Influence of various lipid core on characteristics of SLNs designed for topical delivery of fluconazole against cutaneous candidiasis

Dermal delivery of fluconazole (FLZ) is still a major limitation due to problems relating to control drug release and achieving therapeutic efficacy. Recently, solid lipid nanoparticles (SLNs) were explored for their potential of topical delivery, possible skin compartments targeting and controlled release in the skin strata. The retention and accumulation of drug in skin is affected by composition of SLNs. Hence, the aim of this study was to develop FLZ nanoparticles consisted of various lipid cores in order to optimize the drug retention in skin. SLNs were prepared by solvent diffusion method and characterized for various in vitro and in vivo parameters. The results indicate that the SLNs composed of compritol 888 ATO (CA) have highest drug encapsulation efficiency (75.7?±?4.94%) with lower particle size (178.9?±?3.8?nm). The in vitro release and skin permeation data suggest that drug release followed sustained fashion over 24?h. The antifungal activity shows that SLNs made up of CA lipid could noticeably improve the dermal localization. In conclusion, CA lipid based SLNs are represents a promising carrier means for the topical treatment of skin fungal infection as an alternative to the systemic delivery of FLZ.     

Enhanced ocular bioavailability of fluconazole from niosomal gels and microemulsions: formulation,optimization, and in vitro–in vivo evaluation

Fungal keratitis may cause vision loss if it is not treated. Methods other than ocular delivery exhibited several limitations. No previous studies investigated and compared ocular bioavailability of fluconazole (FLZ) from niosomal gels and microemulsions. Niosomal gels of FLZ (0.3% w/w) based on Span^® 60 and cholesterol (CH) using 1% w/w carbopol^® 934 (CP) were evaluated. FLZ microemulsions (0.3% w/v) containing isopropyl myristate (IPM, as oil phase) and a 3:1 mixture of Tween^® 80 (as surfactant) and polyethylene glycol 400 (PEG 400, as cosurfactant) were characterized. Optimized formulations were compared for their ocular bioavailability in rabbit’s. Nanoscopic niosomes (63.67–117.13?nm) and microemulsions (57.05–59.93?nm) showed respective negative zeta potential ranges of ?45.37 to ?61.40 and ?20.50 to ?31.90?mV and sustained release up to 12?h. Entrapment efficiency (EE%) of niosomes ranged from 56.48% to 70.67%. Niosomal gels were more sustainable than niosomes and microemulsions. The most stable niosomal gel based on Span^® 60 and CH at a molar ratio of 5:5 and microemulsion containing 45% w/w IPM and 40% w/w of 3:1 Tween^® 80-PEG 400 mixture significantly (p?<?0.0001) enhanced FLZ ocular bioavailability compared with its solution. Niosomal gel showed higher bioavailability than microemulsion by ≈2-fold.     

Solid lipid nanoparticles-loaded topical gel containing combination drugs: an approach to offset psoriasis

Aim: The primary aim of present work was to develop effective combination drug therapy for topical treatment of psoriasis.

Methods: Betamethasone dipropionate and calcipotriol loaded solid lipid nanoparticles (CT-BD-SLNs) were prepared by hot melt high shear homogenization technique, which were then incorporated in Carbopol gel matrix. The anti-psoriatic potential was tested by sequential in vitro (skin permeation and dermal distribution, anti-proliferative effect in HaCaT cells) and in vivo (Draize patch irritation, transepidermal water loss (TEWL) and anti-psoriatic mouse tail studies) experiments.

Results: A negligible amount in receptor compartment, yet confined distribution of drugs to epidermal and dermal region of skin was observed in case of SLNs, which is essential for safe and effective anti-psoriatic therapy. Draize patch test and TEWL demonstrated negligible skin irritation and better skin tolerability of SLNs. The in vitro HaCaT cell line study demonstrated that SLNs delayed the abrupt growth of keratinocytes, while in vivo mouse tail model showed that SLNs gel significantly decreased the epidermal thickness and increased melanocyte count in comparison to commercial Daivobet® ointment.

Conclusions: The developed SLNs gel is expected to be potential strategies for treatment of psoriasis and other topical diseases.     

