Solid lipid-based nanoparticulate system for sustained release and enhanced in-vitro cytotoxic effect of 5-fluorouracil on skin Melanoma and squamous cell carcinoma.

The present study aimed to prepare solid lipid-based nanoparticles (SLNs) using Precirol® ATO 5 as solid lipid and Poloxamer 188 and Tween 80 as surfactant and co-surfactant respectively, and SLNs-derived gel for sustained delivery, enhanced in-vitro cytotoxicity, enhanced cellular uptake of 5-FU and enhanced permeation of 5-FU across the skin. The 5-FU-loaded SLNs were prepared by the hot melt encapsulation method and converted into SLN-derived gel using a gelling agent (Carbopol 940). The 5-FU-loaded SLNs had a particle size in the range of 76.82±1.48 to 327±4.46 nm, zeta potential between -11.3±2.11 and -28.4±2.40 mV, and entrapment efficiency (%) in range of 63.46±1.13 and 76.08±2.42. The FTIR analysis depicted that there was no chemical interaction between 5-FU and formulation components. Differential scanning calorimetric analysis showed thermal stability of 5-FU in the nanoparticles and powdered X-ray diffraction analysis revealed successful incorporation of 5-FU in nanoparticles. The in-vitro release study of 5-FU-loaded SLNs showed biphasic release behavior with initial burst release followed by sustained release over 48 hr. The 5-FU-loaded SLNs showed a greater cytotoxic effect on skin melanoma (B16F10 cells) and squamous cell carcinoma (A-431 cells) as compared to free 5-FU drug solution after 48 hr. Flow cytometry and fluorescence microscopy displayed enhanced quantitative and qualitative cellular uptake of SLNs. The SLNs formulation showed acceptable safety and biocompatible profile after an acute toxicity study in Wistar rats. Moreover, ex-vivo permeation studies depicted 2.13±0.076 folds enhanced flux of 5-FU-loaded SLN derived gel compared to 5-FU plain gel, and skin retention studies revealed target efficiency (%) 2.54±0.03 of 5-FU-loaded SLN derived gel compared to 5-FU plain gel.

Ionically Cross-Linked Chitosan Nanoparticles for Sustained Delivery of Docetaxel: Fabrication, Post-Formulation and Acute Oral Toxicity Evaluation.

INTRODUCTION: Polymeric nanoparticles are potential carriers for the efficient delivery of hydrophilic and hydrophobic drugs due to their multifaceted applications. Docetaxel is relatively less hydrophobic and twice as potent as paclitaxel. Like other taxane chemotherapeutic agents, docetaxel is not well tolerated and shows toxicity in the patients. Nanoencapsulation of potent chemotherapeutic agents has been shown to improve tolerability and therapeutic outcome. Therefore, the present study was designed to fabricate chitosan and sodium tripolyphosphate (STPP) based on ionically cross-linked nanoparticles for sustained release of docetaxel. METHODS: Nanoparticles were prepared by the ionic-gelation method by dropwise addition of the STPP solution into the chitosan solution in different ratios. CNPs were characterized for post-formulation parameters like size, zeta potential, scanning electron microscope (SEM), FTIR, DSC/TGA, pXRD, and in-vitro drug release, as well as for acute oral toxicity studies in Wistar rats. RESULTS AND DISCUSSION: The optimized docetaxel loaded polymeric nanoparticles were in the size range (172.6nm-479.65 nm), and zeta potential (30.45-35.95 mV) required to achieve enhanced permeation and retention effect. In addition, scanning electron microscopy revealed rough and porous surface, whereas, FTIR revealed the compatible polymeric nanoparticles. Likewise, the thermal stability was ensured through DSC and TG analysis, and powder X-ray diffraction analysis exhibited solid-state stability of the docetaxel loaded nanoparticles. The in-vitro drug release evaluation in phosphate buffer saline (pH 7.4) showed sustained release pattern, i.e. 51.57-69.93% within 24 hrs. The data were fitted to different release kinetic models which showed Fickian diffusion as a predominant release mechanism (R2 = 0.9734-0.9786, n= 0.264-0.340). Acceptable tolerability was exhibited by acute oral toxicity in rabbits and no abnormality was noted in growth, behavior, blood biochemistry or histology and function of vital organs. CONCLUSION: Ionically cross-linked chitosan nanoparticles are non-toxic and biocompatible drug delivery systems for sustained release of chemotherapeutic agents, such as docetaxel.

