Pectin nanoparticles loaded with nitric oxide donor drug: A potential approach for tissue regeneration.

The process of wound healing and tissue regeneration involves several key mechanisms to ensure the production of new tissues with similar cellular functions. This study investigates the impact of pectin, a natural polysaccharide, and nebivolol hydrochloride (NBV), a nitric oxide (NO) donor drug, on wound healing. Utilizing ionotropic gelation, NBV-loaded pectin nanoparticles were developed following a 2231 full factorial design. The optimized formulation, determined using Design expert® software, exhibited an encapsulation efficiency percentage of 70.68%, zeta potential of -51.4 mV, and a particle size of 572 nm, characterized by a spherical, discrete morphology. An in vivo study was conducted to evaluate the effectiveness of the optimal formulation in wound healing compared to various controls. The results demonstrated the enhanced ability of the optimal formulation to accelerate wound healing. Moreover, histopathological examination further confirmed the formulation's benefits in tissue proliferation and collagen deposition at the wound site 15 days post-injury. This suggests that the developed formulation not only promotes faster healing but does so with minimal side effects, positioning it as a promising agent for effective wound healing and tissue regeneration.

Synergistic therapeutic strategies and engineered nanoparticles for anti-vascular endothelial growth factor therapy in cancer.

Angiogenesis is one of the defining characteristics of cancer. Vascular endothelial growth factor (VEGF) is crucial for the development of angiogenesis. A growing interest in cancer therapy is being caused by the widespread use of antiangiogenic drugs in treating several types of human cancer. However, this therapeutic approach can worsen resistance, invasion, and overall survival. As we proceed, refining combination strategies and addressing the constraint of targeted treatments are paramount. Therefore, major challenges in using novel combinations of antiangiogenic agents with cytotoxic treatments are currently focused on illustrating the potential of synergistic therapeutic strategies, alongside advancements in nanomedicine and gene therapy, present opportunities for more precise interference with angiogenesis pathways and tumor environments. Nanoparticles have the potential to regulate several crucial activities and improve several drug limitations such as lack of selectivity, non-targeted cytotoxicity, insufficient drug delivery at tumor sites, and multi-drug resistance based on their unique features. The goal of this updated review is to illustrate the enormous potential of novel synergistic therapeutic strategies and the targeted nanoparticles as an alternate strategy for t treating a variety of tumors employing antiangiogenic therapy.

Antibacterial and Anti-Inflammatory Activities of Thymus vulgaris Essential Oil Nanoemulsion on Acne Vulgaris.

Antibiotics are frequently used in acne treatment and their prolonged use has led to an emergence of resistance. This study aimed to investigate the use of natural antimicrobials as an alternative therapy. The antimicrobial and anti-inflammatory activities of five commonly used essential oils (EOs) (tea tree, clove, thyme, mentha and basil EOs), and their possible mechanisms of action against Cutibacterium acnes and Staphylococcus epidermidis, were explored. The effect of the most potent EO on membrane permeability was elucidated and its anti-inflammatory action, when formulated as nanoemulsion, was tested in an in vivo acne model. The in vitro studies showed that thyme EO had the most potent antimicrobial and antibiofilm activity, with phenolics and terpenoids as main antimicrobial constituents of EO. Thyme EO affected cell membrane permeability of both bacterial species, evident by the detection of the leakage of intracellular ions and membrane integrity by the leakage of nucleic acids. Morphological alteration in bacterial cells was confirmed by transmission electron microscopy. Thyme EO nanoemulsion led to the suppression of an inflammatory response in acne animal models along with a bacterial load decrease and positive histopathological changes. Collectively, thyme EO nanoemulsion showed potent antimicrobial and anti-inflammatory effects compared to the reference antibiotics, suggesting its effectiveness as a natural alternative in acne treatment.

Itraconazole-Loaded Ufasomes: Evaluation, Characterization, and Anti-Fungal Activity against Candida albicans.

