Vesicular Nanocarriers Research Articles

Nano vesicular lipid carriers of angiotensin II receptor blocker: Anti-hypertensive and skin toxicity study in focus

Objective: Nanoethosomal carriers of valsartan have been previously prepared, characterized and optimized. A gel formulation of valsartan vesicular lipid carriers was composed of Carbopol® (1% w/w), polyethylene glycol-400 (15% w/w) and triethanolamine (0.5% w/w). The influence of the valsartan nanoethosomal formulation developed on the blood pressure of experimental hypertensive rats, and its potential for skin irritation, are presented in this report. Materials and methods: The experimental rats were divided into three groups; the control group received no treatment (Group A). Group B was administered methyl prednisolone acetate (20 mg/kg/week) for two weeks (hypertensive control). Group C received methyl prednisolone acetate, followed by administration of the valsartan ethosomal formulation. The blood pressure of the rats was measured using a non-invasive rat blood pressure instrument based on the tail-cuff technique. The statistical analysis was performed using GraphPad InStat 3 software. Results and discussion: The treatment group showed a significant (P < 0.05) and constant fall in blood pressure, for up to 48 h. The valsartan ethosomal formulation was found to be effective, with a 34.11% reduction in blood pressure. The formulation's potential for skin irritation was assessed by the Draize irritation score test, which ruled out the possibility of any skin irritation caused by application of the formulation in rats. Conclusion: Our results suggest that nanoethosomes are efficient carriers for transdermal delivery of valsartan, for the management of hypertension.

Dual drug encapsulation in a novel nano-vesicular carrier for the treatment of cutaneous melanoma: characterization and in vitro/in vivo evaluation

The objective of this research was to develop and evaluate a dual drug-loaded dermal targeted vesicle for the treatment of cutaneous melanoma.

Pharmaceutical nanotechnology meets natural products

From the end of 90 s the pharmaceutical nanotechnology prompted colloidal drug delivery systems to move from the scientific speculation to the clinical use, thus providing suitable nanomedicines for the efficacious treatment of a number of diseases. The advantage of last generation nanomedicines is their feature to be modulated as a function of the therapeutic requirements. Recently, the pharmaceutical nanotechnology drove the attention also to natural drugs coming from medical plants thus allowing the possibility to achieve nanomedicines based on natural products. Therefore, the use of innovative drug delivery systems can provide an advancement of natural compounds by improving their biopharmaceutical features [1]. The topical application of natural substances to prevent or treat skin disorders represents an interesting and innovative field of application. The potentiality of ultradeformable vesicles as a possible topical delivery system for asiaticoside, a natural compound obtained from Centella asiatica was evaluated [2], because this compound exhibits collagen biosynthesis promoting activity. Asiaticoside-loaded ultradeformable vesicles elicited the greatest degree of collagen biosynthesis in human fibroblasts. Ultradeformable vesicles provided the greatest in vitro skin permeation of asiaticoside showing a 10-fold increase with respect to the free drug solution and favoured an increase in the in vivo collagen biosynthesis. It is also the case of Glycyrrhiza glabra L. extract, which was delivered by both ethosomes® [3] and niosomes [4] thus improving the anti-inflammatory activity of the delivered natural compound as demonstrated using an in vivo model of skin erythema on human volunteers. The use of vesicular nanocarriers allowed also the potential application of Citrus bergamia extracts for dermo-cosmetic use to treat non-pathological disorders, i.e. photo-ageing and photo-induced erythema. Not only topical application but also other administration routes are possible for nanomedicines based on natural compounds as well as their application for the treatment of severe pathologies, i.e. cancer disease.

