Preparation of niosomes as an ocular delivery system for naltrexone hydrochloride : physicochemical characterization

Recent reports have demonstrated that topical and systemic application of naltrexone markedly improves the characteristic signs of diabetic keratopathy; most notably, impaired corneal sensation and delayed wound repair. The aim of this study was to prepare and characterise non-ionic surfactant vesicles (niosomes) for the ocular drug delivery of naltrexone hydrochloride. The niosomes were prepared using the thin film hydration method and characterised using polarized light microscopy, cryo-scanning electron microscopy (Cryo-SEM), percent drug entrapment efficiency (EE %), laser light diffraction and differential scanning calorimetry (DSC). Two classes of non-ionic surfactants (sorbitan esters and polyoxyethylene alkyl ethers) were investigated. The results revealed that tuning of cholesterol concentrations can significantly alter the niosome's physical properties including sizes, EE% and membrane fluidity (thermo-responsiveness). The prepared vesicles were in the range of 7.0 +/- 1.0 to 14.6 +/- 0.8 microm in size. The prepared niosomes showed different abilities to accommodate cholesterol. This was highly dependent on the structure and continuity of the hydrophobic chains of the used surfactants. Span 60-based vesicles containing 30% mol/mol of cholesterol showed the highest EE%. The microstructure and lamellarity of the niosomes were studied using Cryo-SEM. Typical concentric multilayered structures (onion or rose-like) were seen suggesting the formation of multilamellar vesicles. DSC-studies conducted on Span 60-based niosomes containing 30% mol/mol cholesterol revealed liquid-gel transition (T(m) and entropy of 43.5 degrees C and 0.82 kcal/mol, respectively). Such transition reflects potential thermo-responsive properties, which is desirable for ocular delivery

In-Vitro and in-vivo evaluation of carrageenan/methylcellulose polymeric systems for transscleral delivery of macromolecules

In this study, polymeric dispersions composed of methylcellulose (MC) and either kappa carrageenan (KC) or iota carrageenan (IC) were proposed as a platform for transscleral delivery of macromolecules. The additive effects of the two polymers were investigated using oscillatory rheometer and FT-IR spectroscopy. Mechanical spectra demonstrated a conformation dependent association of the two polymers at 37 °C in the presence of selected counter ions. The polymer association was also confirmed by the shifts in MC peaks at 1049.5, 1114 and 1132.9 cm(-1) in the presence of carrageenans, which corresponds to the stretching vibrations of C-O-C bonds of the polysaccharides. The MC-IC polymeric system displayed the highest bio-adhesion, owing to the relatively high negative charge. However, the MC-IC system did not affect the in-vitro scleral permeability of sodium fluorescein and 10 kDa FITC-dextran. Nonetheless, the formulation properties had a substantial impact on the results of the in-vivo studies. The efficacy of transscleral drug delivery was determined using rats with altered connexin 43 (Cx43) levels, a gap junction protein, in the choroid. Periocular injection of Cx43 antisense oligonucleotides (AsODN) incorporated in the MC-IC system lead to a significant reduction in the Cx43 levels in the choroid of rats at 24 h of treatment. AsODN incorporated in phosphate buffered saline (PBS) also demonstrated a trend towards reduced Cx43 levels; however this was not statistically significant owing to great variability between treated animals. Consequently the in-vivo data suggests the transscleral route to be of value in delivering therapeutics to the choroid. Moreover this study identified a new polymeric system based on MC and IC which provides aqueous loading of therapeutics and prolonged retention at the site of administration

Molecular descriptors that influence the amount of drugs transfer into human breast milk

Most drugs are excreted into breast milk to some extent and are bioavailable to the infant. The ability to predict the approximate amount of drug that might be present in milk from the drug structure would be very useful in the clinical setting. The aim of this research was to simplify and upgrade the previously developed model for prediction of the milk to plasma (M/P) concentration ratio, given only the molecular structure of the drug. The set of 123 drug compounds, with experimentally derived M/P values taken from the literature, was used to develop, test and validate a predictive model. Each compound was encoded with 71 calculated molecular structure descriptors, including constitutional descriptors, topological descriptors, molecular connectivity, geometrical descriptors, quantum chemical descriptors, physicochemical descriptors and liquid properties. Genetic algorithm was used to select a subset of the descriptors that best describe the drug transfer into breast milk and artificial neural network (ANN) to correlate selected descriptors with the M/P ratio and develop a QSAR. The averaged literature M/P values were used as the ANN's output and calculated molecular descriptors as the inputs. A nine-descriptor nonlinear computational neural network model has been developed for the estimation of M/P ratio values for a data set of 123 drugs. The model included the percent of oxygen, parachor, density, highest occupied molecular orbital energy (HOMO), topological indices (χV2, χ2 and χ1) and shape indices (κ3, κ2), as the inputs had four hidden neurons and one output neuron. The QSPR that was developed indicates that molecular size (parachor, density) shape (topological shape indices, molecular connectivity indices) and electronic properties (HOMO) are the most important for drug transfer into breast milk. Unlike previously reported models, the QSPR model described here does not require experimentally derived parameters and could potentially provide a useful prediction of M/P ratio of new drugs only from a sketch of their structure and this approach might also be useful for drug information service. Regardless of the model or method used to estimate drug transfer into breast milk, these predictions should only be used to assist in the evaluation of risk, in conjunction with assessment of the infant's response