Numerous obstacles challenge the treatment of fungal infections, including the uprising resistance and the low penetration of available drugs. One of the main active agents against fungal infections is itraconazole (ITZ), with activity against a broad spectrum of fungi while having few side effects. The aim of this study was to design ufasomes, oleic acid-based colloidal carriers, that could encapsulate ITZ to improve its penetration power. Employing a 2231 factorial design, the effect of three independent factors (oleic acid amount, cholesterol concentration, and ITZ amount) was investigated and evaluated for the percentage encapsulation efficiency (%EE), particle size (PS), and zeta potential (ZP). Optimization was performed using Design® expert software and the optimized ITZ-loaded ufasomes obtained had %EE of 99.4 ± 0.7%, PS of 190 ± 1 nm, and ZP of -81.6 ± 0.4 mV, with spherical unilamellar morphology and no aggregation. An in vitro microbiological study was conducted to identify the minimum inhibitory concentration of the selected formula against Candida albicans, which was found to be 0.0625 µg/mL. Moreover, the optimized formula reduced the expression of toll-like receptors-4 and pro-inflammatory cytokine IL-1ß secretion in the C. albicans-infected fibroblasts, indicating that the proposed ITZ-loaded ufasomes are a promising drug delivery system for ITZ.

Triblock Copolymer Bioinks in Hydrogel Three-Dimensional Printing for Regenerative Medicine: A Focus on Pluronic F127.

Three-dimensional (3D) bioprinting is a novel technique applied to manufacture semisolid or solid objects via deposition of successive thin layers. The widespread implementation of the 3D bioprinting technology encouraged scientists to evaluate its feasibility for applications in human regenerative medicine. 3D bioprinting gained much interest as a new strategy to prepare implantable 3D tissues or organs, tissue and organ evaluation models to test drugs, and cell/material interaction systems. The present work summarizes recent and relevant progress based on the use of hydrogels for the technology of 3D bioprinting and their emerging biomedical applications. An overview of different 3D printing techniques in addition to the nature and properties of bioinks used will be described with a focus on hydrogels as suitable bioinks for 3D printing. A comprehensive overview of triblock copolymers with emphasis on Pluronic F127 (PF127) as a bioink in 3D printing for regenerative medicine will be provided. Several biomedical applications of PF127 in tissue engineering, particularly in bone and cartilage regeneration and in vascular reconstruction, will be also discussed. Impact statement The current review highlights the use of three-dimensional (3D) bioprinting for regenerative medicine, stressing the manipulation of hydrogels as the most commonly used bioinks. The advantages and shortcomings of using hydrogels for 3D printing procedures are discussed with a particular focus on triblock copolymers and Pluronics. A brief overview of applying bioink Pluronic F127 in applications of 3D bioprinting for tissue reconstruction is also provided.

Celecoxib repurposing in cancer therapy: molecular mechanisms and nanomedicine-based delivery technologies.

While cancer remains a significant global health problem, advances in cancer biology, deep understanding of its underlaying mechanism and identification of specific molecular targets allowed the development of new therapeutic options. Drug repurposing poses several advantages as reduced cost and better safety compared with new compounds development. COX-2 inhibitors are one of the most promising drug classes for repurposing in cancer therapy. In this review, we provide an overview of the detailed mechanism and rationale of COX-2 inhibitors as anticancer agents and we highlight the most promising research efforts on nanotechnological approaches to enhance COX-2 inhibitors delivery with special focus on celecoxib as the most widely studied agent for chemoprevention or combined with chemotherapeutic and herbal drugs for combating various cancers.

Diacerein-Loaded Hyaluosomes as a Dual-Function Platform for Osteoarthritis Management via Intra-Articular Injection: In Vitro Characterization and In Vivo Assessment in a Rat Model.

The application of intra-articular injections in osteoarthritis management has gained great attention lately. In this work, novel intra-articular injectable hyaluronic acid gel-core vesicles (hyaluosomes) loaded with diacerein (DCN), a structural modifying osteoarthritis drug, were developed. A full factorial design was employed to study the effect of different formulation parameters on the drug entrapment efficiency, particle size, and zeta potential. Results showed that the prepared optimized DCN- loaded hyaluosomes were able to achieve high entrapment (90.7%) with a small size (310 nm). The morphology of the optimized hyaluosomes was further examined using TEM, and revealed spherical shaped vesicles with hyaluronic acid in the core. Furthermore, the ability of the prepared DCN-loaded hyaluosomes to improve the in vivo inflammatory condition, and deterioration of cartilage in rats (injected with antigen to induce arthritis) following intra-articular injection was assessed, and revealed superior function on preventing cartilage damage, and inflammation. The inflammatory activity assessed by measuring the rat's plasma TNF-α and IL-1b levels, revealed significant elevation in the untreated group as compared to the treated groups. The obtained results show that the prepared DCN-loaded hyaluosomes would represent a step forward in the design of novel intra articular injection for management of osteoarthritis.