Nano-proniosomes enhancing the transdermal delivery of mefenamic acid

Mefenamic acid (MA) is a BCS II class NSAID drug. It is available only in the form of tablets, capsules, and pediatric suspensions. Oral administration of MA is associated with severe gastrointestinal side effects. The aim of this study was to develop a convenient and low-cost transdermal drug delivery system for MA using proniosome as a novel carrier without the addition of penetration enhancers. The formulation factors, such as the presence of cholesterol, types of lecithin, and surfactants were investigated for their influence on the entrapment efficiency, rate of hydration, vesicle size, and zeta potential, in vitro drug release and skin permeation in order to optimize the proniosomal formulations with the minimum dose of the drug. Furthermore, the in vivo anti-inflammatory effect was evaluated on a formalin-induced rat paw edema model. The results showed that the type of surfactants had higher impact on the entrapment efficiency than the type of lecithins, with the highest in Span 80 (82.84%). The release of MA from Span 80 proniosomal gel was significantly affected by the type of lecithin used. The addition of cholesterol significantly increased both the drug release and the skin permeation flux of MA. Zeta potential showed a stable A4 noisomal suspension. DSC revealed the molecular dispersion of MA into the loaded proniosomes. In vivo study of the treatment group with MA proniosome gel showed a significant inhibition of rat paw edema compared with the same gel without the drug (control). The results of this study suggest that proniosomes are promising nano vesicular carriers and safe alternatives to enhance the transdermal delivery of MA.

FORMULATION AND IN VITRO EVALUATION OF METHAZOLAMIDE ELASTIC VESICULAR SYSTEMS

Eye is the most unique organ of the body. Various drug delivery systems are used to deliver drug into the eyes but there are various limitations of conventional systems, so various novel approaches like nanovesicular systems were used to improve ocular contact time, bioavailability, residence time and dosing frequency.Nanovesicular system with elastic properties can provide a controlled delivery of Methazolamide (MZA) which is used to treat glaucoma by inhibiting the action of carbonic anhydrase enzyme. The elastic nanovesicular carriers were formulated using Span 60 (SP 60) with one of the following edge activators (EA): Tween 80 (TW80), Tween 60 (TW 60), Brij 35 (BJ 35), and Brij 58 (BJ 58) in the ratio (90:10; 80:20; 70:30 w: w). The prepared formulae were evaluated for their sizes, entrapment efficiencies (EE %), relative deformability, and in vitro release. The results show that the selected formulae (S1, S4, S7, and S8) have the suitable particle size and EE%, thus can be used for any further investigations.

Penetration profile and human cadaver skin distribution of finasteride from vesicular nanocarriers

The skin accumulation of therapeutic agents affects the efficiency of topical drug delivery. In this study, in vitro distribution of finasteride of ethosomes and liposomes in human cadaver skin after percutaneous delivery were investigated. Experiments were performed using modified Franz diffusion cells. Finasteride ethosomes, liposomes or hydroethanolic solutions were used as donor medium. Drug distribution at different skin layers and depths were studied by hotplate separation and frozen horizontal slicing technique. The result showed that the accumulation of finasteride in skin ranged from 9.7–24.3 μg/cm2 at 12 or 24 hours. The ethosomes demonstrated better enhancing ability to deliver finasteride into the dermis layer than liposomes did. The finasteride concentration in the dermis layer from ethosomes was more than sevenfold higher than from liposomes. The finasteride accumulation in ethosomes group showed a distinctive reversed distribution profile. This distinctive reversed distribution profile is meaningful for exerting a favorable pharmacological effect for finasteride. The drug distribution profile in skin layers showed no significant difference between 12 and 24 hours application (p > 0.05). The study demonstrated that finasteride can be accumulated at target site more effectively and maintained at higher level through the application of novel ethosomal carriers.

Development and characterization of stable nanovesicular carrier for drug delivery

Lipid vesicles are an important drug carrier which can serve for controlled delivery of drugs; however, these vesicles are quite unstable at ambient temperature and require stringent storage condition.Present work was done to develop a stable vesicular system for drug delivery. Vesicles of ceramide-2, cholesterol, cholesterol sulfate, and palmitic acid were prepared and compared with phosphatidylcholine vesicles for physicochemical parameters and accelerated stability. Diclofenac sodium was used as a model drug.Based on physicochemical parameter and in vitro release PCV-3 and CV-3 were selected for further studies in three different accelerated stability conditions. PCV-3 showed moderate changes at 4°C but was severely affected at 25°C and 40°C. CV-3 showed stable characteristics at 4°C and 25°C whereas at 40°C, CV-3 showed signs of slight modification owing to moisture absorption.Based on the study, CV-3 containing highest content of palmitic acid was found to be most stable.