Preparation and optimization of monodisperse polymeric microparticles using modified vibrating orifice aerosol generator for controlled delivery of letrozole in breast cancer therapy

Letrozole (LTZ) is effective for the treatment of hormone-receptor-positive breast cancer in postmenopausal women. In this work, and for the first time, using vibrating orifice aerosol generator (VOAG) technology, monodisperse poly-�-caprolactone (PCL), and poly (D, L-Lactide) (PDLLA) LTZ-loaded microparticles were prepared and found to elicit selective high cytotoxicity against cancerous breast cells with no apparent toxicity on healthy cells in vitro. Plackett?Burman experimental design was utilized to identify the most significant factors affecting particle size distribution to optimize the prepared particles. The generated microparticles were characterized in terms of microscopic morphology, size, zeta potential, drug entrapment efficiency, and release profile over one-month period. Long-term cytotoxicity of the microparticles was also investigated using MCF-7 human breast cancer cell lines in comparison with primary mammary epithelial cells (MEC). The prepared polymeric particles were monodispersed, spherical, and apparently smooth, regardless of the polymer used or the loaded LTZ concentration. Particle size varied from 15.6 to 91.6 �m and from 22.7 to 99.6 �m with size distribution (expressed as span values) ranging from 0.22 to 1.24 and from 0.29 to 1.48 for PCL and PDLLA based microparticles, respectively. Upon optimizing the manufacture parameters, span was reduced to 0.162?0.195. Drug entrapment reached as high as 96.8%, and drug release from PDLLA and PCL followed a biphasic zero-order release using 5 or 30% w/w drug loading in the formulations. Long-term in vitro cytotoxicity studies indicated that microparticles formulations significantly inhibited the growth of MCF-7 cell line over a prolonged period of time but did not have toxic effects on the normal breast epithelial cells. ? 2018, ? 2018 Informa UK Limited, trading as Taylor & Francis Group.Qatar University Qatar Foundation Qatar National Research FundScopu

A study of microemulsions as prolonged-release injectables through in-situ phase transition

Microemulsions (MEs) have been studied extensively as colloidal carriers for the delivery of both water-soluble and lipid-soluble drugs. Our previous study showed that addition of water to ME formulations resulted in phase transition to either liquid crystal (LC) or coarse emulsion (CE). The aim of this study was to investigate whether these MEs could be used as drug delivery vehicles for prolonged release through in-situ phase transition following extravascular injection. Three ME formulations from the same pseudo-ternary phase diagram were investigated with respect to their phase transition behavior, and in-vivo drug release; a coarse emulsion-forming ME (CE-ME), an oil rich LC-forming ME (LC-ME1), and an oil poor LC-forming ME (LC-ME2). CE-ME was a W/O ME and both LC-MEs were O/W type. The release profiles of (99m)Tc labeled MEs following subcutaneous (SC) injection in rabbits were investigated with gamma-scintigraphy. The CE-ME dispersed readily in water, forming a CE, whereas the LC-forming MEs formed 'depots' in water. Polarized microscopy revealed a LC boundary spontaneously formed at the water/ME interface for the LC-MEs with the LC-ME2 forming a substantially thicker LC layer. The CE resulting from the water-induced transition of the CE-forming ME had a higher viscosity than the MEs, but lower than the LCs resulted from LC-MEs. Compared to LC-ME1, LC-ME2 underwent more rapid phase transition and the resultant LC had significant higher viscosity. The LCs formed from both ME formulations exhibited pseudoplastic properties; increasing the shear rate decreased the apparent viscosity exponentially. Following SC injection into the animal thigh, the LC-MEs had more prolonged release of (99m)Tc in a first-order manner, than CE-ME. The oil poor LC-ME2 had the slowest release with a t1/2 of 77min, 2.3 times longer than the oil rich LC-ME1; consistent with the thickness of LC layer formation observed in-vitro and their relative viscosities. In conclusion, the present in-vivo study has demonstrated the application of MEs as extravascular injectable drug delivery systems for sustained release. The retention of the vehicles at the injection site and the release rate were determined predominantly by their phase transition rather than ME type or oil content