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.

In vivo and in vitro skin permeation of butyl methoxydibenzoylmethane from lipospheres.

Lipid microparticles (lipospheres) loaded with butyl methoxydibenzoylmethane (BMDBM), a widely used UV-A sunscreen agent, were prepared by melt technique and evaluated for skin permeation both in vivo, by tape stripping method, and in vitro, by a flow-through diffusion chamber. Following in vivo human skin application of an O/W emulsion containing 2% of BMDBM loaded in lipospheres, 15% of the applied sunscreen accumulated in the uppermost layers of the stratum corneum without remarkably modifying the skin permeation of the unencapsulated sunscreen. These results were found to be predicted by an in vitro methodology involving the diffusion of BMDBM through a lipophilized synthetic membrane into a hydrophilic receptor phase, simulating the viable epidermis better than an ethanolic receptor phase.

Distribution of drugs in polymers loaded by swelling.

Ethylene:vinyl acetate pellets were loaded at 20 degrees C by swelling the polymer with 1 and 3% (w/v) chloroformic solutions of tolbutamide. The energy dispersive X-ray analysis showed different concentrations of the tolbutamide sulfur in the pellets sections according to the loading time. At the beginning of the loading process, the sulfur in the pellets showed two concentration peaks which later joined in the center of the section before reaching a homogeneous distribution. The concentration peaks might depend on a drug sieving process as the solution flow reaches a less swollen inner area. Therefore, the concentration distribution of the drug would be affected by the size of the polymer network, which is related to the volume of the solvent in the polymer. Another possible explanation of these concentration profiles is that they could be a result of the solvent evaporation process. The concentration distribution of the drug becomes homogeneous only after the complete swelling of all of the polymer.

Alginate microparticles for enzyme peroral administration.

In order to protect protein and peptide drugs against inactivation by different barriers in the gastro-intestinal tract and to improve their absorption, alginate microparticles as a carrier of L-lactate dehydrogenase, were developed by spray-drying technique. However, alginate complexation and spray-drying conditions led to enzyme activity loss. Such a drawback was overcome by using protectant additives (carboxymethylcellulose sodium salt, polyacrylic acid sodium salt, lactose) preventing the enzyme inactivation by both interaction with alginate and experimental conditions, lactose having the most protective effect. Nevertheless, only polyacrylic acid sodium salt provided a microparticulate structure required for the target of the Peyer's patches.

Surface area and crystallinity of Form A of chloramphenicol palmitic and stearic esters: which one is the limiting factor in the enzymatic hydrolysis?

Chloramphenicol stearic and palmitic esters in the polymorphic Form A, when ground for 85 h showed an in-vitro enzymatic hydrolysis rate constant (Khydr), the value of which was the same as that of a commercial Form B. The increase in the rate of the enzymatic hydrolysis was not related to the specific surface area as shown by the fact that the micronized Form A, having a higher specific surface area value than ground Form A, showed the same Khydr as the unground Form A. The Khydr value of the ground Form A could be the result of an increase in the crystalline disorder brought about by the grinding process.

The concentration of the cross-linking agent as a tool for the control of release and swelling properties of gelatin microspheres.

The effect of the concentration of a cross-linking agent (gelatin hardener) on gelatin microspheres was evaluated. A concentration increase of the gelatin hardener (formaldehyde) produced a decrease of drug loading, swelling degree and drug release rate. The cross-linking agent concentration affected also the kinetics of water absorption and drug release. This paper suggests a decreasing significance of the diffusion-type mechanism of drug release as the concentration of the cross-linking agent increased.

[Energy-dispersive X-ray analysis of pharmaceutical formulations]. / L'analisi EDS nello studio di formulazioni farmaceutiche a rilascio modificato.

Energy-dispersive X-ray analysis (EDS) coupled to a scanning electron microscopy (SEM) could represent a valuable tool in the study of solid dosage forms. In particular, EDS can be useful in the control of conventional pharmaceutical formulations by determining the presence and the distribution of characteristic compounds. More recently, the growth in the development of modified release dosage forms needed the determinations of parameters affecting the drug delivery. Among these, drug distribution, elements involved in crosslinking procedures and coatings of "reservoir" systems could easily and rapidly evaluated by EDS analysis. In this paper, we report the theoretical aspects and some applications of the EDS technique especially concerning controlled release dosage forms in order to show the versatility of such an analytical method which could be widely used in the future.

