A. M. Rabasco

Alginate/chitosan particulate systems for sodium diclofenac release

Alginate/chitosan particles were prepared by ionic gelation (Ca2+ and Al3+) for the sodium diclofenac release. The systems were characterized by electron microscopy and differential scanning calorimetry. The ability to release the active substance was examined as a function of some technological parameters and pH of dissolution medium. The release of sodium diclofenac is prevented at acidic pH, while is complete in a few minutes when pH is raised up to 6.4 and 7.2. The alginate/chitosan ratio and the nature of the gelifying cation allow a control of the release rate of the drug. The release mechanism was briefly discussed.

Didanosine extended-release matrix tablets: optimization of formulation variables using statistical experimental design.

Statistical experimental design was applied to evaluate the influence of some process and formulation variables and possible interactions among such variables, on didanosine release from directly-compressed matrix tablets based on blends of two insoluble polymers, Eudragit RS-PM and Ethocel 100, with the final goal of drug release behavior optimization. The considered responses were the percent of drug released at three determined times, the dissolution efficiency at 6 h and the time to dissolve 10% of drug. Four independent variables were considered: tablet compression force, ratio between the polymers and their particle size, and drug content. The preliminary screening step, carried out by means of a 12-run asymmetric screening matrix according to a D-optimal design strategy, allowed evaluation of the effects of different levels of each variable. The drug content and the polymers ratio had the most important effect on drug release, which, moreover, was favored by greater polymers particle size; on the contrary the compression force did not have a significant effect. The Doehlert design was then applied for a response-surface study, in order to study in depth the effects of the most important variables. The desirability function was used to simultaneously optimize the five considered responses, each having a different target. This procedure allowed selection, in the studied experimental domain, of the best formulation conditions to optimize drug release rate. The experimental values obtained from the optimized formulation highly agreed with the predicted values. The results demonstrated the reliability of the model in the preparation of extended-release matrix tablets with predictable drug release profiles.

Effects of the host cavity size and the preparation method on the physicochemical properties of ibuproxam-cyclodextrin systems

The effect of cyclodextrin (Cd) complexation on ibuproxam (IBUX) dissolution properties was studied by evaluating both the influence of Cd cavity size and the preparation method used for obtaining solid inclusion complexes. Binary systems of IBUX with natural Cds, prepared using different techniques (kneading, sealed-heating, spray-drying), were studied by differential scanning calorimetry (DSC), hot-stage microscopy (HSM), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and their dissolution behavior was evaluated according to the dispersed amount method. The nature and the dissolution performance of the end product appeared to be related to both steric factors of host molecule and preparation method of the solid system. The alpha Cd cavity size was less suitable for accommodating the IBUX molecule, whereas spray-drying and sealed-heating methods led to a true inclusion complex of IBUX in the beta Cd and gamma Cd cavity. In contrast, the kneading method did not lead in any case to a real inclusion complex. Spray-dried systems with beta Cd and gamma Cd were the most effective in achieving the enhancement of the IBUX dissolution rate.

Characterization of Ibuproxam Binary and Ternary Dispersions with Hydrophilic Carriers

This work investigates the possibility of increasing the dissolution properties of ibuproxam (a poorly water‐soluble anti‐inflammatory drug) using hydrophilic carriers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), or urea, alone or in combination. Phase‐solubility studies showed that the carrier solubilizing power was in the order PEG > PVP > urea and evidenced a synergistic effect in drug solubility improvement when using carrier combinations. Binary and ternary systems, at 20/80 or 20/40/40 (w/w) drug/carrier(s) ratios, prepared by coevaporation of their ethanolic solutions or by cogrinding physical mixtures in a high‐energy vibrational micromill, were characterized by differential scanning calorimetry (DSC), hot stage microscopy (HSM), and scanning electron microscopy (SEM) analyses. The results of dissolution tests (USP paddle method), in terms of Dissolution Efficiency, indicated that ternary systems were up to 35% more effective than the corresponding binary preparations and coevaporated products were up to 45% more efficacious than the corresponding coground ones. The IBUX‐PEG‐PVP coevaporated was the best product, allowing a more than three‐times increase in Dissolution Efficiency with respect to drug alone; moreover, t50% ( > 60 min for pure ibuproxam) was < 10 min, and 90% dissolution was achieved after 30 min, whereas only 40% was obtained after 60 min for pure drug. The best performance of this system was attributed to a joined effect of the strong amorphizing power of PVP (as demonstrated by solid state analyses) with the high solubilizing efficacy of PEG (as emerged from phase‐solubility studies). The drug dissolution rate from solid dispersions remained practically unchanged after one‐year storage at room temperature in closed containers.

Relationship Between Drug Percolation Threshold and Particle Size in Matrix Tablets

AbstractPurpose. Since a previous qualitative study carried out by us showed the existence of an important influence of the particle size on the percolation thresholds and taking into account that the existing theoretical models can only provide qualitative explanation to this influence, the purpose of this work is to carry out the first quantitative study of the influence of the particle size over the drug percolation thresholds. Methods. Matrix tablets have been elaborated using potassium chloride as drug model and Eudragit RS-PM as matrix forming material. Five different KC1 particle size fractions have been employed whereas the Eudragit® RS-PM particle size was kept constant. In-vitro release assays were carried out for all the elaborated lots. The drug percolation thresholds were estimated following the method proposed by Bonny and Leuenberger. Results. A linear relationship has been found between the drug particle size and the corresponding drug percolation threshold. Conclusions. This finding confirms the results previously obtained in our qualitative study and has important repercussions in the design of pharmaceutical solid dosage forms. If this linear behaviour is general, the percolation threshold can soon become a useful preformulation parameter.

