriers. RES-loaded BSA NPs, prepared by the desolvation technique, acquired suitable particle size of 177.67 ± 0.95 nm and entrapment efficiency of 98.7 ± 0.35% with perfectly uniform size distribution and high stability. Considering the attributes of the pulmonary route, NPs were co-spray dried with compatible carriers viz. mannitol, dextran, trehalose, leucine, glycine, aspartic acid, and glutamic acid to fabricate SDCMs. All formulations showed suitable mass median aerodynamic diameter<5 µm; that is suitable for deep lung deposition. However, the best aerosolization behavior was attained from using leucine with fine particle fraction (FPF) of 75.74%, followed by glycine with FPF of 54.7%. Finally, a pharmacodynamic study was conducted on bleomycin-induced mice, and it strongly revealed the role of the optimized formulations in alleviating PF through suppressing the levels of hydroxyproline, tumor necrosis factor-α and matrix metalloproteinase-9 with obvious improvements in the treated lung histopathology. These findings indicate that in addition to leucine, the glycine amino acid, which is not commonly used yet, is very promising in the formulation of DPIs.

10-Hydroxy Decanoic Acid-Based Vesicles as a Novel Topical Delivery System: Would It Be a Better Platform Than Conventional Oleic Acid Ufasomes for Skin Cancer Treatment?

10-hydroxy decanoic acid (HDA), a naturally derived fatty acid, was used for the preparation of novel fatty acid vesicles for comparison with oleic acid (OA) ufasomes. The vesicles were loaded with magnolol (Mag), a potential natural drug for skin cancer. Different formulations were prepared using the thin film hydration method and were statistically evaluated according to a Box-Behnken design in terms of particle size (PS), polydispersity index (PDI), zeta potential (ZP), and entrapment efficiency (EE). The ex vivo skin permeation and deposition were assessed for Mag skin delivery. In vivo, an assessment of the optimized formulae using 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin cancer in mice was also conducted. The PS and ZP of the optimized OA vesicles were 358.9 ± 3.2 nm and -82.50 ± 7.13 mV compared to 191.9 ± 6.28 nm and -59.60 ± 3.07 mV for HDA vesicles, respectively. The EE was high (>78%) for both types of vesicles. Ex vivo permeation studies revealed enhanced Mag permeation from all optimized formulations compared to a drug suspension. Skin deposition demonstrated that HDA-based vesicles provided the highest drug retention. In vivo, studies confirmed the superiority of HDA-based formulations in attenuating DMBA-induced skin cancer during treatment and prophylactic studies.

Travoprost Liquid Nanocrystals: An Innovative Armamentarium for Effective Glaucoma Therapy.

To date, the ophthalmic application of liquid crystalline nanostructures (LCNs) has not been thoroughly reconnoitered, yet they have been extensively used. LCNs are primarily made up of glyceryl monooleate (GMO) or phytantriol as a lipid, a stabilizing agent, and a penetration enhancer (PE). For optimization, the D-optimal design was exploited. A characterization using TEM and XRPD was conducted. Optimized LCNs were loaded with the anti-glaucoma drug Travoprost (TRAVO). Ex vivo permeation across the cornea, in vivo pharmacokinetics, and pharmacodynamic studies were performed along with ocular tolerability examinations. Optimized LCNs are constituted of GMO, Tween® 80 as a stabilizer, and either oleic acid or Captex® 8000 as PE at 25 mg each. TRAVO-LNCs, F-1-L and F-3-L, showed particle sizes of 216.20 ± 6.12 and 129.40 ± 11.73 nm, with EE% of 85.30 ± 4.29 and 82.54 ± 7.65%, respectively, revealing the highest drug permeation parameters. The bioavailability of both attained 106.1% and 322.82%, respectively, relative to the market product TRAVATAN®. They exhibited respective intraocular pressure reductions lasting for 48 and 72 h, compared to 36 h for TRAVATAN®. All LCNs exhibited no evidence of ocular injury in comparison to the control eye. The findings revealed the competence of TRAVO-tailored LCNs in glaucoma treatment and suggested the potential application of a novel platform in ocular delivery.