Lycopene from Tomatoes: Vesicular Nanocarrier Formulations for Dermal Delivery

This experimental work aimed to develop a simple, fast, economic, and environmentally friendly process for the extraction of lycopene from tomato and incorporate this lycopene-rich extract into ultradeformable vesicular nanocarriers suitable for topical application. Lycopene extraction was conducted without a cosolvent for 30 min. The extracts were analyzed and incorporated in transfersomes and ethosomes. These formulations were characterized, and the cellular uptake was observed by confocal microscopy. Dermal delivery of lycopene formulations was tested under in vitro and in vivo conditions. Lycopene extraction proved to be quite safe and selective. The vesicular formulation was taken up by the cells, being more concentrated around the nucleus. Epicutaneous application of lycopene formulations decreased the level of anthralin-induced ear swelling by 97 and 87%, in a manner nonstatistically different from the positive control. These results support the idea that the lycopene-rich extract may be a good alternative to the expensive commercial lycopene for incorporation into advanced topical delivery systems.

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 32 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.

A Review of Transdermal Drug Delivery Using Nano-Vesicular Carriers: Transfersomes

Transfersomes are specific deformable vesicles, which are being developed, considering the advantage of phospho-lipids vesicles, for suitable delivery of drug. These are highly elastic in nature, as such they could easily overcome the skin penetration, by squeezing themselves in a self-adapting manner. Also they possess a unique ability to get accommodated with a wide range of solubility and act as an efficient carriers for both low as well as high molecular weight drugs, e.g. analgesic, corticosteroids, hormones, anticancer drugs, insulin, proteins etc with high entrapment efficiency & a unique advantage of protection of the encapsulated drug, from metabolic degradation. However, their major disadvantage arises due to their chemical instability and high susceptibility to oxidative degradation. Transfersomes could be easily prepared using various processes - suspension homogenization process, aqueous lipid suspension process, modified handshaking process and centrifugation process. Transfersomes’ inherent potential advantages are highly utilized in ‘Transdermal Immunization’, ‘Peripheral Drug Targeting’ & for ‘Transdermal Delivery ‘of Insulin, NSAIDs, Heparin, Anti Cancer drugs, etc. Various patent applications have been admitted, using Transfersomes for various applications, e.g., ‘Transcutaneous Administration’ of Antigens, Delivery of larger molecules across nasal mucosa, Intra- Epithelial delivery of chemical agents, Delivery of biologically active drugs, delivery of DNA using lipid vesicles, etc. Recently, marketing approval of Drug ‘diractin’ using ketoprofen has gained its significance for Transferosomal delivery of the drug.

A novel nanovesicular carrier system to deliver drug topically

Context: Ketoconazole, a lipophilic drug with a large molecular weight of 531.44 Da and a limiting aqueous solubility of 0.04 mg/ml is expected to show a poor transport across the skin.Objective: The work describes usefulness of a novel, surfactant based elastic vesicular drug carrier system (SEVs), for enhanced dermal delivery.Materials and methods: The system constitutes Span 60 and an edge activator (Tween 80) and was characterized and monitored for safety and potential to target deeper mice skin layers.Results: Nanosized (126 nm), elastic vesicles showed significantly high skin penetration and retention as compared to free drug suspension. Incorporation into different bases especially a hydrogel showed a significant retention which was even more than the market formulation (Nizral®). Safety was confirmed as cytotoxicity and acute dermal irritation/corrosion. Topically applied fluorescent vesicles labeled with 6-carboxyfluorescein, on mice skin, were observed intact in dermal layer 6 h post application.Conclusion: The results of the present study indicate that SEVs can be used to enhance skin delivery of the model high molecular weight and poorly water-soluble drug ketoconazole. The developed nanorange system is an effective system for targeting deeper mice skin layers which may be translated to human skin with suitable modifications, if required.