Microsponges enriched gel for enhanced topical delivery of 5-fluorouracil

Abstract

This study aimed to develop microsponges based topical gel formulation of 5-Fluorouracil (5-FU) for the treatment of skin cancer with enhanced skin deposition and reduced skin irritation potential. Microsponges were prepared by Quasi-emulsion solvent diffusion method using ethyl cellulose and Eudragit RL 30?D; and was optimised through detailed in vitro characterisation. Brunauer–Emmett–Teller (BET) analysis demonstrated higher surface area (2.4393?m²/g) and pore volume of developed microsponges formulation. Optimised formulation showed better thixotropic and texture properties compared to commercial cream formulation, used as control for comparison purpose. Further, the optimised formulation demonstrated 5.5-fold increase in skin deposition documented via in-vivo local bioavailability study, with significant reduction in skin irritation compared to the commercial formulation. Hence, the developed microsponges based formulation seems to be a viable alternative with enhanced topical delivery of 5-FU as compared to the commercial formulation.     

Nanoemulsion gel-based topical delivery of an antifungal drug: in vitro activity and in vivo evaluation

Abstract

Objective: In this study, attempt has been focused to prepare a nanoemulsion (NE) gel for topical delivery of amphotericin B (AmB) for enhanced as well as sustained skin permeation, in vitro antifungal activity and in vivo toxicity assessment.

Materials and methods: A series of NE were prepared using sefsol-218 oil, Tween 80 and Transcutol-P by slow spontaneous titration method. Carbopol gel (0.5%?w/w) was prepared containing 0.1%?w/w AmB. Furthermore, NE gel (AmB-NE gel) was characterized for size, charge, pH, rheological behavior, drug release profile, skin permeability, hemolytic studies and ex vivo rat skin interaction with rat skin using differential scanning calorimeter. The drug permeability and skin irritation ability were examined with confocal laser scanning microscopy and Draize test, respectively. The in vitro antifungal activity was investigated against three fungal strains using the well agar diffusion method. Histopathological assessment was performed in rats to investigate their toxicological potential.

Results and discussion: The AmB-NE gel (18.09?±?0.6?µg/cm²/h) and NE (15.74?±?0.4?µg/cm²/h) demonstrated the highest skin percutaneous permeation flux rate as compared to drug solution (4.59?±?0.01?µg/cm²/h) suggesting better alternative to painful and nephrotoxic intravenous administration. Hemolytic and histopathological results revealed safe delivery of the drug. Based on combined results, NE and AmB-NE gel could be considered as an efficient, stable and safe carrier for enhanced and sustained topical delivery for AmB in local skin fungal infection.

Conclusion: Topical delivery of AmB is suitable delivery system in NE gel carrier for skin fungal infection.     

Formulation and optimization of nanoemulsion using antifungal lipid and surfactant for accentuated topical delivery of Amphotericin B

The objective of the study was to develop, optimize and evaluate a nanoemulsion (NE) of Amphotericin B (AmB) using excipients with inherent antifungal activities (Candida albicans and Aspergillus niger) for topical delivery. AmB-loaded NE was prepared using Capmul PG8 (CPG8), labrasol and polyethylene glycol-400 by spontaneous titration method and evaluated for mean particle size, polydispersity index, zeta potential and zone of inhibition (ZOI). NE6 composed of CPG8 (15%w/w), S_mix (24%w/w) and water (61%w/w) was finally selected as optimized NE. AmB-NE6 was studied for improved in vitro release, ex vivo skin permeation and deposition using the Franz diffusion cell across the rat skin followed with drug penetration using confocal laser scanning microscopy (CLSM) as compared to drug solution (DS) and commercial Fungisome^®. The results of in vitro studies exhibited the maximum ZOI value of NE6 as 19.1?±?1.4 and 22.8?±?2.0?mm against A. niger and C. albicans, respectively, along with desired globular size (49.5?±?1.5?nm), zeta potential (?24.59?mV) and spherical morphology. AmB-NE6 revealed slow and sustained release of AmB as compared to DS in buffer solution (pH 7.4). Furthermore, AmB-NE6 elicited the highest flux rate (22.88?±?1.7?μg/cm²/h) as compared to DS (2.7?±?0.02?μg/cm²/h) and Fungisome^® (11.5?±?1.0?μg/cm²/h). Moreover, the enhancement ratio and drug deposition were found to be highest in AmB-NE6 than DS across the stratum corneum barrier. Finally, CLSM results corroborated enhanced penetration of the AmB-NE6 across the skin as compared to Fungisome^® and DS suggesting an efficient, stable and sustained topical delivery.     

