Ángela Aguilar-de-Leyva

Study of the critical points and the role of the pores and viscosity in carbamazepine hydrophilic matrix tablets.

Percolation theory has been applied to estimate the Hypromellose (HPMC) percolation thresholds and the influence of the polymer viscosity and the initial porosity on these thresholds in carbamazepine multicomponent matrix formulations. Different batches containing two viscosity grades of HPMC as hydrophilic matrix forming polymer, MCC and lactose as fillers, and a lubricant mixture have been manufactured varying the compression pressure in order to obtain matrices with three levels of initial porosity. The results suggested the existence of an excipient percolation threshold between 13 and 15% v/v of HPMC for the different batches prepared. It has been found that the percolation threshold for this polymer is independent on the formulation factors studied in this paper: polymer viscosity and initial porosity of the matrices.

Release behaviour of clozapine matrix pellets based on percolation theory

The release behaviour of clozapine matrix pellets was studied in order to investigate if it is possible to explain it applying the concepts of percolation theory, previously used in the understanding of the release process of inert and hydrophilic matrix tablets. Thirteen batches of pellets with different proportions of clozapine/microcrystalline cellulose (MCC)/hydroxypropylmethyl cellulose (HPMC) and different clozapine particle size fractions were prepared by extrusion-spheronisation and the release profiles were studied. It has been observed that the distance to the excipient (HPMC) percolation threshold is important to control the release rate. Furthermore, the drug percolation threshold has a big influence in these systems. Batches very close to the drug percolation threshold, show a clear effect of the drug particle size in the release rate. However, this effect is much less evident when there is a bigger distance to the drug percolation threshold, so the release behaviour of clozapine matrix pellets is possible to be explained based on the percolation theory.

Reduction-sensitive functionalized copolyurethanes for biomedical applications

In the present paper we combine functionalization and biodegradation in the rational design of polymers that can be used as carrier systems for drug delivery in the colon. Functionalization of new polyurethanes (PUs) was achieved by thiol–ene coupling reactions, a simple and straightforward procedure included among the so-called click reactions, which are currently accepted as one of the most powerful tools in organic chemistry. Enhancement of the degradability of the new materials by the introduction of disulfide linkages into the polymer backbone has led to a new group of stimulus-responsive sugar-based polyurethanes able to be degraded by tripeptide glutathione under physiological conditions. Atomic Force Microscopy (AFM) on solid-supported multilayered dry polymer films—prepared by spin-coating from dimethylsulfoxide solutions—was used to study the morphology of the polymers and the degradation process in reductive environments. Matrix systems containing polymers selected according to their rheological properties were also investigated as modulated methotrexate-release systems.

A new biodegradable polythiourethane as controlled release matrix polymer

The main aim of this paper is the synthesis and characterization of a new linear functional biodegradable polythiourethane-d,l-1,4-dithiothreitol-hexamethylene diisocyanate [PTU(DTT-HMDI)]. The SeDeM diagram has been obtained to investigate its suitability to be processed through a direct compression process. Furthermore, the ability of this polymer to act as controlled release matrix forming excipient has been studied. Four batches of matrices containing 10-40% of polymer and theophylline anhydrous as model drug have been manufactured. Release studies have been carried out using the paddle method and the polymer percolation threshold has been estimated. The principal parameters of the SeDeM Expert system, such as the parametric profile (mean radius) and the good compression index (IGC=4.59) for the polymer are very close to the values considered as adequate for direct compression even with no addition of flow agents. Furthermore, the results of the drug release studies show a high ability of the polymer to control the drug release. The excipient percolation threshold has been estimated between 20% and 30% w/w of polymer.

Study of the properties of the new biodegradable polyurethane PU (TEG-HMDI) as matrix forming excipient for controlled drug delivery

The purpose of this work is to study the ability of a new biodegradable polyurethane PU(TEG-HMDI) obtained by reaction of triethylene glycol (TEG) with 1,6-hexamethylene diisocyanate (HMDI) to act as matrix forming polymer for controlled release tablets and to estimate its percolation threshold in a matrix system. Matrix tablets weighing 250 mg were prepared by direct compression with 10–30% wt/wt of PU(TEG-HMDI) and anhydrous theophylline as model drug. Release studies were carried out using the paddle method. The results were analyzed using the kinetics models of Higuchi, Korsmeyer-Peppas, and Peppas and Sahlin. These studies confirm the existence of an excipient percolation threshold between 10 and 20 % wt/wt of PU(TEG-HMDI) for the different batches prepared. It has been observed that the new biodegradable polyurethane PU(TEG-HMDI) shows adequate compatibility as well as a high ability to control the drug release.