Amphiphilic Diblock Copolymer and Polycaprolactone Blends to Produce New Vesicular Nanocarriers

New Melatonin-loaded vesicular nanocarriers were prepared by interfacial deposition using a blend of an amphiphilic diblock copolymer, poly(methyl methacrylate)-block-poly(2-(dimethylamino)ethyl methacrylate), PMMA-b-PDMAEMA, with poly(epsilon-caprolactone), PCL. Particle size and morphology of the nanocarriers was evaluated. Dynamic light scattering shows that the nanocarriers have hydrodynamic radii between 100 and 180 nm, with unimodal particle size distribution for each formulation. Shape and structure were visualized by transmission electron microscopy (TEM), cryogenic TEM and scanning electron microscopy. Standard TEM for nanocapsules showed an oily core surrounded by a thin layer composed by PCL/PMMA-b-PDMAEMA. Cryo-TEM also indicated the presence of spherical nano-objects with a diffuse polymer corona. Encapsulation efficiencies were determined assaying the nanoparticles by HPLC and higher values of ca. 25% are shown by the nanocapsules. We could successfully incorporate platinum nanoparticles into the nanocarrier as evidenced by TEM, which opens up the possibility for promising applications like monitoring the encapsulated drug in the body.

Organic nanocarriers for cancer drug delivery

A major focus in translational cancer research is the study of nanocarriers as novel delivery systems for chemotherapeutics. Organic vesicular nanocarriers, such as liposomes and micelles, have the advantage of low toxicity and the versatility to carry diverse drugs and conjugate to targeting agents. This offers the potential for combining treatment and diagnosis (theranostics). Successful incorporation into these nanoformulations has been demonstrated for classical chemotherapeutic drugs that are mostly hydrophobic, small interfering RNA, biological therapeutics and specific nanoparticles, such as superparamagnetic nanoparticles. Liposomes and micelles appear to take advantage of the enhanced permeability and retention (EPR) effect in solid tumours to increase accumulation at the target site (passive targeting). This translates to the clinic, where liposomal drug formulations are reported to exhibit higher efficacy and less side effects. Multidrug formulations and combinations with other treatments, for example, radiation or radiofrequency ablation, to trigger drug release from the nanocarrier at the target site, are mostly at the pre-clinical stage. More complex formulations that incorporate treatment agents together with targeting (active targeting) and imaging molecules have also been investigated in in vivo models with encouraging results.

Sustained Antioxidant Activity of Quercetin-Loaded Lipid-Core Nanocapsules

Lipid-core nanocapsules (LNC) are vesicular nanocarriers prepared by solvent displacement. LNC have been previously prepared using medium-chain triglyceride and sorbitan monostearate as liquid and solid lipophilic components dispersed in the core, surrounded by poly(epsilon-caprolactone) (PCL). Our objective was to investigate the antioxidant activity of LNC containing quercetin (QUE), a radical scavenger, prepared with octyl methoxycinnamate and sorbitan monostearate as lipophilic core components and PCL as the polymer wall. We selected Saccharomyces cerevisae cells as the proposed biological model. QUE-LNC presented z-average diameter of 212 nm, pH of 5.51 and zeta potential of -11 mV. Multiple light scattering analysis (TurbiscanLab) showed a photon path length of 172 microm. Furthermore, a validated turbidimetric study determined that the density of particles in suspension was 1.66 x 10(13). DSC analysis showed that the melting temperature of PCL shifted to lower values when in contact with octyl methoxycinnamate indicating a molecular interaction. After 1 h (7 h), the QUE-LNC formulation and QUE solution incubated with H2O2 showed cell survival of 84.4% (87.7%) and 65.6% (7.3%), respectively. After 35 h of incubation, cell survival was 31.7% and 0.9%, respectively. The QUE-LNC showed sustained antioxidant activity and potential as a nanostructured material to formulate final products.