Ethyl lauroyl arginate-based hydrophobic ion pair complex in lipid nanocapsules: A novel oral delivery approach of rosmarinic acid for enhanced permeability and bioavailability.

Limited oral bioavailability due to high hydrophilicity restricts the beneficial use of Rosmaranic acid (RM) that is characterized by many biological and pharmacological effects. The present work was addressed to extract RM from Rosmarinus officinalis L. leaves and then increase its lipophilicity and permeability through the application of hydrophobic ion pair (HIP) approach using ethyl lauroyl arginate (ELA) as a novel counter-ion. Different RM:ELA ratios were screened to optimize HIP formation process. The encapsulation of the optimized HIP into lipid nanocapsules (LNCs) was then achieved to facilitate oral administration. The results of % transmittance, % complexation efficiency (87.32 ± 0.19%) and partition coefficient revealed the successful formation of the HIP complex occurred at RM:ELA molar ratio of 1:2. The formed HIP was successfully loaded into spherical small sized (39.32 ± 0.18 nm) LNCs. The ex vivo permeability studies across porcine intestine showed that the cumulative RM amount permeated/area after 6 h from HIP and LNCs were 3.79 ± 0.57 and 5.71 ± 0.32 µg/cm2, respectively. Pharmacokinetic study results showed that the maximum RM concentrations in plasma (Cmax) can be arranged in a descending manner as follows; 61.33 ± 8.89 < 42.13 ± 11.22 < 20.96 ± 3.12 ng/ml attained after 4.80, 8.00 and 10.40 h in case of LNC, HIP and solution, respectively. Moreover, the HIP and LNC formulae showed higher total drug amounts in plasma reaching 1.46 and 1.88-fold relative to RM solution, respectively. In conclusion, the HIP complex and HIP loaded LNCs prosper in enhancing the permeability and absorption of the low permeable drugs.

Engineered triamcinolone acetonide loaded glycerosomes as a novel ear delivery system for the treatment of otitis media.

Ear-oriented therapeutics vehiculation strategies are requisites for effective treatment of various otic ailments including otitis media (OM). Conquering minimal permeability of the intrinsic barrier of middle ear; intact tympanic membrane (TM) is still a defiance. In this study, the fabrication of glycerosomes was explored to boost triamcinolone acetonide (TA) delivery to the middle ear via the otic application to improve treatment of OM. Opting a d-optimal design, TA glycerosomes were formulated and optimized using ethanol injection method. The optimized formula was assessed for morphology, viscosity, ex vivo TM permeation and deposition and physical stability. Moreover, OM induction in rats using lipopolysaccharides was conducted, histological and biochemical investigations were performed to assess the therapeutic potential of TA glycerosomes and their tolerability as well. The optimized formula displayed a nanosized value (106.1 ± 2.82), low polydispersity index (0.079 ± 0.04), satisfactory drug entrapment efficiency (80.62 ± 4.41 %), shear thinning behavior and excellent physical stability. Ex-vivo TM permeation and deposition monitoring for 24 h demonstrated greater flux and deposition compared to free drug. More importantly, the in vivo studies demonstrated the supremacy of glycerosomes with respect to tolerability and efficacy in alleviating OM following ototopical application compared to marketed drug. Such therapeutic modality represents a promising option to boost the efficacy of otic drugs, awaiting clinical translation.

Chitosan nanoparticles for intranasal delivery of olmesartan medoxomil: Pharmacokinetic and pharmacodynamic perspectives.

