Comparative evaluation of the effect of permeation enhancers, lipid nanoparticles and colloidal silica on in vivo human skin penetration of quercetin.

BACKGROUND/AIM: The aim of this study was to evaluate emulsions containing a penetration enhancer, lipid nanoparticles (LNs) or colloidal silica as systems to improve the topical delivery of the flavonoid quercetin. METHODS: The skin penetration of quercetin was investigated in vivo on human volunteers by tape stripping. Quercetin-loaded LNs were prepared using hot high-pressure homogenization and characterized by means of dynamic light scattering and release studies. The location of the silica nanoparticles in the skin was determined by inductively coupled plasma mass spectrometry assay of silicon in the stratum corneum strips. RESULTS AND CONCLUSIONS: The penetration enhancer diethylene glycol monoethyl ether did not produce any significant increase in the fraction of the applied quercetin dose permeated in vivo into human stratum corneum (17.1 ± 3.2%) compared to the control emulsion (18.1 ± 2.3%). A greater but statistically nonsignificant accumulation of the flavonoid in the human horny layer (21.2 ± 2.9% of the applied dose) was measured following topical application of quercetin-loaded LNs (mean particle size: 527 nm). On the other hand, the addition of colloidal silica (average particle diameter: 486 nm) to the emulsion (2%, w/w) significantly increased the in vivo uptake of quercetin by the human stratum corneum to 26.7 ± 4.1% of the applied dose, the enhancing effect on permeation being more marked in the deepest horny layer strips. The measured in vivo skin penetration profile of colloidal silica showed that silica particles diffused down to the intermediate region of the human horny layer and hence could act as carrier for quercetin.

Effect of the surfactant on the availability of piroxicam as a poorly hydrosoluble drug from suppositories.

The use of surfactants in suppository formulations has been suggested to improve availability of poorly soluble drugs. In the present study, different kinds of surfactants have been investigated to clarify the influence on piroxicam release from suppositories formulated with both lipophilic and hydrophilic bases. Two hydrophilic glucose-derivate surfactants, and a polyoxylglyceride amphiphilic surfactant, all with high HLB values, were investigated for their use in improving drug availability. The two glucose derivate surfactants reduced drug availability from both lipophilic suppositories and hydrophilic formulations, according to longer disintegration times and drug micellization. The more complex surfactant, a lauroyl macrogolglyceride, showed an increase in piroxicam availability from lipophilic suppositories at the higher tested concentrations (15% and 20%). Otherwise, when used in hydrophilic formulations, it was less effective in promoting drug release and even reduced drug availability.

Effects of surfactant characteristics on drug availability from suppositories.

The addition of surfactants to suppository formulations is referred to in the scientific literature, but their effects on drug availability remain uncertain. Surfactants are reported to improve drug dispersion into hard fatty excipients, to increase the spreading of the melted suppository on the rectal mucosa leading to a greater contact surface, to reduce the viscosity of the molten mass and to reduce the pathway of drug particles to the interface. In the present study a systematic investigation based on tensiometric and rheological methods was carried out to evaluate the effects of nonionic surfactants with different HLBs (hydrophilic-lipophilic-balance) on drug availability and to clarify the possible mechanisms involved in the release process. The relationship between the melted suppositories and a membrane simulating the rectal barrier were investigated in the course of the in vitro release test by measuring their energy characteristics. At the same time, the potential influences of such interactions on drug release were investigated in suppositories formulated with different kinds and concentrations of surfactant additives. Drug availability was influenced not only by the interaction between the suppository and the rectal membrane but also by the interaction between surfactant, lipophilic excipient and suspended drug particles. Such interactions appear to greatly influence drug release from suppositories, which, in turn, is the main parameter determining drug availability.

Development and bioadhesive properties of chitosan-ethylcellulose microspheres for nasal delivery.

Loratadine-loaded microspheres were prepared by spray-drying of dispersions, emulsions and suspensions differing in polymeric composition and solvents used. Conventional microspheres were obtained by spray-drying of dispersions composed of chitosan (CM) as only polymer, while composed microspheres were obtained by spray-drying of two-phase systems composed of chitosan and ethylcellulose (EC). Microspheres differed in EC/CM weight ratio (0:1, 1:2 and 1:3) and in loratadine/polymers weight ratio (1:6 and 1:8). The entrapment efficiencies were between 67.9 and 86.1%; less loratadine was entrapped as polymer/drug ratio decreased. In comparison to one-phase systems composed of CM as only polymer, spray-drying of two-phase systems composed of both, CM and EC resulted in improved loratadine entrapment (80.1-86.1%). All microspheres were positively charged, indicating the presence of chitosan at the surface, regardless of the drug content and the type of spray-dried system. The highest zeta-potential was measured for loratadine-free conventional microspheres, consisting of chitosan only (32.7+/-1.3 mV). Tensile studies showed that both, EC/CM ratio and the type of spray-dried system influenced the bioadhesive properties of the microspheres in a way that the microspheres with higher chitosan content were more bioadhesive and microspheres prepared from suspensions were more bioadhesive than those prepared from emulsions, regardless of the same polymeric composition. The results suggested that the spray-drying method is useful to produce bioadhesive loratadine-loaded microspheres.