Cellular uptake and toxicity of microparticles in a perspective of polymyxin B oral administration.

Alginate/chitosan microparticles with a mean size less than 1 microm, designed in a previous work for the targeting of polymyxin B to M-cells and, then, to the lymphatic system, were assayed for transport ability by enterocytes. Caco-2 cell monolayer model, combined with confocal microscopy, showed that microparticles were endocytosed by the cells through an energy-dependent process, being the process saturable at 6 h incubation. Furthermore, microparticles maintained the biological activity of the antibiotic and decreased the antibiotic cytotoxicity against Vero cell cultures. Therefore, simultaneous pathways via both M-cells and enterocytes could be proposed for such a microparticulate carrier.

Alginate/chitosan microparticles for tamoxifen delivery to the lymphatic system.

Oral administration of the nonsteroidal anti-estrogen tamoxifen (TMX) is the treatment of choice for metastatic estrogen receptor-positive breast cancer. With the aim to improve TMX oral bioavailability and decrease its side effects, crosslinked alginate microparticles for the targeting to the lymphatic system by Peyer's patch (PP) uptake were developed and in vitro characterized. TMX was molecularly dispersed inside the microparticles and an electrostatic interaction involving the TMX tertiary amine was detected by rheological and FT-IR assays. Microparticles showed a size less than 3mum, then suitability to be taken up by M cells in PP and a positive surface charge. Moreover, TMX loading level as well as in vitro release behaviour was affected by the polymer network connected with the mannuronic/guluronic ratio of the alginate chains.

Polysaccharide film-coating process for freely swellable hydrogels.

In order to control the drug release from coated hydrogels by preventing membrane fractures, an intramembrane freely swellable matrix device was designed by enclosing a void space between a crosslinked poly(vinyl alcohol) (PVA) matrix and a calcium alginate membrane. The highly swellable PVA matrix loaded with diltiazem hydrochloride was obtained by means of a simplified procedure of the polymer crosslinking reaction using glutaraldehyde in solution with ammonium persulfate. The undried swollen matrix was coated with a calcium alginate membrane employing an ionotropic gelation of sodium alginate induced by calcium ions. The subsequent drying process generated a void space separating the inner core from the membrane. The resulting calcium alginate membrane, which was uniform and compact in the structure, increased in thickness according to the coating time. Coating times exceeding 5 min allowed modification of the drug release profile providing, after a short burst period, sustained and constant rate phases in both simulated gastric fluid and simulated intestinal fluid. Because the inner hydrogel expanded freely inside the device, the unstressed and intact membrane could act as the rate-controlling factor in the drug release process. Owing to the pH-dependent behavior of the membrane, most of the drug was delivered in intestinal fluid. Therefore, the device proposed could be advantageously used for drug targeting to the small intestine.

Papaverine hydrochloride release from ethyl cellulose-walled microcapsules.

The mechanism of papaverine hydrochloride release from ethyl cellulose-walled microcapsules in both simulated gastric and intestinal fluid is discussed. The microcapsules were prepared by coacervation using different core: wall ratios. The rupture of the thin-walled microcapsules after release in simulated gastric fluid was shown and attributed to the internal osmotic pressure, supporting a mechanism for drug dissolution. The internal osmotic pressure produced only a few small holes in the thin-walled microcapsules after release in simulated intestinal fluid. No rupture of the thick-walled microcapsules after release in either medium was shown. Therefore these release data fitted diffusion-type kinetics. It is suggested that the internal osmotic pressure developed after penetration of the medium is affected by the ratio between the core dissolution rate and the drug diffusion rate through the wall.

Alginate microparticles for Polymyxin B Peyer's patches uptake: microparticles for antibiotic oral administration.