Design and evaluation of novel inhalable sildenafil citrate spray-dried microparticles for pulmonary arterial hypertension.

Pulmonary delivery of vasodilators is a promising alternative for the intravenous and oral treatment of pulmonary arterial hypertension (PAH). The aim of this study was to design and evaluate hydrogel microparticles as a carrier for sustained pulmonary delivery of sildenafil citrate. Spray dried hydrogel microparticles containing biodegradable sodium carboxymethyl cellulose, sodium alginate, and sodium hyaluronate polymers at variable concentrations were prepared. A design of experiment using the "Extreme Vertices Mixture" design was executed. The design was used to study the influence of polymer concentration and their interactions on the physicochemical properties of the formulations in terms of particle size, particle size distribution, product yield, entrapment efficiency, and in-vitro drug release. Selected formulations were also evaluated for swelling, biodegradation, moisture content, in-vitro aerodynamic performance, and cytotoxicity. In addition, a lung deposition and pharmacokinetic study was conducted in rats to study drug accumulation in lungs and blood after intratracheal administration of the spray dried inhalable hydrogel microparticles in comparison to orally administered Viagra®. The results demonstrated that formulated microparticles had a mean geometric particle size between 2 and 5 µm, entrapment efficiency of >80%, and yield ranging between 47 and 66% w/w. The in-vitro drug release profiles showed a sustained drug release of sildenafil citrate for over 24 h. The statistical design showed a significant influence of the microparticulate composition on the physicochemical properties. Furthermore, selected formulations were evaluated for their aerodynamic properties. The aerodynamic properties included fine particle fraction ranging between 24 and 30%, dose recovery percent of 68-8 5%, and average mass median aerodynamic diameter of 4.6-4.8 µm. The in-vivo pharmacokinetic study showed that inhaled spray dried hydrogel microparticles (M6) formulation had significantly higher lung/blood Cmax, AUC, extended half-life, and mean residence time in comparison to orally administered sildenafil citrate of the same dose. In conclusion, the formulated drug-loaded spray dried hydrogel microparticles showed promising in-vitro and in-vivo results for the pulmonary delivery of sildenafil citrate. The spray dried hydrogel microparticles formulation can be considered as a potential alternative of oral sildenafil citrate for treatment of PAH.

Bioavailability Enhancement of Aripiprazole Via Silicosan Particles: Preparation, Characterization and In vivo Evaluation.

The aim of this study was to design a novel carrier for enhancing the bioavailability of the poorly water-soluble drug, aripiprazole (ARP). Silicosan, the applied carrier, was obtained by chemical interaction between tetraethyl orthosilicate (TEOS) and chitosan HCl. Different ARP-loaded silicosan particles were successfully prepared in absence and presence of one of the following surfactants; Tween 80, Poloxamer 407 and cetyltrimethylammonium bromide (CTAB). The prepared ARP-loaded silicosan particles were thoroughly investigated for their structures using FTIR, XRD, and DSC analysis as well as their particle size, zeta potential, flowability, drug content, and in vitro drug release efficiencies. The prepared ARP-loaded silicosan particles were characterized by amorphous structure, high drug entrapment efficiency and a remarkable improvement in the release of aripiprazole in simulated gastric fluid. SEM and EDX revealed that the morphology and silica atom content in the prepared ARP-loaded silicosan particles were affected by the used surfactant in their formulations. The selected ARP-loaded silicosan particles were subjected to in vivo study using rabbits. The obtained pharmacokinetic results showed that the relative bioavailability for orally administered ARP-loaded silicosan particles (SC-2-CTAB) was 66% higher relative to the oral suspension (AUC0-10h was 16.38 ± 3.21 and 27.23 ± 2.35 ng.h/mL for drug powder and SC-2-CTAB formulation, respectively). The obtained results suggested the unique-structured silicosan particles to be used as successful vehicle for ARP.

Origanum vulgare L. Essential Oil as a Potential Anti-Acne Topical Nanoemulsion-In Vitro and In Vivo Study.