Melt pelletization in high shear mixer using a hydrophobic melt binder: influence of some apparatus and process variables.

The effects of process conditions and the apparatus variables on the granulometric characteristics of a formulation containing a hydrophobic binder (stearic acid), lactose and paracetamol prepared by melt pelletization process were investigated in a 10-litre high shear mixer. The factors under investigation were: impeller speed, massing time, type of impeller blades and presence of the deflector and their reciprocal interactions. Two granule characteristics were analysed: the percentage of aggregates larger than 3000 microm (Y(1)) and the yield of the 2000-microm pellet size fraction (Y(2)). In order to estimate simultaneously the above-mentioned factors, a particular experimental design was adopted, that allowed the reduction of the number of trials from 378 to 35 and took into consideration other uncontrolled factors with the aid of a block variable. Using the postulated model, we found the optimal operating conditions to minimize Y(1) and increase Y(2) by selecting the type of impeller, and by using an impeller speed lower than 300 rpm, a massing time of 8-9 min and by not using the deflector. Finally, the validity of the adopted strategy has been proved with an additional check point.

Characterisation of nimesulide-betacyclodextrins systems prepared by supercritical fluid impregnation.

The purpose of this study was to apply the supercritical CO(2) impregnation process for preparing solvent-free nimesulide (NMS)-betacyclodextrins (BCD) association systems with enhanced drug dissolution rate. Several drug-to-carrier molar ratios were tested (1:1; 1:2.5; 1:3.5) at different conditions of temperatures (40, 100, and 130 degrees C) and pressures (140, 190 or 220 bar). The physical and morphological characterisation of the systems using powder X-ray diffraction, thermal analysis, diffuse reflectance Fourier transform-infrared spectroscopy and scanning electron microscopy was carried out to understand the influence of this technological process on the physical status of single components and binary systems and to detect possible interactions between drug and carrier. These analyses provided no evidence of a complete inclusion of NMS in the carrier but the existence of interactions between drug and carrier together with a partial dehydration of the BCD and the formation of drug crystallites with lower melting point and heat of fusion than the native NMS. These phenomena were more intense when severe conditions of pressure and temperature (220 bar and 130 degrees C) were used during impregnation trials and when the amount of BCD augmented in the systems. These activated solid state of the impregnated systems promoted an enhancement of drug dissolution rate that, in keeping with the results of the physical characterisation, was function of the process conditions and BCD content.

High shear mixer granulation using food grade binders with different thickening power.

Mixer agglomeration, in particular high shear wet granulation, is a unit operation typically used in the pharmaceutical industry to improve the flowability, the compressibility, the dosing accuracy during tableting or the content uniformity of a blend. Thanks to its advantages (production of spherical and dense granules, reduction of production time), this technique can be potentially successful also in the food industry as for example in the production of dietary supplements. In this work four thickening agents (povidone, maltodextrin, k-carrageenan and xanthan gum) have been tested to study their effects on the granule growth behavior and on some technologically relevant granule properties (size, shape, strength and flowability). Experiments highlighted the full feasibility of the process and the possibility of using these agents to get products with satisfactory technological properties. The dependence of product properties on the formulation variables (water and binder amount) has been analyzed according to a multivariate approach and a robust predictive tool for the granule size has been developed. Furthermore it was observed that a reduced amount of binding liquid (water) can be used in the presence of strongly thickening binders with a reduction up to 25%. This would decrease drying time and energy requirement and be beneficial especially in the food and food supply industry where products have generally lower added value than in the pharmaceutical one and reducing production costs is critical.

A new approach to enhance oral bioavailability of Silybum Marianum dry extract: association of mechanochemical activation and spray congealing.

The aim of the work was to produce a delivery system for Silybum Marianum dry extract with enhanced oral bioavailability by combining two technologies (mechanochemical activation and spray congealing). Initially, the active was coground with sodium croscarmellose in a planetary mill in order to reach an activated state more prone to dissolution. DSC, XRD, FT-IR and LD analyses showed the formation of nanosized particles of dry extract, with reduced degree of crystallinity of the main crystalline flavolignans (silybine A and B). Then, microparticles containing the activated coground and, as comparison, the corresponding physical mixture of extract and polymer and the dry extract alone were produced by spray congealing technology using Gelucire(®) 50/13 as a hydrophilic low m.p. carrier. Microparticles containing the activated coground were produced spherical in shape, achieved satisfactory yield and high encapsulation efficiency. These microparticles, in addition to a favourable in vitro solubilisation kinetic, in a preliminary in vivo study in five rats demonstrated their ability to improve very significantly the oral bioavailability of the main flavolignans of Silybum Marianum dry extract (silybin A and B). These results suggested that the association of mechanochemical activation and spray congealing could be considered an innovative and very useful approach to the oral delivery of Silybum Marianum. Furthermore, for the first time the possibility of successfully applying the spray congealing technology for the preparation of a herbal drug delivery system was shown.