Evaluation of topical econazole nitrate formulations with potential for treating Raynaud’s phenomenon

The purpose of this work was to design and characterize a topical formulation of econazole nitrate (EN) with potential for treating Raynaud’s phenomenon (RP). Four topical dosage forms (F1_topical solution, F2_HPMC or hydroxypropyl methylcellulose dispersion, F3_VersaBase^® cream, and F4_{_}Lipoderm^® Activemax? Cream) containing 3% w/w EN were prepared and characterized for drug content, pH, viscosity, spreadability, drug crystallinity, stability, and in vitro permeation using Franz cells across pig ear skin, and results were compared to the 1% marketed EN cream. All four formulations had acceptable physical and visual characteristics required for topical application, with 3% w/w EN. The order of amount of drug permeated from highest to lowest was F2 (10.27%) > F4 (2.47%) > F1 (2.28%) > F3 (1.47%) > marketed formulation (0.22%). Formulation F2 showed better penetration of the drug into the stratum corneum, epidermis, and dermis layers. The drug concentration in the stratum corneum and epidermis was approximately 10–20 times higher with F2 compared to the marketed formulation. All formulations were found to be stable for up to 6 months. All four EN formulations were found to be better than the 1% marketed cream. Formulation F2_{_}HPMC dispersion could be further explored as a treatment option for RP.     

Polymeric microparticles-based formulation for the eradication of cutaneous candidiasis: development and characterization

Abstract

Cutaneous candidiasis is a common topical fungal infection which may be more prominent in patients associated with AIDS. It is usually treated by conventional formulations such as cream, gel, which show various adverse effects on skin along with systemic absorption. To overcome these drawbacks, various novel drug delivery systems have been explored. Poly(lactic-co-glycolic acid) (PLGA)-based microparticulate systems have shown good dermal penetration after topical application. Therefore, in the present study clotrimazole-loaded PLGA microspheres were prepared for targeted dermal delivery. Microspheres were prepared by using a single emulsification (oil-in-water, O/W) evaporation technique and characterized for different parameters. Prepared microparticulate systems were dispersed in Carbopol 934® gel and antifungal activity was carried out on experimentally induced cutaneous candidiasis in immunosuppressed guinea pigs. Particle size of optimized formulation was 2.9?µm along with 74.85% entrapment of drug. Skin retention studies revealed that drug accumulation in the skin was higher with microspheres gel as compared to marketed gel. Confocal microscopy of skin further confirmed penetration of microspheres up to 50?µm into the dermal region. In-vivo antifungal activity studies demonstrated that microsphere gel showed better therapeutic activity, lowest number of cfu/ml was recorded, as compared to marketed gel after 96?h of application. Based on the results of the study, it can be concluded that PLGA microparticles may be promising carriers to deliver clotrimazole intradermally for the treatment of invasive fungal infections.     

Solid lipid nanoparticles bearing oxybenzone: In-vitro and in-vivo evaluation

In the present project, Solid Lipid Nanoparticles (SLNs) bearing oxybenzone were prepared by ethanol injection method to improve its effectiveness as sunscreen. SLNs were characterized for particle size, polydispersity index, zeta potential and surface morphology. The optimized SLNs bearing oxybenzone were incorporated into water-removable cream base and compared with SLNs unloaded water-removable cream base for in vitro and in vivo parameters. Cream base formulation containing SLNs (Csd) with 5% oxybenzone showed slow drug release and better sun protecting factor (more than 25) compared to cream base containing 5% oxybenzone. Confocal Laser Scanning Microscopy was used to visualize the distribution of developed formulations in skin. CLSM indicated prolonged retention of SLNs in the stratum corneum as compared to plain cream base. These studies revealed that the cream base bearing SLNs exhibited good skin retention as well as enhanced sun protection effect compared to cream base.     