Antibiotics are often prescribed in acne treatment; however, Propionibacterium acnes and Staphylococcus epidermidis, the two of the major acne-associated bacteria, developed antibiotic resistance. Essential oils (EOs) present a natural, safe, efficacious and multifunctional alternative treatment. This study aimed to assess the potential anti-acne activity of selected seven EOs commonly used in Mediterranean folk medicine. Antimicrobial activity screening of these oils showed oregano to exhibit the strongest antimicrobial activity with minimum inhibitory concentration (MIC) of 0.34 mg/mL and minimum bactericidal concentration (MBC) of 0.67 mg/mL against P. acnes; and MIC of 0.67 mg/mL and MBC of 1.34 mg/mL against S. epidermidis. The composition of the most effective EOs (oregano and thyme) was determined using gas chromatography-mass spectrometry (GC-MS). Monoterpenoid phenols predominated oregano and thyme EO with thymol percentile 99 and 72, respectively. Thymol showed MIC 0.70 mg/mL against both P. acnes and S. epidermidis whereas MBC was 1.40 and 2.80 mg/mL against P. acnes and S. epidermidis, respectively. Moreover, oregano exhibited the strongest anti-biofilm effect against S. epidermidis with MBIC 1.34 mg/mL and killing dynamic time of 12 and 8 h against P. acnes and S. epidermidis, respectively. Oregano, the most effective EO, was formulated and tested as a nanoemulsion in an acne animal mouse model. The formulation showed superior healing and antimicrobial effects compared to the reference antibiotic. Collectively, our data suggested that oregano oil nanoemulsion is a potential natural and effective alternative for treating acne and overcoming the emerging antibiotic resistance.

Preparation of 99mTc-levetiracetam intranasal microemulsion as the first radiotracer for SPECT imaging of the Synaptic Vesicle Protein SV2A.

Selective receptors imaging using gamma emitting radiopharmaceuticals allows accurate diagnosis and follow up of many brain related disorders. Levetiracetam, a selective SV2A receptor antiepileptic, was successfully radiolabeled using 99mTc. Different conditions affecting the labelling process were studied and optimum radiochemical yield of 89.8% was obtained. 99mTc-levetiracetam was effectively formulated and characterized as microemulsion with particle size of 16.34 ±â€¯5.58 nm and polydispersity index of 0.382 ±â€¯0.05. Parallel biodistribution studies were performed comparing brain targeting efficiency of I.V 99mTc-levetiracetam solution, I.N 99mTc-levetiracetam solution and I.N 99mTc-levetiracetam microemulsion. Brain radioactivity uptake and brain/blood uptake ratio for I.N 99mTc-levetiracetam microemulsion were higher than the other two routes at all time intervals. Such results present intranasal 99mTc-levetiracetam microemulsion as the first SPECT tracer for imaging SV2A receptor.

Novel instantly-dispersible nanocarrier powder system (IDNPs) for intranasal delivery of dapoxetine hydrochloride: in-vitro optimization, ex-vivo permeation studies, and in-vivo evaluation.

Dapoxetine (D) suffers from poor oral bioavailability (42%) due to extensive metabolism in the liver. The aim of this study was to enhance the bioavailability of D via preparing instantly-dispersible nanocarrier powder system (IDNPs) for intranasal delivery of D. IDNPs were prepared using the thin film hydration technique, followed by freeze-drying to obtain easily reconstituted powder providing rapid and ready method of administration. The produced nanocarrier systems were evaluated for drug content, entrapment efficiency percentage, particle size, polydispersity index, zeta potential, and drug payload. The optimized nanocarrier system was morphologically evaluated via transmission electron microscopy and the optimized freeze-dried IDNPs were evaluated for ex-vivo permeation and in-vivo pharmacokinetic studies in rabbits following intranasal and oral administration. The relative bioavailability of D after intranasal administration of freeze-dried IDNPs was about 235.41% compared to its corresponding oral nanocarrier formulation. The enhanced D permeation and improved bioavailability suggest that IDNPs could be a promising model for intranasal delivery of drugs suffering from hepatic first pass effect.

Facile development, characterization, and optimization of new metformin-loaded nanocarrier system for efficient colon cancer adjunct therapy.