Percolation theory: application to the study of the release behaviour from inert matrix systems

Abstract In the present paper, release profiles obtained from matrix tablets prepared with Eudragit ® RS-KC1 and a usual eccentric machine were studied. The results were in agreement with previously reported release studies for compacts prepared using a hydraulic press. The most outstanding aspect is the study of the influence of the particle size of drug and excipient on the release behaviour of the matrices, and its evaluation on the basis of percolation theory. The influence of soluble drug loading has also been studied. This new theory has been shown to be a useful tool to explain the release profiles from inert matrix compressed tablets.

Development of sustained release matrix tablets of didanosine containing methacrylic and ethylcellulose polymers.

Didanosine, a nucleoside analog used in the treatment of acquired immuno deficiency syndrome (AIDS), has been incorporated into directly compressed monolythic matrices whose excipients were mixtures at different ratios of a methacrylic resin (Eudragit RSPM) and an ethylcellulose (Ethocel 100), both water-insoluble and pH-independent polymers. Technological characterization (drug particle morphology, mean weight, diameter, thickness and hardness of tablets) was carried out and in vitro drug release behaviour was measured using the USP basket apparatus. The effect of varying the Eudragit-Ethocel ratio, as well as the drug-polymeric matrix ratio, was evaluated. The results showed the suitability of Eudragit-Ethocel mixtures as matrix-forming material for didanosine sustained release formulations. Combination of the moderate swelling properties of Eudragit RSPM with the plastic properties of the more hydrophobic Ethocel 100 allowed suitable modulation of didanosine release.

New "drug-in cyclodextrin-in deformable liposomes" formulations to improve the therapeutic efficacy of local anaesthetics.

The combined approach of cyclodextrin complexation and entrapment in liposomes was investigated to develop a topical formulation of local anaesthetics. For both benzocaine (BZC) and butamben (BTM), hydroxypropyl-beta-cyclodextrin (HPbetaCD) was a better partner than betaCD; drug-HPbetaCD coevaporated products showed the best solubility and dissolution properties, and were selected for loading into liposomes. Addition of stearylamine to the phosphatidylcholine-cholesterol mixture of the vesicle bilayer allowed obtainment of deformable liposomes with improved permeation and in vivo drug anaesthetic effect (P<0.05). Double-loaded deformable liposomes were obtained by adding the drug-HPbetaCD complex at its maximum aqueous solubility in the vesicles hydrophilic phase, and the remaining amount up to 1% as free drug in the lipophilic phase. The properties of double-loaded liposomes were compared with those of classic single-loaded ones, obtained by adding 1% free drug in the aqueous or lipophilic phase of the vesicles. Size, charge, morphology and entrapment efficiency of the different batches were investigated, respectively, by light scattering, confocal laser scanning microscopy and dialysis, while their therapeutic efficacy was evaluated in vivo on rabbits. For both drugs, double-loaded liposomes, exploiting the favourable effects of drug-CD complexation, allowed a significant (P<0.05) enhancement of intensity and duration of anaesthetic effect with respect to those single-loaded.

The role of the drug/excipient particle size ratio in the percolation model for tablets.

AbstractPurpose. In previous papers, a linear relationship between drug particle size and drug percolation threshold was found in inert matrix tablets. The main objectives of the present work are: to study the influence of the excipient particle size on the drug percolation threshold and to investigate if the change in the drug percolation threshold is due either to the absolute or to the relative drug particle size. Methods. Matrix tablets have been prepared using KC1 (7 different particle size fractions) as a drug model and Eudragit® RS-PM (4 granulommetric fractions) as matrix forming material. In vitro release assays were carried out on the 66 lots of tablets. The drug percolation thresholds were estimated following the method of Bonny and Leuenberger. Results. The particle size of the excipient has shown an opposite effect to the drug size on the drug percolation threshold. Nevertheless, the influence of drug and excipient sizes on the drug percolation threshold are of the same magnitude. Conclusions. The drug percolation threshold depends linearly on the relative drug particle size. This finding is in agreement with percolation theory and can facilitate the use of the percolation threshold as a preformulation parameter to improve the pharmaceutical dosage forms design.

Charged liposomes as carriers to enhance the permeation through the skin

Introduction: In recent years, there has been increased interest in developing charged liposomes as carriers for transdermal drug delivery. It is necessary to modify the basic composition of the liposomes in order to enhance the penetration properties of the vesicles through the skin. Charged liposomes offer several advantages compared with previous drug delivery systems. Areas covered: This paper provides a brief overview of the different drug delivery systems that exist which aim to improve the permeation of drugs through the skin, focusing on the use of charged liposomes for transdermal delivery. We propose a classification of such liposomes based on the origin of the charge given to the vesicles. Expert opinion: Despite the advances that are occurring in the design of charged liposomes for transdermal drug delivery, the long-term stability continues to be a drawback in such systems. The presence of charge on the surface of the vesicles favors the electrostatic repulsion among them, creating a ζ potential positive or negative that prevents their aggregation and flocculation. However, there is loss of the encapsulated drug, which limits the in vivo use of these systems. It should be emphasized that charged liposomes are indeed a promising candidate for use in gene therapy and vaccine targeting, in a great diversity of diseases, for which drugs are administered by the percutaneous route.