Nanostructured lipid carriers (NLCs) versus solid lipid nanoparticles (SLNs) for topical delivery of meloxicam

Abstract

Objective: The aim of this study was to develop nanostructured lipid carriers (NLCs) as well as solid lipid nanoparticles (SLNs) and evaluate their potential in the topical delivery of meloxicam (MLX).

Materials and methods: The effect of various compositional variations on their physicochemical properties was investigated. Furthermore, MLX-loaded lipid nanoparticles-based hydrogels were formulated and the gels were evaluated as vehicles for topical application.

Results and discussion: The results showed that NLC and SLN dispersions had spherical shapes with an average size between 215 and 430?nm. High entrapment efficiency was obtained ranging from 61.94 to 90.38% with negatively charged zeta potential in the range of ?19.1 to ?25.7?mV. The release profiles of all formulations exhibited sustained release characteristics over 48?h and the release rates increased as the amount of liquid lipid in lipid core increased. Finally, Precirol NLC with 50% Miglyol® 812 and its corresponding SLN were incorporated in hydrogels. The gels showed adequate pH, non-Newtonian flow with shear-thinning behavior and controlled release profiles. The biological evaluation revealed that MLX-loaded NLC gel showed more pronounced effect compared to MLX-loaded SLN gel.

Conclusion: It can be concluded that lipid nanoparticles represent promising particulate carriers for topical application.     

Formulation,characterisation and in vivo evaluation of lipid-based nanocarrier for topical delivery of diflunisal

Diflunisal (DIF) is non-steroidal anti-inflammatory drug used in the treatment of rheumatoid arthritis, osteoarthritis. The current engrossment was aimed at formulation and assessment of DIF-loaded solid lipid nanoparticles (SLNs) for topical/dermal application. SLNs formulated by hot homogenisation method based on microemulsification technique were spherical with a mean size of 124.0?±?2.07?nm; PDI 0.294?±?0.15. The cumulative amount permeated/area was 109.99?±?0.008?μg/cm², along with permeation flux (6.30?±?0.09?μg/cm²/h) and skin retention (11.74?±?0.155?μg/cm²) across mice skin. The SLNs of DIF showed significant decrease in fluid volume, granuloma tissue weight, leukocyte count/mm³ after application of SLN formulation in mice air pouch model. Similarly, in mice ear oedema and rat paw oedema model, there was 2.30 and 1.29 time increase in percentage inhibition of oedema after SLN formulation application, respectively, as compared with conventional cream. Hence, the SLNs of DIF may prove to be a potential nanocarrier to effectively treat the local inflammatory conditions associated with arthritis.     

In vitro synergism of a water insoluble fraction of Uncaria tomentosa combined with fluconazole and terbinafine against resistant non-Candida albicans isolates

Context: Uncaria tomentosa D.C. (Rubiaceae) has several biological activities, including activity against resistant Candida strains. The synergistic interaction with terbinafine or fluconazole can be an important alternative to overcome this resistance.

Objectives: The potential synergy between a water insoluble fraction (WIF) from Uncaria tomentosa bark and the antifungals terbinafine (TRB) and fluconazole (FLZ) against non-Candida albicans resistant strains was investigated.

Materials and methods: TRB and FLZ, alone and combined with WIF, were tested by the checkerboard procedure using the micro-dilution technique against seven isolates of Candida glabrata and C. krusei. The molecular interactions occurring outside the cell wall were evaluated by scanning electron microscopy, Fourier transform infrared (FT-IR) and differential scanning calorimetry (DSC) analysis.

Results: The checkerboard inhibitory assay demonstrated synergy for WIF:TRB and WIF:FLZ combinations, respectively. The best synergistic cell damage was demonstrated unequivocally for the associations of WIF and TRB (1.95:4.0?μg/mL) and WIF and FLZ (1.95:8.0?μg/mL). The comparison of the FT-IR spectra of the antifungal alone, and in combination with WIF, allows recognizing clear differences in 3000, 1600, 1400, and 700–800?cm^?1 bands. Additionally, modifications on TRB and FLZ thermograms were clearly noticed after their combination with WIF.