PURPOSE: Metformin hydrochloride (MF) repurposing as adjuvant anticancer therapy for colorectal cancer (CRC) proved effective. Several studies attempted to develop MF-loaded nanoparticles (NPs), however the entrapment efficiency (EE%) was poor. Thus, the present study aimed at the facile development of a new series of chitosan (CS)-based semi-interpenetrating network (semi-IPN) NPs incorporating Pluronic® nanomicelles as nanocarriers for enhanced entrapment and sustained release of MF for efficient treatment of CRC. METHODS: The NPs were prepared by ionic gelation and subsequently characterized using FTIR, DSC, TEM, and DLS. A full factorial design was also adopted to study the effect of various formulation variables on EE%, particle size, and zeta-potential of NPs. RESULTS: NPs had a spherical shape and a mean particle size ranging between 135 and 220 nm. FTIR and DSC studies results were indicative of successful ionic gelation with the drug being dispersed in its amorphous form within CS-Pluronic® matrix. Maximum EE% reaching 57.00 ± 12.90% was achieved using Pluronic®-123 based NPs. NPs exhibited a sustained release profile over 48 h. The MF-loaded NPs sensitized RKO CRC cells relative to drug alone. CONCLUSION: The reported results highlighted the novel utility of the developed NPs in the arena of colon cancer treatment.

Non-ionic Surfactant Based In Situ Forming Vesicles as Controlled Parenteral Delivery Systems.

Non-ionic surfactant (NIS) based in situ forming vesicles (ISVs) present an affordable alternative to the traditional systems for the parenteral control of drug release. In this work, NIS based ISVs encapsulating tenoxicam were prepared using the emulsion method. Tenoxicam-loaded ISVs were prepared using a 22.31 full factorial experimental design, where three factors were evaluated as independent variables; type of NIS (A), molar ratio of NIS to Tween®80 (B), and phase ratio of the internal ethyl acetate to the external Captex® oil phase (C). Percentage drug released after 1 h, particle size of the obtained vesicles and mean dissolution time were chosen as the dependent variables. Selected formulation was subjected to morphological investigation, injectability, viscosity measurements, and solid state characterization. Optimum formulation showed spherical nano-vesicles in the size of 379.08 nm with an initial drug release of 37.32% in the first hour followed by a sustained drug release pattern for 6 days. DSC analysis of the optimized formulation confirmed the presence of the drug in an amorphous form with the nano-vesicles. Biological evaluation of the selected formulation was performed on New Zealand rabbits by IM injection. The prepared ISVs exhibited a 45- and 28-fold larger AUC and MRT values, respectively, compared to those of the drug suspension. The obtained findings boost the use of ISVs for the treatment of many chronic inflammatory conditions.

Design of novel injectable in-situ forming scaffolds for non-surgical treatment of periapical lesions: In-vitro and in-vivo evaluation.

Periapical lesions are considered one of the common pathological conditions affecting alveolar bone. The primary focus of this study was to investigate the effectiveness of formulating an injectable in-situ forming scaffold-loaded with risedronate (bone resorption inhibitor) and with lornoxicam (anti-inflammatory drug) for the non-surgical treatment of periapical lesions. The scaffolds were prepared using solvent-induced phase inversion technique. Two insoluble copolymers were investigated namely; PLGA (ester-terminal) and PLGA-A (acid-terminal), additionally, SAIB was added as a high viscosity water-insoluble carrier. The addition of porogenic agents like hydrolyzed collagen was also investigated. The prepared scaffolds were characterized by analyzing their in-vitro release, DSC and rheological properties, besides their morphological properties. The results showed that the scaffolds prepared using 30% (w/v) PLGA or combined PLGA: SAIB (1:1, w/w) with total polymer concentration of 30% (w/v) possessed the most sustained drug release profile. Selected scaffolds were tested for their therapeutic effect to study the effect of porogenic agent, anti-inflammatory drug and risedronate in periapical lesions induced in dogs' teeth. Results declared that the selected scaffolds succeeded in improving the inflammation and enhancing the formation of new bony regions confirming the success of the prepared scaffolds as an innovative approach in the treatment of bone defects.

Novel instantly-soluble transmucosal matrix (ISTM) using dual mechanism solubilizer for sublingual and nasal delivery of dapoxetine hydrochloride: In-vitro/in-vivo evaluation.