Nasal drug delivery has the potential to improve the systemic bioavailability of drugs with low oral bioavailability. Olmesartan medoxomil (OLM) is one of the most popular drugs for the treatment of hypertension with poor oral bioavailability of approximately 26 %. In this context, the goal of this work was to synthesize chitosan nanoparticles (CS NPs) loaded with OLM using the ionotropic gelation method to enhance the bioavailability and decrease oral side effects through nasal route. The particle size (PS), zeta potential (ZP), entrapment efficiency (%EE), and ex-vivo transmucosal permeation study of CS NPs were all evaluated. The pharmacokinetic and pharmacodynamic studies of selected formula compared to oral and nasal OLM suspensions were conducted. Successful formation of spherically shaped OLM CS NPS in the nano-range (240.02-344.45 nm) favorable for the intranasal absorption with high %EE (75.2-83.51 %) was achieved. The ability of OLM CS NPs to permeate efficiently across the nasal mucosa was proven in an ex vivo permeation experiment. Pharmacokinetic study demonstrated that the intranasal administration of OLM CS NPs exhibited improved bioavailability by 11.3-folds relative to oral OLM suspension as indicated by higher AUC value. The superior effect of intranasal OLM CS NPs was also accentuated in l-NAME induced hypertensive rats compared to intranasal and oral OLM suspension by reducing the high blood pressure (BP) and improving the heart rate (HR) of the induced group. Histological examinations revealed no damage occurred to nasal mucosa. In conclusion, OLM CS NPs had the ability to significantly improve the bioavailability of OLM and decrease BP and HR, suggesting the potential application of CS NPs as a promising carrier for the systemic delivery of OLM via intranasal route.

Evaluation of lyophilized royal jelly and garlic extract emulgels using a murine model infected with methicillin-resistant Staphylococcus aureus.

The limited therapeutic options associated with methicillin-resistant Staphylococcus aureus (MRSA) necessitate search for innovative strategies particularly, use of natural extracts such as lyophilized royal jelly (LRJ) and garlic extract (GE). Therefore, out study aimed to formulate emulgels containing different concentrations of both LRJ and GE and to evaluate their activities using a murine model infected with MRSA clinical isolate. Four plain emulgel formulas were prepared by mixing stearic acid/yellow soft paraffin-based O/W emulsion formulae based on Carbopol 940, Na alginate, Na carboxymethylcellulose or Hydroxypropyl methyl cellulose E4. Sodium alginate-based emulgel was selected for preparation of four medicated emulgel formulations combining LRJ and GE at four different concentrations. The selected medicated emulgels were used for the in vivo studies. The emulgel formulated with Na alginate and HPMC (MF3) exhibited optimum smooth homogeneous consistency, neutral pH, acceptable viscosity, spreadability, extrudability values and best storage stability properties. In vivo results revealed that, the wounds infected with MRSA isolate in rates were wet (oozing) and showed pus formation when compared to injured uninfected wounds. MF3 formula containing 4% LRJ and 50% GE showed the maximum wound healing properties, both in the apparent physical wound healing measurements and in the histopathological examination. In conclusion, the medicated emulgel formulation (MF3) prepared with Na alginate was found optimum for topical application. MF3 formula containing 4% LRJ and 50% GE has shown the highest in vivo wound healing capacities. Further clinical studies should be conducted to prove both its safety and efficacy and the potential use in human.

Moxifloxacin-loaded in situ synthesized Bioceramic/Poly(L-lactide-co-ε-caprolactone) composite scaffolds for treatment of osteomyelitis and orthopedic regeneration.

High local intraosseous levels of antimicrobial agents are required for adequate long-term treatment of chronic osteomyelitis (OM). In this study, biodegradable composite scaffolds of poly-lactide-co-ε-caprolactone/calcium phosphate (CaP) were in-situ synthesized using two different polymer grades and synthesis pathways and compared to composites prepared by pre-formed (commercially available) CaP for delivery of the antibiotic moxifloxacin hydrochloride (MOX). Phase identification and characterization by Fourier transform infra-red (FTIR) spectroscopy, X-ray powder diffraction (XRPD) and scanning electron microscope (SEM) confirmed the successful formation of different CaP phases within the biodegradable polymer matrix. The selected in-situ formed CaP scaffold showed a sustained release for MOX for six weeks and adequate porosity. Cell viability study on MG-63 osteoblast-like cells revealed that the selected composite scaffold maintained the cellular proliferation and differentiation. Moreover, it was able to diminish the bacterial load, inflammation and sequestrum formation in the bones of OM-induced animals. The results of the present work deduce that the selected in-situ formed CaP composite scaffold is a propitious candidate for OM treatment, and further clinical experiments are recommended.

Chitosan-calcium phosphate composite scaffolds for control of post-operative osteomyelitis: Fabrication, characterization, and in vitro-in vivo evaluation.

