Ruggero Bettini

Swellable matrices for controlled drug delivery: gel-layer behaviour, mechanisms and optimal performance.

The majority of oral drug delivery systems (DDS) are matrix-based. Swellable matrices are monolithic systems prepared by compression of a powdered mixture of a hydrophilic polymer and a drug. Their success is linked to the established tabletting technology of manufacturing. Swellable matrix DDS must be differentiated from true swelling-controlled delivery systems. This review focuses on hydrophilic swellable matrix tablets as controlled DDS. Gel-layer behaviour, front movement and release are described to show the dependence of the release kinetics on the swelling behaviour of the system. In vivo behaviour of matrix systems is also considered.

Analysis of the swelling and release mechanisms from drug delivery systems with emphasis on drug solubility and water transport

The movement of the penetrant and polymer fronts and the drug dissolution in highly loaded swellable matrix tablets were studied with the aim of establishing relationships between front position and drug release kinetics. Three boundaries were identified corresponding to the swelling, diffusion and erosion fronts. The kinetics of drug release depended on the relative movement of the erosion and swelling/diffusion fronts. Under certain conditions of drug solubility and loading in the matrix, the last two could move separately. The data obtained demonstrated that the difference between the diffusion and erosion fronts is decisive for the release kinetics. This leads to a new finding that the distance between diffusion and erosion fronts (dissolved drug gel layer thickness) is the most important parameter for drug release, instead of the distance between swelling and erosion fronts (whole gel layer thickness).

Translocation of drug particles in HPMC matrix gel layer: effect of drug solubility and influence on release rate.

The aim of this work was to study the release mechanisms of drugs having different solubility (buflomedil pyridoxalphosphate 65%, sodium diclofenac 3.1%, nitrofutantoin 0.02% w/v,) from hydroxypropyl methylcellulose (HPMC) matrices by concomitantly studying swelling, diffusion and erosion fronts movement and drug delivery. The main goal was to clarify the role played by polymer swelling in drug transport. The results showed that the rate and amount of drug released from swellable matrices was dependent not only from drug dissolution and diffusion but also from solid drug translocation in the gel due to polymer swelling. In fact, as drug solubility decreased, the slower drug dissolution rate in the gel layer allowed drug particles to be transported close to the matrix erosion front. The presence of solid particles in the gel reduced the swelling and the entanglement of polymer chains and affected the resistance of gel towards erosion. As a consequence, the matrix became more erodible. The erosive delivery accelerated after the matrix had been completely transformed into the rubbery state, particularly when a considerable amount of solid drug particles remained in the gel phase.

Observation of swelling process and diffusion front position during swelling in hydroxypropyl methyl cellulose (HPMC) matrices containing a soluble drug

The behavior of gel layer thickness in swellable hydroxypropyl methyl cellulose matrices loaded with increasing amounts of soluble and colored drug and exhibiting swelling, diffusion and erosion fronts, was studied using a colorimetric technique. The effect of the drug loading on the front position in the gel layer, in particular, on the presence of a diffusion front and its movement, was investigated. In addition, the swelling, diffusion and erosion front positions at different releasing times were measured and a theoretical analysis of the overall process was provided. It was found that the diffusion front was visible in systems with more than 30% drug, due to the presence of an undissolved drug layer. The physical analysis of such systems clearly showed the importance of drug solubility and loading in the observation of the diffusion front.

Swelling and drug release in hydrogel matrices: polymer viscosity and matrix porosity effects

Abstract Hydroxypropylmethylcellulose (HPMC) represents the most frequently used polymer in the formulation of hydrogel matrices for controlled drug delivery. Drug release from these matrices is related to the area exposed to the dissolution medium. This work focused on the release of buflomedil pyridoxalphosphate from hydrogel matrices containing HPMC having different grades of viscosity and partially coated with an impermeable film. Drug release was discussed as a function of the dimensional modification of the matrices during release. It was found that the release kinetics is controlled by the increase in releasing area produced by the swelling phenomenon. The precence of an impermeable coating on the hydrogel matrix changes the swelling kinetics, and as a consequence the systems can become more liable to erosion. Drug release is slightly influenced by the viscosity of the polymer. The initial porosity of the hydrogel matrices, in the range studied, does not affect drug release.