Enhancement of Dissolution and Skin Permeability of Pentazocine by Proniosomes and Niosomal Gel.

Proniosomes (PN) are the dry water-soluble carrier systems that may enhance the oral bioavailability, stability, and topical permeability of therapeutic agents. The low solubility and low oral bioavailability due to extensive first pass metabolism make Pentazocine as an ideal candidate for oral and topical sustained release delivery. The present study was aimed to formulate the PNs by quick slurry method that are converted to niosomes (liquid dispersion) by hydration, and subsequently formulated to semisolid niosomal gel. The PNs were found in spherical shape in the SEM and stable in the physicochemical and thermal analysis (FTIR, TGA, and XRD). The quick slurry method produced high recovery (> 80% yield) and better flow properties (θ = 28.1-37.4°). After hydration, the niosomes exhibited desirable entrapment efficiency (44.45-76.23%), size (4.98-21.3 µm), and zeta potential (- 9.81 to - 21.53 mV). The in vitro drug release (T100%) was extended to more than three half-lives (2-4 h) and showed good fit to Fickian diffusion indicated by Korsmeyer-Peppas model (n = 0.136-0.365 and R2 = 0.9747-0.9954). The permeation of niosomal gel was significantly enhanced across rabbit skin compared to the pure drug-derived gel. Therefore, the PNs are found promising candidates for oral as dissolution enhancement and sustained release for oral and topical delivery of pentazocine for the management of cancer pain.

Development of Eudragit RS 100 Microparticles Loaded with Ropinirole: Optimization and In Vitro Evaluation Studies.

The current study aimed to develop novel pH independent microparticles loaded with ropinirole (ROP) for sustained drug release. Eudragit RS 100 was used as release retardant and microparticles were fabricated by oil-in-oil emulsion solvent evaporation method. A three-factor three-level Box-Behnken design using Design-Expert software was employed to optimize formulation variables. Ropinirole loaded microparticles were evaluated with respect to morphology, particle size, encapsulation efficiency, and in vitro release profile. Optical microscopy and SEM micrographs indicated spherical shape with smooth surface and well-defined boundary. The particle size was in the range of 98.86 to 236.29 µm, being significantly increased with increasing polymer concentration. Higher polymer load also increased the thickness of internal polymer network, which led to reduced drug loss and higher entrapment efficiency (89%). The cumulative in vitro release was found to be in the range of 54.96 to 99.36% during the release studies (12 h) following zero order release kinetics and non-Fickian diffusion pattern. The developed microparticles have the potential to sustain the release of ropinirole, which may lead to a reduction in its adverse effects and improved management of Parkinson's disease.

Solid and liquid lipid-based binary solid lipid nanoparticles of diacerein: in vitro evaluation of sustained release, simultaneous loading of gold nanoparticles, and potential thermoresponsive behavior.

Binary fatty acid mixture-based solid lipid nanoparticles (SLNs) were prepared for delivery of diacerein, a novel disease-modifying osteoarthritis drug, with and without simultaneously loaded gold nanoparticles (GNPs). In order to optimize SLNs for temperature-responsive release, lipid mixtures were prepared using different ratios of solid (stearic acid or lauric acid) and liquid (oleic acid) fatty acids. SLNs were prepared by microemulsification (53 nm), hot melt encapsulation (10.4 nm), and a solvent emulsification-evaporation technique (7.8 nm). The physicochemical characteristics of SLNs were studied by Zetasizer, Fourier transform infrared, and X-ray diffraction analysis. High encapsulation of diacerein was achieved with diacerein-loaded and simultaneously GNP-diacerein-loaded SLNs. In vitro dissolution studies revealed a sustained release pattern for diacerein over 72 hours for diacerein-loaded SLNs and 12 hours for GNP-diacerein-loaded SLNs. An increase in diacerein payload increased the release time of diacerein while GNPs decreased it. In addition, rapid release of diacerein over 4 hours was observed at 40°C (melting point of optimized fatty acid mixture), demonstrating that these binary SLNs could be used for thermoresponsive drug delivery. Kinetic modeling indicated that drug release followed zero order and Higuchi diffusion models (R(2)>0.9), while the Korsmeyer-Peppas model predicted a diffusion release mechanism (n<0.5).