Osteomyelitis is a progressive inflammatory disease requiring prolonged systemic treatment with high antibiotic doses, and is very challenging to be treated. The use of locally applied antibiotics loaded on a biodegradable carrier at surgery sites is hypothesized to prevent post-operative osteomyelitis, while providing site-specific drug release. In this work, chitosan-based calcium phosphate composites were prepared and loaded with moxifloxacin hydrochloride. The in-situ formation of calcium phosphates within the composite was experimentally confirmed by Fourier transform infra-red spectroscopy, X-ray powder diffraction, and scanning electron microscopy. Results showed that the composites provided complete drug release over three days, and the selected composite formulation induced differentiation and proliferation of osteoblasts, while reducing bacterial count, inflammation and intra-medullary fibrosis in bone tissue specimens of osteomyelitis-induced animal model. Hence, we can conclude that the in situ prepared antibiotic-loaded calcium phosphate chitosan composite is promising in preventing post-operative osteomyelitis, and is worthy of clinical experimentation.

Delineating penetration enhancer-enriched liquid crystalline nanostructures as novel platforms for improved ophthalmic delivery.

Liquid crystalline nanostructures (LCNs), for instance cubosomes, have been widely used as a promising carrier for drug delivery through the last few years. To date, the ophthalmic application of these platforms was not well explored, and the effect of integrating penetration enhancers (PEs) into LCNs has not been investigated yet. Hence, the present work aimed coupling novel PEs into glyceryl monooleate-based cubosomes for ocular administration. Various enhancers viz, free fatty acids (oleic and linoleic acids), natural terpenes (D-limonene and cineole), medium-chain triglycerides (Captex® 1000 and Captex® 8000), mono-/di-glycerides (Capmul® MCM, Capmul® PG-8, and Capmul® PG-12) were tested at different amounts. The morphology of the formed LCNs was investigated using transmission electron microscopy (TEM). The crystallinity and thermal behavior studies were also conducted. The ocular safety of optimized formulae was tested via hen's egg test-chorioallantoic membrane (HET-CAM), rabbit eye Draize test, and histopathological examinations of ocular tissues. Confocal laser scanning microscopy (CLSM) was utilized to assess the enhanced permeation of fluorescently-labeled LCNs across corneal layers. The acceptable formulations exhibited relatively homogenous particle nano-sizes ranging from 139.26 ± 3.68 to 590.56 ± 24.86 nm carrying negative surface charges. TEM images, X-ray patterns and DSC thermograms demonstrated the influential effect of PEs in developing altered crystalline structures. The ocular compatibility of optimized LCNs was confirmed. The corneal distribution using CLSM proved the disseminated fluorescence intensity of LCNs enriched with oleic acid, Captex® 8000 and Capmul® MCM. Selected LCNs showed good physical stability upon storage and lyophilization. The results demonstrated the efficiency of tailored PE-modified LCNs in enhancing the ocular transport with no evidence of any irritation potential, and hence suggested their prospective applicability in ophthalmic drug delivery.

Microparticles-in-Thermoresponsive/Bioadhesive Hydrogels as a Novel Integrated Platform for Effective Intra-articular Delivery of Triamcinolone Acetonide.