Conclusions: DSC and infrared analysis demonstrated intermolecular interactions between WIF and either TRB or FLZ. Hence, quite likely the synergistic effect is related to interaction events occurring outside the cell wall between antifungal and cat’s claw proanthocyanidins. A direct action on the cell wall is suggested, without connection with the ABC efflux pump mechanism.     

Novel nail penetration enhancer containing vesicles “nPEVs” for treatment of onychomycosis

Context: The systemic treatment of onychomycosis has been hampered by the reported side effects of antifungals in addition to the limited blood circulation to the affected nails. Topical ungual treatment would circumvent the limitations of systemic onychomycosis treatment.

Objective: Preparation and characterization of nail penetration enhancer containing nanovesicles (nPEVs) loaded with sertaconazole for topical treatment of onychomycosis.

Materials and methods: nPEVs were prepared using different nail penetration enhancers (N-acetyl-L-cysteine, thioglycolic acid, thiourea and ethanol) by the thin film hydration method, and characterized for their particle size, zeta potential, entrapment efficiency (EE%), elasticity, viscosity, physical stability and morphology. The selected nPEVs formula and the marketed Dermofix® cream were compared in terms of nail hydration, transungual drug uptake and antifungal activity against Trichophyton rubrum.

Results: N-acetyl-l-cysteine was the optimum nail penetration enhancer for incorporation within vesicles. nPEVs showed high EE% of sertaconazole ranging from 77 to 95%, a size ranging from 38–538?nm and a zeta potential ranging from +48 to +72?mV. The selected nPEVs formula displayed spherical morphology and good storage stability. Compared to the conventional marketed cream, the selected nPEVs formula showed 1.4-folds higher hydration and drug uptake enhancement into nail clippings. Furthermore, it showed significantly higher zone of inhibition for Trichophyton rubrum (20.9?±?0.25?mm) than the marketed cream (11.6?±?0.44?mm).

Conclusion: Nail penetration enhancer containing nanovesicles (nPEVs) present a very promising option, worthy of clinical experimentation on onychomycotic patients.     

Topical ketoprofen nanogel: artificial neural network optimization,clustered bootstrap validation,and in vivo activity evaluation based on longitudinal dose response modeling

Objectives: This work aimed at investigating the potential of solid lipid nanoparticles (SLN) as carriers for topical delivery of Ketoprofen (KP); evaluating a novel technique incorporating Artificial Neural Network (ANN) and clustered bootstrap for optimization of KP-loaded SLN (KP-SLN); and demonstrating a longitudinal dose response (LDR) modeling-based approach to compare the activity of topical non-steroidal anti-inflammatory drug formulations.

Methods: KP-SLN was fabricated by a modified emulsion/solvent evaporation method. Box–Behnken design was implemented to study the influence of glycerylpalmitostearate-to-KP ratio, Tween 80, and lecithin concentrations on particle size, entrapment efficiency, and amount of drug permeated through rat skin in 24?hours. Following clustered bootstrap ANN optimization, the optimized KP-SLN was incorporated into an aqueous gel and evaluated for rheology, in vitro release, permeability, skin irritation and in vivo activity using carrageenan-induced rat paw edema model and LDR mathematical model to analyze the time course of anti-inflammatory effect at various application durations.

Results: Lipid-to-drug ratio of 7.85 [bootstrap 95%CI: 7.63–8.51], Tween 80 of 1.27% [bootstrap 95%CI: 0.601–2.40%], and Lecithin of 0.263% [bootstrap 95%CI: 0.263–0.328%] were predicted to produce optimal characteristics. Compared with profenid® gel, the optimized KP-SLN gel exhibited slower release, faster permeability, better texture properties, greater efficacy, and similar potency.

Conclusions: SLNs are safe and effective permeation enhancers. ANN coupled with clustered bootstrap is a useful method for finding optimal solutions and estimating uncertainty associated with them. LDR models allow mechanistic understanding of comparative in vivo performances of different topical formulations, and help design efficient dermatological bioequivalence assessment methods.     

