Nano-carrier systems: Strategies to overcome the mucus gel barrier.

The present review provides an overview of nanotechnology-based strategies to overcome various mucus gel barriers including the intestinal, nasal, ocular, vaginal, buccal and pulmonary mucus layer without destroying them. It focuses on the one hand on strategies to improve the mucus permeation behavior of particles and on the other hand on systems avoiding the back-diffusion of particles out of the mucus gel layer. Nanocarriers with improved mucus permeation behavior either exhibit a high density of positive and negative charges, bearing mucolytic enzymes such as papain and bromelain on their surface or display a slippery surface due to PEG-ylation. Furthermore, self-nanoemulsifying-drug-delivery-systems (SNEDDS) turned out to exhibit comparatively high mucus permeating properties. Strategies in order to avoid back-diffusion are based on thiolated polymers reacting to a higher extent with cysteine subunits of the mucus at pH 7 in deeper mucus regions than at pH 5 being prevalent in luminal mucus regions of the intestinal and vaginal mucosa. Furthermore, particles changing their zeta potential from negative to positive once they have reached the epithelium seem to be promising carriers. The summarized knowledge should provide a good starting point for further developments in this field.

Deposition and fine particle production during dynamic flow in a dry powder inhaler: a CFD approach.

In this work the dynamic flow as well as the particle motion and deposition in a commercial dry powder inhaler, DPI (i.e., Turbuhaler) is described using computational fluid dynamics, CFD. The dynamic flow model presented here is an extension of a steady flow model previously described in Milenkovic et al. (2013). The model integrates CFD simulations for dynamic flow, an Eulerian-fluid/Lagrangian-particle description of particle motion as well as a particle/wall interaction model providing the sticking efficiency of particles colliding with the DPI walls. The dynamic flow is imposed by a time varying outlet pressure and the particle injections into the DPI are assumed to occur instantaneously and follow a prescribed particle size distribution, PSD. The total particle deposition and the production of fine particles in the DPI are determined for different peak inspiratory flow rates, PIFR, flow increase rates, FIR, and particle injection times. The simulation results for particle deposition are found to agree well with available experimental data for different values of PIFR and FIR. The predicted values of fine particle fraction are in agreement with available experimental results when the mean size of the injected PSD is taken to depend on the PIFR.

Flow and particle deposition in the Turbuhaler: a CFD simulation.

In this work the steady-state flow in a commercial dry powder inhaler device, DPI (i.e., Turbuhaler) is described using computational fluid dynamics. The Navier-Stokes equations are solved using commercial CFD software considering different flow models, i.e., laminar, k-ε, k-ε RNG, and k-ω SST as well as large Eddy simulation. Particle motion and deposition are described using a Eulerian-fluid/Lagrangian-particle approach. Particle collisions with the DPI walls are taken to result in deposition when the normal collision velocity is less than a critical capture velocity. Flow and particle deposition, for a range of mouthpiece pressure drops (i.e., 800-8800 Pa), as well as particle sizes corresponding to single particles and aggregates (i.e., 0.5-20 µm), are examined. The total volumetric outflow rate, the overall particle deposition as well as the spatial distribution of deposition sites in the DPI are determined. The transitional k-ω SST model for turbulent flow was found to produce results most similar to a reference solution obtained with LES, as well as experimental results for the pressure drop in the DPI. Overall, the simulation results are found to be in agreement with the available experimental data for local and total particle deposition.

Synthesis and release studies of shikonin-containing microcapsules prepared by the solvent evaporation method.

Microcapsules, containing the pharmaceutical substance shikonin, were prepared by the solvent evaporation method in order to enhance shikonin stability (reduce photo-oxidation, polymerization), decrease its hydrophobicity and control its release rate. The effect of various parameters, such as type of polymer, type and concentration of surfactant, solvent volume and mastic gum (Pistacia lentiscus resin) content/concentration as core additive, on the characteristics of the produced microcapsules and the release rate of shikonin, were experimentally investigated. Among the polymers tested for matrix, ethylcellulose (EC) of viscosity 10 cp was the most successful; EC 100 cp and mastic gum result in larger/compact particles with no pores and much slower release. Sodium dodecyl sulphate (SDS) results in microcapsules with desirable morphological and physicochemical characteristics, while polyethylene glycol (PEG) and polyvinyl alcohol (PVA) are not indicated as surfactants in shikonin microencapsulation. Decreasing the solvent volume (dichloromethane) results in increased mean particle size and, thus, in slower release rate of shikonin, while the incorporation of mastic gum in the capsule core results in better control of shikonin release. Finally, the combination of EC 10 cp as matrix, mastic gum as core additive, low dichloromethane (DCM) volume and low SDS concentration results in microcapsules with the best characteristics in terms of efficiency, loading, release and particle size distribution.

Synthesis and characterization of cross-linked chitosan microspheres for drug delivery applications.

