M. Fernández-Arévalo

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.

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.

Synthesis of lidocaine-loaded PLGA microparticles by flow focusing Effects on drug loading and release properties

In the present work, two methods for the preparation of lidocaine-loaded PLGA microparticles are compared. The differences between the polymeric particles obtained by solvent evaporation (SEVM) or flow focusing (FF) were studied by means of scanning electron microscopy and surface thermodynamics determinations. A detailed investigation of the capabilities of the polymer particles to load this drug is described. The physical state of the drug in the polymeric particles and the existence of interactions between both entities were studied by differential scanning calorimetry. The main factors determining the lidocaine incorporation and the release kinetics were the synthesis procedure followed, the amount of drug dissolved in the organic phase during the synthesis routine, the type of polymer (molecular weight and end chemical groups) and the size and the hydrophobic/hydrophilic properties of the particles. The FF technology allowed higher drug incorporations and slower release kinetics. The release studies showed a biphasic profile probably due to diffusion-cum-degradation mediated processes.

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.

Development of Enteric-coated Timed-release Matrix Tablets for Colon Targeting

A new oral drug delivery system for colon targeting has been developed based on enteric-coated matrix tablets which suitably exploits both pH-sensitive and time-dependent functions. Matrix-tablets were prepared by direct compression of mixtures of hydroxyethylcellulose (HEC), a hydrophilic swellable polymer, with the inert insoluble ethylcellulose (EC) or micro-crystalline cellulose (MCC) polymers, in which theophylline, selected as model drug, was dispersed. Eudragit S100, a methacrylic acid copolymer soluble at pH 7, was used as pH-sensitive coating polymer. The influence of varying the cellulose-derivative combinations and their relative ratios as well as the level of the coating polymer was investigated. Surface morphology of the tablets was monitored by SEM analysis before and after the release test. The results of release studies, performed according to the USP basket method using a sequence of dissolution media simulating the gastrointestinal physiological pH variation, indicated that the Eudragit S100 enteric-coated matrix tablets were successful in achieving gastric resistance and timed-release of the drug, assuring an adequate lag time for the intended colonic targeting, followed by a controlled-release phase. The enteric-coating level emerged as the critical factor in determining the duration of the lag-phase, whereas the release rate mainly depended on the matrix composition. Formulations with higher HEC content showed a faster drug release rate than those with greater content in inert polymer and the MCC–HEC combinations were more effective than the corresponding EC–HEC ones. The best results were given by the 27% coated 1:0.3:0.7 (w/w) drug/MCC/HEC tablets, which, after a 260 min lag time, regularly released the drug, achieving about 90% of release after 10 h.

Dissolution rate of diazepam from polyethylene glycol 6000 solid dispersions

Abstract A method for the elaboration of solid dispersions, the weight ratios of diazepam to polyethylene glycol 6000 and the particle size of drug in the solid dispersion have been investigated. The preparation method and diazepam-polyethylene glycol 6000 ratio influence the dissolution rate of the drug. It is observed that faster release characteristics were obtained with solid dispersions prepared by the fusion method and by increasing the carrier percentage. The increase in dissolution rate can be considered to result from crystal size reduction and the solubilizing effect of polyethylene glycol 6000. An intrinsic effect of the carrier also increases the dissolution rate of diazepam, since a physical mixture of the same composition dissolves more slowly than the solid dispersions. It is concluded that such a difference must be attributed to a significant reduction of the drug particle size in the carrier matrix.

Physical characterization of carteolol: Eudragit® L binding interaction

Eudragit® L 30D was used as a carrier to prepare carteolol polymeric complexes in order to obtain controlled release dosage forms. The polyanionic form of the polymer, neutralized at different degrees, reacts readily with carteolol hydrochloride to give water-insoluble complexes. Carteolol complexes were characterized by differential scanning calorimetry, IR, 1H- and 13C-NMR spectroscopy. In fact, results indicated that there were intermolecular associations between the polymer and the drug consisting in ammonium salt interactions. Maximum carteolol content was found to be 22% in the complexes.

Cannabinoid derivate-loaded PLGA nanocarriers for oral administration: formulation, characterization, and cytotoxicity studies

CB13 (1-Naphthalenyl[4-(pentyloxy)-1-naphthalenyl]methanone)-loaded poly(lactic-co-glycolic acid) nanoparticles (NPs) were produced by nanoprecipitation and tested for their in vitro release behavior and in vitro cytotoxicity assays. The effects of several formulation parameters such as polymer type, surfactant concentration, and initial drug amount were studied. NPs had a particle size 90–300 nm in diameter. Results obtained show that the main influence on particle size was the type of polymer employed during the particle production: the greater the hydrophobicity, the smaller the particle size. In terms of encapsulation efficiency (%), high values were achieved (∼68%–90%) for all formulations prepared due to the poor solubility of CB13 in the external aqueous phase. Moreover, an inverse relationship between release rate and NP size was found. On the other hand, low molecular weight and low lactide content resulted in a less hydrophobic polymer with increased rates of water absorption, hydrolysis, and erosion. NPs showed no cytotoxicity and may be considered to be appropriate for drug-delivery purposes.

Drug targeting to cancer by nanoparticles surface functionalized with special biomolecules.

Nanoparticulate-based drug carriers have been developed to overcome the problems of conventional anticancer pharmacotherapy, i.e., the little specificity and low accumulation of the drug into the tumor interstitium, and the extensive biodistribution leading to severe toxicity. Unfortunately, conventional nanoparticles have been demonstrated to merely accumulate the loaded drug into organs associated to the reticuloendothelial system, e.g., the liver. Recently, drug delivery strategies involving the use of nanoplatforms surface decorated with unique biomolecules have demonstrated their potential in concentrating the chemotherapy agent specifically into the malignant cells. This review will be focused on the analysis of the current state of the art and future perspectives of such passive and active targeting strategies based on the enhanced permeability and retention effect and on a ligand-mediated transport, respectively. Special attention will be given to the use of these surface functionalized nanocarriers to overcome multi-drug resistances in cancer cells.

Communications Simultaneous Hplc Determination of some Drugs Commonly Used in Cold Medications: Dextromethorphan, Dephenhydramine, Phenylephrine, Phenylpropanolamine and Pseudoephedrine

AbstractIn the present paper, a simple, direct, accurate and sensitive HPLC method applied over combinations of dextromethorphan, diphenhydramine, phenylephrine, phenylpropanolamine and pseudoephedrine is presented. The use of alumina particles bonded with polybutadiene as stationary phase allows the use of an alkaline mobile phase which provides an important improvement of the assay.