Formulation design and characterization of a non-ionic surfactant based vesicular system for the sustained delivery of a new chondroprotective agent

Diacerein is used for symptomatic relief and cartilage regeneration in osteoarthritis. Due to gastrointestinal side effects, poor aqueous solubility and low bioavailability, its clinical usage has been restricted. The objective of the present study was to enhance its dissolution profile and to attain sustained release by designing a novel delivery system based on niosomes. Five niosomal formulations (F1-F5) with non-ionic surfactant (sorbitan monostearate) and cholesterol in varying ratios of 5:5, 6:4, 7:3, 8:2 and 9:1 were developed by the reverse-phase evaporation technique. The size and polydispersivity index (PDI) were found in the range of 0.608 µm to 1.010 µm and 0.409 to 0.781, respectively. Scanning electron microscopy (SEM) of the selected formulation (F3) revealed spherical vesicles, and 79.8% entrapment was achieved with F3 (7:3). Dissolution studies using the dialysis method showed sustained release behaviour for all formulations. The optimized surfactant-to-cholesterol concentration (7:3) in formulation F3sustained the drug-release time (T50%) up to 10 hours. Kinetic modelling exhibited a zero-order release (R2=0.9834) and the release exponent 'n' of the Korsmayer-Peppas model (n=0.90) confirmed non-fickian and anomalous release. The results of this study suggest that diacerein can be successfully entrapped into niosomes using sorbitan monostearate and that these niosomes have the potential to deliver diacerein efficiently at the absorption site.

A diacereína é usada para o alívio sintomático e para a regeneração da cartilagem na osteoartrite. Devido aos efeitos adversos gastrointestinais, baixa solubilidade aquosa e biodisponibilidade, o seu uso clínico tem sido restrito. O objetivo do presente estudo foi melhorar o perfil de dissolução deste fármaco e obter liberação prolongada através do planejamento de um novo sistema de liberação designado de niossoma. Cinco formulações distintas de niossomas (F1 a F5) contendo tensoativos não iônicos (monoestearato de sorbitano) e colesterol, em diferentes proporções, de 5:5, 6:4, 7:3, 8:2 e 9:1, foram desenvolvidas através da técnica de evaporacão de fase reversa. Os tamanhos e índices de polidispersibilidade (PDI) obtidos variam entre 0,608 e 1,01 µm e entre 0,409 e 0,7781, respectivamente. Imagens de microscopia electrônica de varrimento (SEM) da formulação selecionada (F3) revelaram vesículas esféricas. Obteve-se encapsulação de 79,8% com a formulação F3 (7:3). Estudos de dissolução usando o método de diálise demonstraram padrão de liberacão prolongada para todas as formulações. A proporção de tensoativo e colesterol (7:3) na formulacão F3 prolongou o tempo de liberação do fármaco (T50%) até 10 horas. Estudos de modelação cinética demonstraram ordem de liberacão zero (R2=0,9834) e o expoente de liberação "n" do modelo de Korsmayer-Peppas (n=0.90) confirmou a liberação não-fickiana e anômala. Os resultados deste estudo sugerem que a diacereína pode ser encapsulada com sucesso no interior de niossomas, utilizando monostearato de sorbitano, o qual tem potencial para liberar, eficientemente, a diacereína no local de absorção.