Characterization of a surface modified dry powder inhalation carrier prepared by particle smoothing

Atomic force microscopy (AFM) was used to investigate drug‐carrier interactions between beclometasone dipropionate (BDP) and a series of untreated and modified lactose surfaces. This quantitative information was correlated with bulk characterization methods and an in‐vitro study. Modified lactose surfaces were prepared using a proprietary process referred to as “particle smoothing” to obtain smooth carrier surfaces with or without the presence of magnesium stearate. The engineering of lactose carrier surfaces using the particle smoothing process resulted in significant differences in surface morphology when compared with the “as supplied” starting material. The energy of separation, between BDP and lactose samples, determined by AFM suggested similar lognormal distributions with a rank decrease in median separation energy (e0.5) (26.7, 20.6 and 7.7 μJ for untreated, particle‐smoothed and particle‐smoothed with magnesium stearate, respectively). A series of in‐vitro twin stage impinger studies showed good correlation with the AFM separation energy measurements. The mean fine particle dose increased for the two processed lactose samples, with a significant increase for the lactose processed with magnesium stearate, 102.0 ± 16 μg compared with 24.2 ± 10.7 μg for the untreated lactose. Thus, the AFM presents as a possible pre‐formulation tool for rapid characterization of particle interactions.

Are pharmaceutics really going supercritical

The present work focuses on some applications of supercritical fluids in the pharmaceutical field, provides a critical review of the most recent advances and aims to give a vision on the future of this technology. In particular, processes such as particle and crystal engineering, formation of cyclodextrin complexes, coating, foaming and tissue engineering, extrusion, production of liposomes, formulation of biotechnological compounds, sterilization and solvent removal are described and discussed.

Solubility effects on drug transport through pH-sensitive, swelling-controlled release systems: Transport of theophylline and metoclopramide monohydrochloride

The swelling behavior of and solute transport in swellable, ionic copolymers of 2-hydroxyethyl methacrylate and methacrylic acid was studied for a wide range of copolymer compositions. The swelling behavior was determined by investigating the time-dependent change of the swelling and erosion front positions and the associated gel layer as a function of the percentage of the ionic component (MAA). Release of theophylline and metoclopramide-HCl were studied as a function of time. The swelling and release behavior were interpreted in terms of the significant solubility of the drugs tested and their possible association with the polymer matrices. It was concluded that the water uptake was mainly governed by the degree of ionization, and that the diffusion of non-ionized drugs in the hydrogels was controlled only by the volume swelling ratio of the polymer. For metoclopramide monohydrochloride, the drug diffusivity varied with copolymer composition.

Novel Platforms for Oral Drug Delivery

The aim of this review is to provide the reader general and inspiring prospects on recent and promising fields of innovation in oral drug delivery. Nowadays, inventive drug delivery systems vary from geometrically modified and modular matrices, more close to “classic” pharmaceutical manufacturing processes, to futuristic bio micro-electro-mechanical systems (bioMEMS), based on manufacturing techniques borrowed from electronics and other fields. In these technologies new materials and creative solutions are essential designing intelligent drug delivery systems able to release the required drug at the proper body location with the correct release rate. In particular, oral drug delivery systems of the future are expected to have a significant impact on the treatment of diseases, such as AIDS, cancer, malaria, diabetes requiring complex and multi-drug therapies, as well as on the life of patients, whose age and/or health status make necessary a multiple pharmacological approach.

Drug volume fraction profile in the gel phase and drug release kinetics in hydroxypropylmethyl cellulose matrices containing a soluble drug.

In the present work, the drug volume fraction profiles of a colored and very soluble drug, buflomedil pyridoxal phosphate, in the gel layer of initially glassy hydroxypropylmethyl cellulose matrices were studied, using image analysis of pictures of the matrices during swelling and release. The goal was to correlate the drug release kinetics with the dynamic behavior of the drug gradient in the gel layer. An inert (nonswellable) matrix, manufactured by substituting hydroxypropylmethyl cellulose with an inert polymer and containing the same amount of buflomedil pyridoxal phosphate, was prepared as well. The drug color gradient in the partially extracted region and the flux of this matrix were compared to the swellable matrix. The drug gradient in the dissolved drug gel layer of swellable matrices was observed. It was demonstrated that drug release kinetics does not only depend on drug diffusion and matrix erosion, but also on drug dissolution in the gel and on polymer relaxation.