A vaginal drug delivery model.

Efficient drug delivery at vaginal cavity is often a challenge owing to its peculiar physiological variations including vast differences in pH. Keeping in view this attribute of the target site, the current work was aimed at developing formulation strategies which could overcome this and successfully deliver molecules like itraconazole through SLNs. Optimized SLNs with the given composition was selected for further development into mucoadhesive and thermosensitive gel. Stearic acid and Compritol 888 (1:1, w/w ratio) as lipid, a mixture of 3% Poloxomer 188 and 0.5% sodium taurocholate as surfactant and organic to aqueous ratio of 10:50 was taken. Carbopol 934 and Pluronic F 127 were taken for the development of gel. Optimized gel exhibited a desired gelling temperature (35 °C); viscosity (0.920 PaS) and appreciable in vitro drug release (62.2% in 20 h). MTT assay did not show any cytotoxic effect of the gel. When evaluated in vivo, it did not exhibit any irritation potential despite appreciable bioadhesion. A remarkable decrease in CFUs was also observed in comparison with control and marketed formulation when evaluated in rat infection model. Thus, the proposed study defines the challenges for developing a suitable formulation system overcoming the delivery barriers of the vaginal site.

Optimized permeation enhancer for topical delivery of 5-fluorouracil-loaded elastic liposome using Design Expert: part II.

OBJECTIVE: To prepare and optimize the topical elastic liposome (EL)-loaded carbopol-980 gel of 5-Fluorouracil (5-FU) containing permeation enhancers (azone, propylene glycol (PG) and lauryl alcohol (LA)) and further evaluation for permeation flux of 5-FU, the activation energy and irritation in the rat skin. METHODS: EL formulations were prepared using phosphatidylcholine and varied surfactants (Span 60, Span 80 and Tween-80) by rotator evaporation method and optimized by experimental design. In vitro characterizations dictated the EL containing Span 80 (lipid:surfactant = 7:3) (EL3-S80) for further optimization of gel. Different gel formulations (5% w/w) with varying concentration (1-3%) of permeation enhancers were prepared and evaluated for viscosity, spreadability, the 5-FU permeation and deposition. The activation energy using the Franz diffusion cell and the plausible irritation using the Draize test were assessed on the albino rat and rabbit, respectively. RESULTS AND DISCUSSION: EL3-S80 was selected as an optimized EL owing to maximum desirability (0.99) and enhanced 5-FU flux (187.86 ± 14.1 µg/cm(2)/h). EL3-S80 suspension loaded gels (0.5%) revealed reduced viscosity leading to higher spreadability than blank gel. EL containing 3% azone in gel, EL containing 3% LA in gel and EL containing 3% PG in gel portrayed 187.86 ± 14.1, 117.7 ± 13.4 and 106.7 ± 7.3 µg/cm(2)/h as enhanced 5-FU flux values, respectively as compared to drug solution (8.8 ± 0.76 µg/cm(2)/h). Furthermore, reduced value of activation energy (2.63-folds) and the non-irritancy of gel could be effective and safe. CONCLUSION: ELA-3 gel formulation could be used as an effective and economic gel in cutaneous cancer and skin-related keratoses.

Enhanced stability and permeation potential of nanoemulsion containing sefsol-218 oil for topical delivery of amphotericin B.

AIM: To characterize the enhanced stability and permeation potential of amphotericin B nanoemulsion comprising sefsol-218 oil at varying pH and temperature of aqueous continuous phase. METHODOLOGY: Several batches of amphotericin B loaded nanoemulsion were prepared and evaluated for their physical and chemical stability at different pH and temperature. Also, a comparative study of ex vivo drug permeation across the albino rat skin was investigated with commercial Fungisome® and drug solution at 37 °C for 24 h. The extent of drug penetrated through the rat skin was thereby evaluated using the confocal laser scanning microscopy (CLSM). RESULTS AND CONCLUSIONS: The optimized nanoemulsion demonstrated the highest flux rate 17.85 ± 0.5 µg/cm(2)/h than drug solution (5.37 ± 0.01 µg/cm(2)/h) and Fungisome® (7.97 ± 0.01 µg/cm(2)/h). Ex vivo drug penetration mechanism from the developed formulations at pH 6.8 and pH 7.4 of aqueous phase pH using the CLSM revealed enhanced penetration. Ex vivo drug penetration studies of developed formulation comprising of CLSM revealed enhanced penetration in aqueous phase at pH 6.8 and 7.4. The aggregation behavior of nanoemulsion at both the pH was found to be minimum and non-nephrotoxic. The stability of amphotericin B was obtained in terms of pH, optical density, globular size, polydispersity index and zeta potential value at different temperature for 90 days. The slowest drug degradation was observed in aqueous phase at pH 7.4 with shelf life 20.03-folds higher when stored at 4 °C (3.8 years) and 5-fold higher at 25 °C (0.951 years) than at 40 °C. The combined results suggested that nanoemulsion may hold an alternative for enhanced and sustained topical delivery system for amphotericin B.

Nanocarrier-based topical drug delivery for an antifungal drug.