Intra-articular (IA) injection of thermoresponsive hydrogels coupled with microparticles (MPs) possess the benefit of sustaining the anti-inflammatory drug effect within the joint cavity for rheumatoid arthritis treatment. Star-shaped thermoresponsive poly(polyethylene glycol) methacrylate [Poly(PEGMA)] copolymers were synthesized using free radical polymerization technique and fully characterized. Triamcinolone acetonide (TA)-loaded PLA/mPEG-PDL MPs, previously optimized, were integrated into the synthesized copolymer solutions at various concentrations and tested for their gelation temperatures. The MPs-in-hydrogel formulations were characterized using scanning electron microscope (SEM), viscosity measurements, ex vivo bioadhesion, and in vitro release studies. The anti-inflammatory effect of integrated systems was assessed in adjuvant-induced monoarthritic rat knee joints and compared to Kenacort and TA-loaded MPs. Two copolymers were successfully synthesized; G-1 = poly(PEGMA188-ME-co-PEGMA475-ME) and G-2 = poly(PEGMA246-EE-co-PEGMA475-ME). Using the tube inversion technique, the gel formation was found dependent on copolymer concentration. An irreversible aggregation was obtained at copolymer concentrations ≤10% (w/v), while a gel was formed at 20 and 30% (w/v) of both copolymers upon increasing temperature. The MP-hydrogel formulations were optimized at 20 and 30% (w/v) of G-1 and G-2 with gelation temperatures of 33 and 37 °C, respectively. SEM images revealed the porous microstructures of hydrogels and their adsorption on MP surfaces. The integrated formulas showed pseudoplastic behaviors, while the bioadhesion study confirmed their bioadhesiveness on excised cartilage. The in vitro release study confirmed drug sustainment from MPs-hydrogels compared to MPs. In vivo studies proved the superiority of MP-in-hydrogels in treatment of induced arthritis, relative to Kenacort and MPs alone, suggesting the applicability of this integrated platform in IA drug delivery.

Boosting transdermal delivery of atorvastatin calcium via o/w nanoemulsifying system: Two-step optimization, ex vivo and in vivo evaluation.

A nanoemulsion system was designed for Atorvastatin calcium (ATOR) transdermal delivery to overcome its poor bioavailability of (30%) resulting from the extensive first-pass effect and dissolution rate-limited in vivo absorption. Pseudo ternary phase diagrams were developed, and various NE formulae were prepared using oleic acid (OA), Tween 80 as surfactant and PEG 400 as cosurfactant, ethanol and limonene as permeation enhancers (PEs). NEs were characterized for morphology, droplet size, zeta potential and in vitro release. The optimized formulae were assessed for ex vivo transdermal permeation and in vivo pharmacodynamic/pharmacokinetic studies. Hypocholesterolemic effect after 7 days skin treatment was detected and compared to oral ATOR dispersion. Finally, blood plasma levels were measured for 24 h for rats received the selected transdermal NE and transdermal drug in OA. The obtained results suggested the low potentiality of NE systems in transdermal delivery of lipophilic drugs, only the addition of PEs is driving factor for increasing drug flux through full thickness rat skin. In the optimized formula, the presence of ethanol and PEG 400 disrupts SC lipids exhibiting rapid ex vivo release profile compared to other NEs and to ATOR in OA. In contrast, the optimized NE achieved a prolonged plasma profile. Transdermal NE was significantly more efficient than oral administration in lowering cholesterol plasma level and in increasing ATOR bioavailability. In conclusion, data revealed no correlation between ex vivo and in vivo studies explained by the collapse of the follicles in ex vivo skin permeation study, leaving only the lipoidal pathway for NE to pass through, thus only NE components, neither nanosizing nor other reported mechanisms, are the main influencing factors. In vivo experiments suggested that o/w NE changed ATOR pathway to follicular delivery leading to accumulation of NE in follicles and consequently a prolonged plasma profile.

Triamcinolone acetonide-loaded PLA/PEG-PDL microparticles for effective intra-articular delivery: synthesis, optimization, in vitro and in vivo evaluation.

Nowadays the use of sustainable polymers as poly-lactic acid (PLA) and poly-δ-decalactone (PDL) in drug delivery is advantageous compared to polymers derived from fossil fuels. The present work aimed to produce microparticles (MPs) derived from novel sustainable polymers, loaded with triamcinolone acetonide (TA) for treatment of rheumatoid arthritis via intra-articular (IA) delivery. PDL was synthesized from green δ-decalactone monomers and co-polymerized with methoxy-polyethylene glycol (mPEG) forming PEG-PDL with different molecular weights. The Hansen's solubility parameters were applied to select the most compatible polymer with the drug. An o/w emulsion/solvent evaporation technique was used for MPs fabrication, using 3 [3] full factorial design. Selection of the optimized MPs was performed using Expert Design® software's desirability function. The optimized formulations were characterized using scanning electron microscope, powder X-ray diffraction, differential scanning calorimetry, infrared spectroscopy and in vitro release studies. The inhibition percents of inflammation and histopathological studies were assessed in complete Freund's adjuvant-induced rats' knee joints evaluating the effect of IA injections of selected MPs compared to the free drug suspension. Solubility studies revealed high compatibility and miscibility between TA and PEG-PDL1700, which was blended with PLA for convenient MPs formation. The in vitro characterization studies confirmed the formation of drug-copolymer co-crystals. The in vivo studies ensured the superiority of the newly designed composite MPs in inflammation suppression, compared to the free drug suspension and PLA MPs as well. The present study proved the advantage of using sustainable polymers in a novel combination for effective drug delivery and suggesting its usefulness in designing versatile platforms for therapeutic applications.