Dapoxetine (D) suffers from poor oral bioavailability (42%) due to extensive first pass metabolism. The usefulness of transmucosal (sublingual and intranasal) drug delivery to improve bioavailability of D, a weak basic drug, has been hampered by its poor solubility in the neutral pH of the body fluids. In this study, instantly-soluble transmucosal matrices (ISTMs) of D, containing dual mechanism solubilizer (Pluronic F-127/citric acid mixture), were prepared by lyophilization technique to enhance matrix disintegration, dissolution and transmucosal permeation. The matrices were evaluated for in-vitro disintegration, wetting time, in-vitro dissolution, ex vivo transmucosal permeation, scanning electron microscopy and in-vivo studies. Dissolution studies confirmed the higher ability of ISTMs to enhance the early time point dissolution and maintain complete drug dissolution in pH 6.8 compared to conventional lyophilized matrices. The optimized ISTM gave approximately 77.54 and 88.40 folds increase of D dissolution after 1 and 3min relative to the drug powder in pH 6.8. ISTMs containing the highest F127 concentration (2%) and the lowest gelatin and mannitol concentrations (1%) exhibited the shortest in-vitro disintegration times (<10s), the fastest dissolution in the neutral pH of body fluids (∼99% in 3min) and the highest enhancement of transmucosal permeation. The relative bioavailabilities of D after sublingual and intranasal administration of ISTMs to rabbits were about 124.58% and 611.15%, respectively, in comparison to the oral market tablet. The significant increase of drug dissolution in nasal fluids, rapid permeation rate together with the improved bioavailability propose that ISTMs could be promising for intranasal delivery of drugs suffering from oral hepatic metabolism and have limited solubility in nasal fluids.

Trans-nasal zolmitriptan novasomes: in-vitro preparation, optimization and in-vivo evaluation of brain targeting efficiency.

Migraine attack is a troublesome physiological condition associated with throbbing, intense headache, in one half of the head. Zolmitriptan is a potent second-generation triptan, prescribed for patients with migraine attacks, with or without an aura, and cluster headaches. The absolute bioavailability of zolmitriptan is about 40% for oral administration; due to hepatic first metabolism. Nasal administration would circumvent the pre-systemic metabolism thus increasing the bioavailability of zolmitriptan. In addition, due to the presence of microvilli and high vasculature, the absorption is expected to be faster compared to oral route. However, the bioavailability of nasal administered drugs is particularly restricted by poor membrane penetration. Thus, the aim of this work is to explore the potential of novel nanovesicular fatty acid enriched structures (novasomes) for effective and enhanced nasal delivery of zolmitriptan and investigate their nose to brain targeting potential. Novasomes were prepared using nonionic surfactant, cholesterol in addition to a free fatty acid. A 23 full factorial design was adopted to study the influence of the type of surfactant, type of free fatty acid and ratio between the free fatty acid and the surfactant on novasomes properties. The particle size, entrapment efficiency, polydispersity index, zeta potential and % zolmitriptan released after 2 h were selected as dependent variables. Novasomes were further optimized using Design Expert® software (version 7; Stat-Ease Inc., Minneapolis, MN), and an optimized formulation composed of Span® 80:Cholesterol:stearic acid (in the ratio 1:1:1) was selected. This formulation showed zolmitriptan entrapment of 92.94%, particle size of 149.9 nm, zeta potential of -55.57 mV, and released 48.43% zolmitriptan after 2 h. The optimized formulation was further examined using transmission electron microscope, which revealed non-aggregating multi-lamellar nanovesicles with narrow size distribution. DSC, XRD examination of the optimized formulation confirmed that the drug have been homogeneously dispersed throughout the novasomes in an amorphous state. In-vivo bio-distribution studies of 99mTc radio-labeled intranasal zolmitriptan loaded novasomes were done on mice, the pharmacokinetic parameters were compared with those following administration of intravenous 99mTc-zolmitriptan solution. Results revealed the great enhancement in zolmitriptan targeting to the brain, with drug targeting potential of about 99% following intranasal administration of novasomes compared with the intravenous drug solution. Zolmitriptan loaded novasomes administered via the nasal route may therefore constitute an advance in the management of acute migraine attacks.

Contribution of both olfactory and systemic pathways for brain targeting of nimodipine-loaded lipo-pluronics micelles: in vitro characterization and in vivo biodistribution study after intranasal and intravenous delivery.