Critical points in ethylcellulose matrices: Influence of the polymer, drug and filler properties

Percolation theory has been applied to study the drug release behaviour in multicomponent inert matrices containing ethylcellulose as a matrix forming polymer. Global influence of major formulation factors such as polymer viscosity, polymer particle size, drug and filler solubility and porosity of the tablets in drug release kinetics has been studied for the first time. Batches containing three viscosity grades of Ethocel™, microcrystalline cellulose (MCC) and lactose as fillers, a lubricant and flow aid mixture and three drugs with different solubility have been manufactured. For some batches, compression pressure was varied in order to obtain matrices with five levels of initial porosity. The behaviour of inert matrices was explained based on the percolation ranges of the main components of the formulation. The effect of the porosity percolation threshold was observed and the existence of a tricoherent drug-polymer-filler system is hypothesized.

Development and characterization of new functionalized polyurethanes for sustained and site-specific drug release in the gastrointestinal tract

&NA; The main objective of the present paper has been the development and study of two new biodegradable polyurethanes, PU(dithiodiethanol‐DTDI) and PU[(iPr)Man‐DTDI], to be used as sustained matrix forming excipients. Furthermore, their capacity to act as excipient for colon drug delivery systems has been evaluated. Thus, SeDeM diagrams have been obtained to investigate their suitability to be processed through a direct compression process. Matrices containing 10–30% w/w of the polymers and theophylline anhydrous as model drug have been manufactured. Release studies have been carried out using a modified dissolution assay simulating pH and redox conditions for the gastro intestinal tract, including colon. Drug dissolution data have been analyzed according to the main kinetic models and their Excipient Efficiencies for prolonged release have been calculated. The principal parameters of the SeDeM Expert system, such as the parametric profile (mean radius) and the good compression index obtained for the polymers are above the values considered as adequate for direct compression even without addition of flow agents. The obtained values for Excipient Efficiency show good ability of the polymer to control the drug release. Finally, in the case of PU(dithiodiethanol‐DTDI), a clear increase in the release rate has been observed when the formulation is subjected to colon simulating conditions. Graphical Abstract Figure. No caption available.

A new deferiprone controlled release system obtained by ultrasound-assisted compression.

Abstract Objectives: This study implements the design of an innovative dosage form using ultrasound-assisted compression of thermoplastic polymers and the development of controlled release tablets for the oral administration of deferiprone in two doses per day. Methods: Binary matrix tablets containing deferiprone and thermoplastic polymers have been prepared using an ultrasound-assisted tableting machine. Scanning electron microscopy has been employed to determine a sintering phenomenon of the excipients. Water uptake and drug release studies have been carried out to evaluate the ability of the polymers to control the drug release. Results: SEM micrographs showed that some polymers underwent the sintering process and the in vitro dissolution test showed good fit of the release data from these tablets to the zero-order kinetic model. Conclusions: Carbopol 974P and 971P have been selected as matrix forming polymers for the final formulation. The polymer percolation threshold has been exceeded with 15% w/w of polymer. Therefore, sustained release tablets have been developed with only 15% of excipient. This implies that matrix tablets containing 750 mg of API, intended for two administrations a day, can be obtained with a similar weight to those existing in the market containing 500 mg of API for three administrations a day.

Collaboration between HPMC and NaCMC in order to reach the polymer critical point in theophylline hydrophilic matrices.

Percolation theory has been applied in order to study the existence of critical points as well as the possibility to find a “combined percolation threshold” for ternary hydrophilic matrices prepared with HPMC, NaCMC, and theophylline. For this purpose, different batches of ternary as well as binary hydrophilic matrices have been prepared. Critical points have been found for binary hydrophilic matrices between 21.5 and 31.3% (v/v) of HPMC and between 39 and 54% (v/v) of NaCMC, respectively. In a previous work carried out with the same polymers but a much more soluble drug (KCl), it was demonstrated the existence of a partial collaboration between the polymers in order to establish the gel layer. In this work, it has been observed for the first time the need of a minimum concentration of one of the matrix-forming polymer (between 10 and 20% v/v, approximately) for establishing an effective collaboration.