Tailoring novel soft nano-vesicles 'Flexosomes' for enhanced transdermal drug delivery: Optimization, characterization and comprehensive ex vivo - in vivo evaluation.

The transdermal route is a convenient non-invasive way for drug delivery, however, the hydrophobic compact nature of stratum corneum (SC) forms an obstacle hindering the diffusion of drugs particularly hydrophilic ones. Hence, the purpose of this study was to develop novel soft nano-vesicles, entitled Flexosomes, amalgamating two penetration enhancers, ethanol and one edge activator (EA) from various types and different hydrophilic-lipophilic balances. The tailored vesicles were loaded with tropisetron hydrochloride (TRO), a potent highly-soluble anti-emetic, and compared with ethosomes. Aiming to preclude the formation of rigid non-deformable mixed micelles, all critical parameters; EA type, phosphatidylcholine-to-EA molar ratio, and cholesterol concentration, were optimized proving their influences on vesicle-to-micelle transitions. The prepared formulations were characterized in terms of visual inspection, particle size, polydispersity, zeta potential, turbidity measurements, entrapment efficiency, and vesicle morphology. The permeation mechanisms were assessed by differential scanning calorimetry on isolated SC. The modified vesicles, based on ethanol and either vitamin E or PEGylated castor oil derivatives exhibited the highest transdermal fluxes confirmed by a deeply tracking to dermis using confocal laser microscopy. Both vesicles demonstrated higher bioavailability relative to ethosomes, topical and oral aqueous solutions. The findings endorsed the effectiveness of tailored nano-vesicles in boosting TRO skin transport suggesting their applicability with various drug entities for enhanced transdermal delivery.

Stealth lipid polymer hybrid nanoparticles loaded with rutin for effective brain delivery - comparative study with the gold standard (Tween 80): optimization, characterization and biodistribution.

The blood-brain barrier is considered the leading physiological obstacle hindering the transport of neurotherapeutics to brain cells. The application of nanotechnology coupled with surfactant coating is one of the efficacious tactics overcoming this barrier. The aim of this study was to develop lipid polymer hybrid nanoparticles (LPHNPs), composed of a polymeric core and a phospholipid shell entangled, for the first time, with PEG-based surfactants (SAA) viz. TPGS or Solutol HS 15 in comparison with the gold standard Tween 80, aiming to enhance brain delivery and escape opsonization. LPHNPs were successfully prepared using modified single-step nanoprecipitation technique, loaded with the flavonoid rutin (RU), extracted from the flowers of Calendula officinalis L., and recently proved as a promising anti-Alzheimer. The effect of the critical process parameters (CPP) viz. PLGA amount, Wlecithin/WPLGA ratio, and Tween 80 concentration on critical quality attributes (CQA); entrapment, size and size distribution, was statistically analyzed via design of experiments, and optimized using the desirability function. The optimized CPP were maintained while substituting Tween 80 with other PEG-SAA. All hybrid particles exhibited spherical shape with perceptible lipid shells. The biocompatibility of the prepared NPs was confirmed by hemolysis test. The pharmacokinetic assessments, post-intravenous administration to rats, revealed a significant higher RU bioavailability for NPs relative to drug solution. Biodistribution studies proved non-significant differences in RU accumulation within brain, but altered phagocytic uptake among various LPHNPs. The present study endorses the successful development of LPHNPs using PEG-SAA, and confirms the prospective applicability of TPGS and Solutol in enhancing brain delivery.