Nimodipine (NM) is the only FDA-approved drug for treating subarachnoid hemorrhage induced vasospasm. NM has poor oral bioavailability (5-13%) due to its low aqueous solubility, and extensive first pass metabolism. The objective of this study is to develop radiolabeled NM-loaded LPM and to test its ability prolong its circulation time, reduce its frequency of administration and eventually target it to the brain tissue. NM was radiolabeled with 99mTc by direct labeling method using sodium dithionite. Different reaction conditions that affect the radiolabeling yield were studied. The in vivo pharmacokinetic behavior of the optimum NM-loaded LPM formulation in blood, heart, and brain tissue was compared with NM solution, after intravenous and intranasal administration. Results show that the radioactivity percentage (%ID/g) in the heart of mice following administration of 99mTc-NM loaded LPM were lower compared with that following administration of 99mTc-NM solution, which is greatly beneficial to minimize the cardiovascular side effects. Results also show that the %ID/g in the blood, and brain following intravenous administration of 99mTc-NM-loaded LPM were higher at all sampling intervals compared with that following intravenous administration of 99mTc-NM solution. This would be greatly beneficial for the treatment of neurovascular diseases. The drug-targeting efficiency of NM to the brain after intranasal administration was calculated to be 1872.82%. The significant increase in drug solubility, enhanced drug absorption and the long circulation time of the NM-loaded LPM could be promising to improve nasal and parenteral delivery of NM.

Novel self-assembled nano-tubular mixed micelles of Pluronics P123, Pluronic F127 and phosphatidylcholine for oral delivery of nimodipine: In vitro characterization, ex vivo transport and in vivo pharmacokinetic studies.

Subarachnoid hemorrhage (SAH) is a major cause of death in patients suffering from stroke. Nimodipine (NM) is the only FDA-approved drug for treating SAH-induced vasospasm. However, NM suffers from poor oral bioavailability (5-13%) due to its low aqueous solubility, extensive first pass metabolism and short elimination half-life (1-2h). The objective of this study was to develop NM-loaded Pluronic/phosphatidylcholine/polysorbate 80 mixed micelles (PPPMM) that can solubilize NM in aqueous media even after dilution, prolong its circulation time, improve its bioavailability and eventually help in targeting it to the brain tissue. PPPMM formulations were prepared using the thin film hydration technique, and evaluated for drug payload, solubilization efficiency (SE), micellar size, zeta potential, transmission electron microscopy (TEM) and ex vivo transport through rat intestine. The selected NM-loaded PPPMM, containing PC to Pluronics(®) molar ratio of 75:25, showed a drug payload, SE, micellar size and zeta potential of 1.06 ± 0.03 mg/mL, 99.2 ± 2.01%, 571.5 ± 11.87 nm and -31.2 ± 0.06 mv, respectively. The selected formulation had a much larger hydrophobic core volume for solubilization of NM and exhibited the highest NM transport. TEM micrographs illustrated the formation of highly flexible nano-tubular mixed micelles (NTMM). The in vivo pharmacokinetic study showed greater bioavailability of NM in plasma (232%) and brain (208%) of rats from NM-loaded PPPMM compared to that of the drug solution due to the efficiency of flexible NTMM to enhance absorption of NM from the intestinal mucosa. The significant increase in drug solubility, enhanced drug absorption and the long circulation time of the NTMM could be promising to improve oral and parenteral delivery of NM.

Design and optimization of surfactant-based nanovesicles for ocular delivery of Clotrimazole.

The objective of this study was to develop an efficient ocular nanovesicular carrier providing a controlled delivery of Clotrimazole (CLT); a water insoluble antifungal drug. The nanovesicular carriers were formulated using Span 60 with one of the following edge activators (EA): Tween 80 (TW80), sodium cholate (SC) or sodium deoxycholate (SDC). A 3(2) full factorial design was used to study the effect of two independent variables, namely, the type of EA and the ratio of Span 60 to EA. The effects of these parameters on the mean particle size, entrapment efficiency (EE) and zeta potential (ZP) were investigated as dependent variables. Then, optimization was performed producing the best optimized formulation composed of SDC as an EA at the ratio of 90:10 (Span 60:EA) with an average diameter of 479.60 nm, EE of 87.92% and ZP of -33.7 mV. The optimized nanovesicular carriers appeared as spherical unilamillar vesicles with CLT in an amorphous state as evidenced by the differential scanning calorimetry study. The antifungal activity against Candida albicans compared to niosomal formulation as well as the CLT suspension was determined. CLT-loaded nanovesicular carriers displayed sustained antifungal effect over 12 h. The AUC of the optimized formulation was 3.09 times more than that of drug suspension with no sign of irritation after testing for ocular tolerance. Therefore, the present study showed the feasibility of using non-ionic surfactant nanovesicles as carrier systems for prolonged ocular delivery of CLT.