Efinaconazole 10% topical solution for the topical treatment of onychomycosis of the toenail

Efinaconazole 10% topical solution is a new antifungal therapy for the topical treatment of mild to moderate toenail onychomycosis. In vitro and in vivo data have shown significant antifungal activity against dermatophytes, Candida spp. and nondermatophyte molds, and its mechanism of action is through inhibition of fungal lanosterol 14α-demethylase. In two parallel, double-blind, randomized, controlled, Phase III trials, complete cure rates were 17.8 and 15.2%, respectively, and mycological cure rates were 55.2 and 53.4%, respectively, for efinaconazole 10% topical solution, which were superior to vehicle, with minimal adverse events. This drug profile reviews the most recent basic science and clinical data for efinaconazole in the treatment of toenail onychomycosis.     

Reversal of fluconazole resistance induced by a synergistic effect with Acca sellowiana in Candida glabrata strains

Context: The increased incidence of non-albicans Candida (NAC) resistant to fluconazole (FLZ) makes it necessary to use new therapeutic alternatives. Acca sellowiana (O.berg) Burret (Myrtaceae) is a guava with several proven biological activities. The interaction with fluconazole can be a feasible alternative to overcome this resistance.

Objective: This study evaluates the in vitro antifungal activity of fractions obtained from the lyophilized aqueous extract of the leaves of A. sellowiana against resistant strains of NAC.

Materials and methods: The antifungal activity of the fractions was evaluated at 500?μg/mL by microdilution method. Checkerboard assay was performed to determine the effect of the combination of the F2 fraction and antifungal at concentrations: MIC/4, MIC/2, MIC, MIC?×?2 and MIC?×?4.

Results: Candida glabrata showed the lowest MIC values (500–3.90?μg/mL) and the F2 active fraction was the most effective. The association of F2 with FLZ showed a strong synergistic effect (FICI?≤?0.5) against 100% of C. glabrata resistant isolates. Moreover, the F2 active fraction has demonstrated that probably acts in the cell wall of these yeasts. There was no observed acute dermal toxicity of lyophilized aqueous extract of leaves of A. sellowiana on pig ear skin cells.

Discussion and conclusion: The interaction between substances present in the F2 active fraction is possibly responsible for the antifungal activity presented by this fraction. This study is unprecedented and suggests that the combination of F2 active fraction and FLZ might be used as an alternative treatment for mucocutaneus infections caused by C. glabrata resistant.     

Novel solidified reverse micellar solution-based mucoadhesive nano lipid gels encapsulating miconazole nitrate-loaded nanoparticles for improved treatment of oropharyngeal candidiasis

Objective: To develop and evaluate solidified-reverse-micellar-solution (SRMS)-based oromucosal nano lipid gels for improved localised delivery of miconazole nitrate (MN).

Methods: Phospholipon^® 90G and Softisan^® 154 (3:7) were used to prepare SRMS by fusion. Solid lipid nanoparticles (SLNs, 0.25–1.0% w/w MN) formulated with the SRMS by high shear homogenisation were employed to prepare mucoadhesive nano lipid gels. Physicochemical characterisation, drug release in simulated salivary fluid (SSF) (pH 6.8) and anti-candidal activity were carried out.

Results: The SLNs were spherical nanoparticles, had mean size of 133.8?±?6.4 to 393.2?±?14.5?nm, low polydispersity indices, good encapsulation efficiency (EE) (51.96?±?2.33–67.12?±?1.65%) and drug loading (DL) (19.05?±?2.44–24.93?±?1.98%). The nano lipid gels were stable, spreadable, pseudoplastic viscoelastic mucoadhesive systems that exhibited better prolonged release and anti-candidal properties than marketed formulation (Daktarin^® oral gel) (p?Conclusion: This study has shown that SRMS-based nano lipid gels could be employed to prolong localised oromucosal delivery of MN.     