OBJECTIVE: The conventional liposomal amphotericin B causes many unwanted side effects like blood disorder, nephrotoxicity, dose-dependent side effects, highly variable oral absorption and formulation-related instability. The objective of the present investigation was to develop cost-effective nanoemulsion as nanocarreir for enhanced and sustained delivery of amphotericin B into the skin. METHODS AND CHARACTERIZATIONS: Different oil-in-water nanoemulsions were developed by varying the composition of hydrophilic (Tween(®) 80) surfactants and co-surfactant by the spontaneous titration method. The developed formulation were characterized, optimized, evaluated and compared for the skin permeation with commercial formulation (fungisome 0.01% w/w). Optimized formulations loaded with amphotericin B were screened using varied concentrations of surfactants and co-surfactants as decided by the ternary phase diagram. RESULTS AND DISCUSSION: The maximum % transmittance obtained were 96.9 ± 1.0%, 95.9 ± 3.0% and 93.7 ± 1.2% for the optimized formulations F-I, F-III and F-VI, respectively. These optimized nanoemulsions were subjected to thermodynamic stability study to get the most stable nanoemulsions (F-I). The results of the particle size and zeta potential value were found to be 67.32 ± 0.8 nm and -3.7 ± 1.2 mV for the final optimized nanoemulsion F-I supporting transparency and stable nanoemulsion for better skin permeation. The steady state transdermal flux for the formulations was observed between 5.89 ± 2.06 and 18.02 ± 4.3 µg/cm(2)/h whereas the maximum enhancement ratio were found 1.85- and 3.0-fold higher than fungisome and drug solution, respectively, for F-I. The results of the skin deposition study suggests that 231.37 ± 3.6 µg/cm(2) drug deposited from optimized nanoemulsion F-I and 2.11-fold higher enhancement ratio as compared to fungisome. Optimized surfactants and co-surfactant combination-mediated transport of the drug through the skin was also tried and the results were shown to have facilitated drug permeation and skin perturbation (SEM). CONCLUSION: The combined results suggested that amphotericin B nanoemulsion could be a better option for localized topical drug delivery and have greater potential as an effective, efficient and safe approach.

Concentration-dependent toxicity of iron oxide nanoparticles mediated by increased oxidative stress.

Iron oxide nanoparticles with unique magnetic properties have a high potential for use in several biomedical, bioengineering and in vivo applications, including tissue repair, magnetic resonance imaging, immunoassay, drug delivery, detoxification of biologic fluids, cell sorting, and hyperthermia. Although various surface modifications are being done for making these nonbiodegradable nanoparticles more biocompatible, their toxic potential is still a major concern. The current in vitro study of the interaction of superparamagnetic iron oxide nanoparticles of mean diameter 30 nm coated with Tween 80 and murine macrophage (J774) cells was undertaken to evaluate the dose- and time-dependent toxic potential, as well as investigate the role of oxidative stress in the toxicity. A 15-30 nm size range of spherical nanoparticles were characterized by transmission electron microscopy and zeta sizer. MTT assay showed >95% viability of cells in lower concentrations (25-200 µg/mL) and up to three hours of exposure, whereas at higher concentrations (300-500 µg/mL) and prolonged (six hours) exposure viability reduced to 55%-65%. Necrosis-apoptosis assay by propidium iodide and Hoechst-33342 staining revealed loss of the majority of the cells by apoptosis. H2DCFDDA assay to quantify generation of intracellular reactive oxygen species (ROS) indicated that exposure to a higher concentration of nanoparticles resulted in enhanced ROS generation, leading to cell injury and death. The cell membrane injury induced by nanoparticles studied using the lactate dehydrogenase assay, showed both concentration- and time-dependent damage. Thus, this study concluded that use of a low optimum concentration of superparamagnetic iron oxide nanoparticles is important for avoidance of oxidative stress-induced cell injury and death.

Development and in-vivo evaluation of insulin-loaded chitosan phthalate microspheres for oral delivery.

Novel chitosan phthalate microspheres containing insulin were prepared by emulsion cross-linking technique. The feasibility of these microspheres as oral insulin delivery carriers was evaluated. The pH-responsive release behaviour of insulin from microspheres was analysed. The ability of chitosan phthalate-insulin microspheres to enhance intestinal absorption and improve the relative pharmacological availability of insulin was investigated by monitoring the plasma glucose and insulin level of streptozotocin-induced diabetic rats after oral administration of microspheres at insulin dose of 20 IU kg(-1). In simulated gastric fluid (pH 2.0), insulin release from the microspheres was very slow. However, as the pH of the medium was changed to simulated intestinal fluid (pH 7.4), a rapid release of insulin occurred. The relative pharmacological efficacy for chitosan phthalate microspheres (18.66 +/- 3.84%) was almost four-fold higher than the efficacy of the chitosan phthalate-insulin solution administration (4.08 +/- 1.52%). Chitosan phthalate microspheres sustained the plasma glucose at pre-diabetic level for at least 16 h. These findings suggest that the microsphere is a promising carrier as oral insulin delivery system.

Multiple emulsions: an overview.

Multiple emulsions are complex polydispersed systems where both oil in water and water in oil emulsion exists simultaneously which are stabilized by lipophillic and hydrophilic surfactants respectively. The ratio of these surfactants is important in achieving stable multiple emulsions. Among water-in-oil-in-water (w/o/w) and oil-in-water-in-oil (o/w/o) type multiple emulsions, the former has wider areas of application and hence are studied in great detail. Formulation, preparation techniques and in vitro characterization methods for multiple emulsions are reviewed. Various factors affecting the stability of multiple emulsions and the stabilization approaches with specific reference to w/o/w type multiple emulsions are discussed in detail. Favorable drug release mechanisms and/or rate along with in vivo fate of multiple emulsions make them a versatile carrier. It finds wide range of applications in controlled or sustained drug delivery, targeted delivery, taste masking, bioavailability enhancement, enzyme immobilization, etc. Multiple emulsions have also been employed as intermediate step in the microencapsulation process and are the systems of increasing interest for the oral delivery of hydrophilic drugs, which are unstable in gastrointestinal tract like proteins and peptides. With the advancement in techniques for preparation, stabilization and rheological characterization of multiple emulsions, it will be able to provide a novel carrier system for drugs, cosmetics and pharmaceutical agents. In this review, emphasis is laid down on formulation, stabilization techniques and potential applications of multiple emulsion system.