Microparticles with size less than 3 microm, able to be taken up by M cell of Peyer's patches for the drug delivery to the Gut Associated Limphoid Tissue (GALT), were developed in order to improve oral bioavailability of Polymyxin B (PMB). Less than 3 microm alginate microparticles resistant to gastro-intestinal media were prepared by spray-drying technique and cross-linking by calcium ions and chitosan. The cross-linked microparticles were evaluated for PMB content by spectrophotometric method, alginate/PMB interaction by rheological study, cross-linking degree by EDS analysis and PMB activity by microbiological assay. By modulating the polymer cross-linking degree, cationic PMB interacted on alginate chains leading to a proper PMB loading as well as antibiotic retention in gastric environment and sustained delivery in intestinal fluid. Moreover, the procedure resulted suitable for PMB biological activity preservation.

Effect of montmorillonite on drug release from polymeric matrices.

Drug release from matrices of polyvinyl alcohol was affected by molecular weight and solubility of the drugs (either sodium salicylate or papaverine hydrochloride), and by the matrix loading. - Montmorillonite addition to the matrix formulation modified only the release constant of papaverine hydrochloride owing to drug interaction with the clay by an ionic exchange process. The kinetics exponent was affected a little bit by interaction of the drug with montmorillonite, whereas the influence of the matrix loading was more remarkable.

PVP solid dispersions for the controlled release of furosemide from a floating multiple-unit system.

The poor bioavailability of orally dosed furosemide (FUR) is due to the presence of a biological window in the upper gastrointestinal tract. The purpose of the present study was to develop and optimize in vitro a multiple-unit floating system with increased gastric residence time for FUR. The incomplete release of FUR from the units, related to its low water solubility, led to the preparation and evaluation of different FUR samples to be incorporated into the units. The complete dose release over the actual intragastric residence time of the system (about 8 hr) was achieved by loading both the core and the membrane forming the units with a 1:5 FUR/polyvinylpyrrolidone (FUR/PVP) solid dispersion. Physicochemical analyses suggested the predominant role of the amorphous state of FUR in producing enhanced drug solubility and dissolution rate, which led to the desired release profile from the floating units.

Protein immobilization in crosslinked alginate microparticles.

Oral administration of peptide and protein drugs requires their protection from the acidic and enzymatic degradation in the gastro-intestinal environment and their targeting to the absorption zone. For this purpose, an alginate microsystem, as a carrier of bovine serum albumin (BSA), as a model protein, was developed using a spray-drying technique. A hardening process with Ca2+ and chitosan (CS) provided a system with resistance to the gastro-intestinal barriers and of appropriate size for targeting to the Peyer's patches. The present work aims to evaluate the effects of the ratio of sodium alginate (Na-A) and BSA as well as the pH of the crosslinking medium on the microsystem properties. Microparticle morphological and dimensional characteristics did not change significantly with the formulation variables. BSA loading at a pH value less than the protein isoelectric point (pI) was higher than that at a pH similar to the pI owing to an electrostatic interaction between the charged protein and the polyanionic alginate. The maximum encapsulation efficiency was obtained at the highest Na-A/BSA ratio. Protein release in a simulated gastro-intestinal fluid was not affected by the preparative variables, but was controlled by the pH-dependent nature of the polymer material. Polyacrylamide gel electrophoresis (PAGE) demonstrated the stability of the protein to both the preparative conditions and the gastro-intestinal pH values.

Chitosan-alginate microparticles as a protein carrier.

The oral administration of peptidic drugs requires their protection from degradation in the gastric environment and the improvement of their absorption in the intestinal tract. For these requirements, a microsystem based on cross-linked alginate as the carrier of bovine serum albumin (BSA), used as a model protein, was proposed. A spray-drying technique was applied to BSA/sodium alginate solutions to obtain spherical particles having a mean diameter less than 10 microm. The microparticles were hardened using first a solution of calcium chloride and then a solution of chitosan (CS) to obtain stable microsystems. The cross-linking process was carried out at different CS concentrations and pH values of the cross-linking medium. The CS concentration affected the BSA loading in the microparticles prepared at a pH value less than the protein isoelectric point (pI). Moreover, the BSA loading at a pH value less than the pI was higher than that at a pH similar to the pI regardless of the CS concentration. This finding could be attributable to the formation of a BSA/alginate complex. The evaluation of the interaction between BSA and alginate at different pH values by means rheological measurements confirmed this hypothesis. This approach may represent a promising way to devise a microcarrier system with appropriate size for targeting the Peyer's patches, with appropriate immobilization capacity, and suitable for the oral administration of peptidic drugs.