Thermoreversible gel for delivery of activin receptor-like kinase 5 inhibitor SB-505124 for glaucoma filtration surgery

The purpose of this study is to investigate a thermoreversible gel using Pluronic^® F-127 to deliver an activin receptor-like kinase 5 (ALK-5) inhibitor SB-505124 in glaucoma filtration surgery (GFS). The gel was characterized for in vitro drug release and viscosity studies. Cytotoxicity of Pluronic® F-127 was examined by MTT assay using cultured rabbit subconjunctival fibroblasts. In addition, Pluronic® F-127 gel (18% w/v) containing 5?mg of SB-505124 was applied at the surgical site in an in vivo rabbit GFS model. In the in vitro viscosity study, the gel showed a change in viscosity (from 1000 cps to 45,000 cps) from low temperature (10°C) to body temperature (37°C). The in vitro drug release study demonstrated 100% drug release within 12?h. The gel did not show cytotoxicity to the cultured rabbit subconjunctival cells by MTT assay. In the in vivo rabbit GFS model, the drug was successfully delivered by injection and no severe post-surgical complications were observed. A thermoreversible gel system with SB-505124 was successfully prepared and delivered for the rabbit GFS model, and it may provide a novel delivery system in GFS.     

Fluconazole nanoparticles prepared by antisolvent precipitation technique: Physicochemical,in vitro,ex vivo and in vivo ocular evaluation

The goal of this research was to prepare and characterize nanonized particles of the antifungal drug, fluconazole (FLZ) using antisolvent precipitation nanonization technique to improve its ocular permeation. The impact of various concentrations of different stabilizers, namely Pluronic F-127 (PL F 127), Kollicoat IR (KL), hydroxypropyl methylcellulose E3 (HPMC), xanthan gum (XG), polyvinyl pyrrolidone K30 (PVP), and sodium lauryl sulfate (SLS) upon the resulting nanoparticles was investigated. Additionally, the ex vivo release of the FLZ nanonized particles from ophthalmic gel bases was studied by using goat cornea, and the ocular pharmacokinetics of appropriate ophthalmic gel base containing optimized drug nanoparticle formula compared to the untreated drug were studied in rabbits. FLZ nanoparticles were successfully prepared with different concentrations of stabilizers. However, the effects of these stabilizers on nanoparticle size and zeta potential values varied according to the concentration and type of stabilizer used. Based on differential scanning calorimetry, the drug was in its amorphous state in the tested nanoparticle formulations. The results of ex vivo ocular diffusion of the FLZ nanoparticle gel formulations revealed an improvement compared to that with the FLZ untreated gel. Nanoparticle formula (F3) prepared by using 5% PL F127 showed small particle size (352 ± 6.1 nm) with zeta potential value of −18.3 mV with highest ex vivo release rate from goat cornea (100% after 6 h). Moreover, the AUC_0-8h from ocular application of FLZ from sodium alginate gel containing nanoparticle formula F3 was 1.4-fold higher than that after its administration in the untreated formula. Based on our findings, the ophthalmic gel formulations containing FLZ nanoparticles enhanced drug corneal permeation and improved the ocular pharmacokinetic parameters.     

Cytotoxicity of Solid Lipid Nanoparticles as a Function of the Lipid Matrix and the Surfactant

Purpose. Assessment of the in vitro cytotoxicity of solid lipid nanoparticles (SLNs) as a function of lipid matrix (Dynasan 114, Compritol ATO 888), and stabilizing surfactant (poloxamers, Tween 80, soya lecithin, and sodium dodecyl sulphate). Comparison with other colloidal carriers should determine their potential use in the clinic. Methods. SLNs were produced by high pressure homogenisation. Cytotoxicity was assessed by measuring the viability of HL60 cells and human granulocytes after incubation with SLNs. Particle internalisation was quantified by chemiluminescence measurements. Results. The nature of the lipid had no effect on viability; distinct differences were found for the surfactants. Binding to the SLN surface reduced markedly the cytotoxic effect of the surfactants, e.g., up to a factor of 65 for poloxamer 184. The permanent HL60 cell line— differentiated from cells with granulocyte characteristics by retinoic acid treatment—yielded results identical to freshly isolated human granulocytes. In general, the SLNs showed a lower cytotoxicity compared to polyalkylcyanoacrylate and polylactic/glycolic acid (PLA/ GA) nanoparticles. Conclusions. Because the results are identical when using human granulocytes, differentiated HL60 cells can be used as an easily accessible in vitro test system for i.v. injectable SLN formulations. The SLNs appear suitable as a drug carrier system for potential intravenous use due to their very low cytotoxicityin vitro.