Ethosomes and ultradeformable liposomes for transdermal delivery of clotrimazole: A comparative assessment

The objective of work was to formulate, evaluate and compare the transdermal potential of novel vesicular nanocarriers: ethosomes and ultradeformable liposomes, containing clotrimazole (CLT), an anti-fungal bioactive. The ethosomal formulation (ET4) and ultradeformable liposomal (UL) formulation (TT3) showed highest entrapment 68.73±1.4% and 55.51±1.7%, optimal nanometric size range 132±9.5nm and 121±9.7nm, and smallest polydispersity index 0.027±0.011 and 0.067±0.009, respectively. The formulation ET4 provided enhanced transdermal flux 56.25±5.49μg/cm2/h and decreased the lag time of 0.9h in comparison to TT3 formulation (50.16±3.84μg/cm2/h; 1.0h). Skin interaction and FT-IR studies revealed greater penetration enhancing effect of ET4 than TT3 formulation. ET4 formulation also had the highest zone of inhibition (34.6±0.57mm), in contrast to TT3 formulation (29.6±0.57mm) and marketed cream formulation (19.0±1.00mm) against candidal species. Results suggested ethosomes to be the most proficient carrier system for dermal and transdermal delivery of clotrimazole.

Spanlastics—A novel nanovesicular carrier system for ocular delivery

The work describes usefulness of a novel, surfactants based elastic vesicular drug carrier system (spanlastics), for targeting topically applied drug(s) to the posterior segment of the eye. The system constituted span 60 and a edge activator (tween 80). Ketoconazole, a lipophilic drug with a large molecular weight of 531.44 Da and a limiting solubility of 0.04 mg/ml is expected to show a poor transport across the cornea; hence no ocular formulations are available. Developed spanlastics were of nanosize and elastic in nature. They showed 2 times better corneal permeation ( p ≤ 0.001) in comparison to correspondingly prepared niosomal formulation. The system was tested for stability for 2 months under refrigerated conditions. It was found to be safe in terms of genotoxicity (Ames test), cytotoxicity (MTT assay; Normal human gingival fibroblast), acute dermal/eye irritation/corrosion and chronic eye irritation/corrosion tests (OECD guidelines). Safety was an important issue considering that the system is novel (Indian Patent Application 2390/DEL/2008; 1447/DEL/2010) and is totally surfactant based (spans plus edge activators). Fluorescent vesicles labeled with 6-carboxyfluorescein when applied topically to the rabbit eye were observed intact in vitreous and the internal eye tissues 2 h post application. Results confirm that spanlastics can be used to deliver drugs to the posterior segment of the eye.

Biodegradable vesicular nanocarriers based on poly(ɛ-caprolactone)-block-poly(ethyl ethylene phosphate) for drug delivery

Abstract Biodegradable polymer vesicle for drug delivery is reported. Poly(ɛ-caprolactone)- block -poly(ethyl ethylene phosphate) with well-defined structure (PCL 150 - b -PEEP 30 ) has been prepared by ring-opening polymerization. It forms vesicles in aqueous solution using the thin-film hydration method and further exclusion of the as-formed vesicles results in vesicles at nano-size, demonstrated by confocal laser scanning microscope (CLSM) and transmission electron microscopy observations. Doxorubicin (DOX) has been loaded into the vesicles with a loading content of 4.38% using an acid gradient method. The release of DOX from the vesicles is accelerated in the presence of an enzyme phosphodiesterase I that is known to catalyze the degradation of polyphosphoester, achieving 83.8% release of total loaded DOX in 140 h. The DOX-loaded vesicles can be successfully internalized by A549 cells, and it results in enhanced inhibition to A549 cell proliferation, likely owning to the sustained intracellular release of DOX as observed by CLSM. With these properties, the vesicles based on the block copolymer of PCL and PEEP are attractive as drug carriers for pharmaceutical application.