The present study deals with the synthesis and characterization of cross-linked chitosan microspheres containing an hydrophilic drug, hydroquinone. The microspheres were prepared by the suspension cross-linking method using glutaraldehyde as the cross-linking agent of the polymer matrix. Perfectly spherical cross-linked hydrogel microspheres loaded with hydroquinone were obtained in the size range of 20-100 microm. The effect of the degree of polymer cross-linking, chitosan molecular weight, chitosan concentration and amount of the encapsulated drug on the hydroquinone release kinetics was extensively investigated. It was found that slower drug release rates were obtained from microspheres prepared by using a higher initial concentration of chitosan, a higher molecular weight of chitosan or/and a lower drug concentration. Most importantly, it was shown that the release rate of hydroquinone was mainly controlled by the polymer cross-linking density and, thus, by the degree of swelling of the hydrogel matrix.

Surface characterization of oil-containing polyterephthalamide microcapsules prepared by interfacial polymerization.

Oil-containing polyterephthalamide microcapsules were synthesized by the interfacial polymerization of an oil-soluble monomer (terephthaloyl dichloride, TDC) and a mixture of two water-soluble monomers (diethylenetriamine, DETA, and 1, 6-hexamethylenediamine, HMDA). The influence of several synthesis parameters (e.g. concentration ratio of the two amine monomers, stirring rate, concentration of the steric stabilizer PVA) on the size distribution, the membrane morphology and the electrokinetic properties of the microcapsules, was thoroughly investigated. Morphological analysis by electron microscopy showed a strong dependence of the membrane external morphology on the functionality of the water-soluble amine monomer. High stabilizer concentrations and agitation rates during emulsification favoured the production of smaller microcapsules with non-porous and rigid membranes. The electro-chemical interfacial properties of the microcapsules were investigated using a combination of potentiometric, conductimetric and electrokinetic measurements. The dependence of the mean surface charge density on pH revealed the presence of essentially two kinds of chemical groups (e.g. amino and carboxylic groups) on the microcapsule external surface. The total concentration of surface chemical groups and the isoelectric pH were measured as a function of the microcapsule synthesis conditions. Using the experimental data and an appropriate interfacial ionization model, the ratio of the surface groups densities, R = (S - COOH)/(S NH3(+) ), was evaluated and rationalized with respect to the microcapsules synthesis parameters.

Production of water-containing polymer microcapsules by the complex emulsion/solvent evaporation technique. Effect of process variables on the microcapsule size distribution.

The complex emulsion/solvent evaporation technique was employed for the production of water-containing polymer microcapsules. The inner phase of the microcapsules consisted of an aqueous solution of gelatin. Several polymers (e.g. poly(styrene), poly(methyl methacrylate), ethyl cellulose, poly(vinyl chloride)) were utilized as wall-forming materials and the effect of the polymer type on the size and the surface characteristics of the microcapsules was experimentally investigated. The size of the microcapsules was strongly affected by the conditions applied during the formation of both simple (w/o) and complex (w/o)/w emulsions. Poly(styrene) microcapsules with a mean Sauter diameter in the range of 4-12 microns were prepared by varying the rate of agitation (1500-4000 rpm) and the concentration of stabilizer (potassium oleate, 0.1-1.5% w/v) used in the formation of the (w/o)/w emulsion. High stabilizer concentrations and agitation rates resulted in a significant reduction of the mean size of the complex droplets and in a simultaneous increase of the breadth of the capsule size distribution.

An experimental investigation of enzyme release from poly(vinyl alcohol) crosslinked microspheres.

Crosslinked poly(vinyl alcohol) particles were prepared by the addition of glutaraldehyde into a PVA methanol/water solution in the presence of 0.2 N sulphuric acid. The polymer solution was dispersed in mineral oil in a jacketed vessel, with the aid of a six-blade impeller. Spherical crosslinked particles in the size range 30-80 microns were obtained by varying the degree of agitation or/and the amount of suspending agent. The crosslinked particles, after washing and drying, were placed into a protease enzyme solution for loading. The enzyme-containing water-swollen particles were subsequently removed from the solution and the enzyme release kinetics determined by a UV spectrophotometer. The influence of the degree of crosslinking, ionic strength, pH, particle size, and degree of hydrophilicity of the polymer on the enzyme activity was retained during the adsorption-desorption studies. The release behaviour of enzymes from crosslinked PVA particles exhibited a biphasic kinetic model, with an initial fast release followed by a much slower release rate.

Production of oil-containing polyterephthalamide microcapsules by interfacial polymerization. An experimental investigation of the effect of process variables on the microcapsule size distribution.

Oil-containing polyterephthalamide microcapsules were prepared by the interfacial polymerization technique. The inner phase of the microcapsules consisted of a mixture of an organic solvent, toluene, and a commercial oil, santosol. Microcapsules with mean Sauter diameters in the range 0.5-20 microns were prepared by varying the rate of agitation (2000-7000 rpm) and the concentration of a poly(vinyl alcohol) stabilizer (0.1-1.0 wt% w/v), in the presence of several ionic and non-ionic cosurfactants. High agitation rates resulted in a significant reduction of the mean size of the oil droplets, although a slight increase in the breadth of the droplet size distribution was observed. High concentrations of PVA also resulted in a decrease of the microcapsule size, although the effect of stabilizer concentration was generally less important than that of the agitation speed. Finally, the effect of various ionic and non-ionic cosurfactants on the microcapsule size distribution was investigated. It was found that the addition of a cosurfactant significantly reduced the mean droplet size of the initial emulsion, leading to the formation of microcapsules in the submicron range.