A. La Manna

Drug release modulation by physical restrictions of matrix swelling

Abstract Swellable matrix systems with anomalous release kinetics are suitable solutions for drug release control for oral administration. Generally, the release rate modulation is achieved through the use of different types of polymer or the employment of soluble or insoluble fillers. The resulting release mechanism depends on the relative importance of tablet relaxation and drug diffusion rates. By adjusting these two rates, it is possible simultaneously to control the release mechanism and the release rate. In this work, we present the results obtained by changing the relaxation rate of the matrix by means of the application of impermeable coatings that partially cover the matrix. The applied impermeable coating modifies the relaxation rate of the matrix by affecting the dimension of the swelling of the plain matrix while leaving the diffusion characteristics of the drug practically intact. The overall result is that the original kinetics of the uncoated matrix is shifted towards constant release, dependent on the extension and position of the impermeable coating.

Multi-layered hydrophilic matrices as constant release devices (GeomatrixTM systems)

Abstract In recent years many attempts have been made to modify drug release profiles from hydrophilic matrix tablets. Recently a new method based on the application of an inert impermeable coating on different sides of a matrix tablet was proposed. The coating delays the interaction of the matrix with the dissolution medium. In this way the hydration rate of the active core is slowed and its release surface is reduced. As a result the release extent is increased, while the dissolution profile tends to shift toward constant drug release compared with the uncoated matrix. In this article the design and technological development (up to the industrial production) of these types of devices is described: the film coatings are replaced by a polymeric barrier applied on the tablet bases during tableting. The effectiveness, the reproducibility and the technological characteristics of the new multi-layer systems are described.

Swelling-activated drug delivery systems

A previous paper dealt with the preparation of an in vitro programmable zero-order drug delivery system in which the area of the surface exposed to the dissolution medium and the macromolecular relaxation of polymer controlled the release of the drug. In the present study, the preparation of similar delivery systems is described, in which differing drugs and polymers were used to ascertain the mechanism governing the drug-release kinetics. The movement of the interfaces between solvent and system was measured during drug release in systems with varying composition. The results indicate that the synchronization of the movement of swelling and eroding fronts at the solvent-system interface determines the achievement of the linear-release kinetics of such swelling activated systems and that the swelling and dissolution characteristics of the polymer employed for core preparation govern front movement.

Press-coated tablets for time-programmed release of drugs

A new dry-coated device for the release of drug after a programmable period of time is proposed. It is intended to be used mainly in the therapy of those diseases which depend on circadian rhythms. Some core formulations, characterized by different release rates and mechanisms (containing diltiazem hydrochloride or sodium diclofenac as model drugs), were coated by compression with different polymeric barrier layers (press-coated systems). The shell formulations tested contained either gellable or erodible polymers. The dissolution profiles of uncoated cores and press-coated devices were compared. The gellable and/or erodible characteristics (properties) of the barrier formulations were also examined by means of a penetrometer. The coatings prevent drug release from the core until the polymeric shell is completely eroded or swollen. This delay in release start is not influenced by the core composition and depends only on the shell formulation. Except for the time-lag, the release kinetics of the drug contained in the core are not significantly influenced by the presence of the erodible barrier, but can be widely modulated using a swellable polymeric shell.

Compressed polymeric mini-matrices for drug release control

Abstract Matrices of reduced dimensions of either inert or swellable polymers for multiple-unit administration, containing diprophylline as the model drug, were made by compression. Some swellable mini-matrices prepared from poly(vinyl alcohol) were externally crosslinked by soaking in an acidic formalin solution, and subsequent drying and exposure to UV or thermal energy sources. The release kinetics of the model drug from the mini-matrices was investigated by analyzing the early time portion of the release curves according to a simplified exponential equation which allows the comprehension of the release mechanism. The results showed that the release kinetics may be Fickian or anomalous nonFickian depending on the solubility of the polymer employed. Zero-order release kinetics were obtained by using mini-matrices, which were crosslinked at the surface.

Water Uptake and Disintegrating Force Measurements: Towards a General Understanding of Disintegration Mechanisms

Water penetration and disintegrating force measurements were combined with the aim of assessing the role played by various mechanisms in the disintegration process.Nine tablet series, made of differing base materials (α-lactose monohydrate, dicalcium phosphate dihydrate and acetylsalicylic acid) such as are likely to elicit differing disintegration mechanisms and containing differing disintegrates in varying percentages were prepared and checked for Water penetration, disintegrating force development and disintegration time.The results obtained show that, in tablets made of dicalcium phosphate dihydrate or acetylsalicylic acid, a correlation exists between disintegration time and disintegrating force kinetics, which indicates that active mechanisms play the prevailing role in the disintegration process.On the contrary, the lack of such a correlation in lactose monohydrate tablets indicates that passive mechanisms are also involved in the disintegration process and prevail over active mechanisms. In this c...

A New Ibuprofen Pulsed Release Oral Dosage Form

AbstractDrug constant release is not always the desired solution for controlled drug administration; some therapeutic situations require consecutive pulses of active principleA biphasic oral delivery system able to release an immediate dose of therapeutic agent as well as a further pulse of drug after some hours could be interestingIn order to obtain such desired releasing performances, a new system (three layer tablet) has been designed with the following characteristics- an energy source, able to deliver the two divided doses of drug- a control element, between the drug layers, able to delay the release of the second dose of drug. This control element acts as a barrier and is made with a mixture of water swellable polymers- an outer film, which is made of water impermeable polymer, that covers the second dose of drug and the barrierThe new system works through subsequent interactions with aqueous fluids of the three different layers of material in the following order1 - rapid interaction of the uncoated...

Hydrophilic matrices for the extended release of a model drug exhibiting pH-dependent solubility

Abstract After oral administration of basic drugs, the different pH values of the gastrointestinal tract can result in drastic changes in drug solubility, which can be very high at acidic pH values and dramatically low at neutral/basic pH, with consequent problems for the design of oral extended release formulations. In this paper, the preparation of an oral extended release formulation containing a basic drug is proposed, using dipyridamole as model. Three-component modified release granules capable of moderating the drastic dissolution behavior of dipyridamole were prepared by loading a swellable polymer (cross-linked sodium carboxymethylcellulose) with both the drug and an enteric polymer (cellulose acetate phthalate or cellulose acetate trimellitate). In vitro dissolution tests of modified release granules in USP gastric fluid showed a modulation of the high dissolution rate of dipyridamole at the acidic pH values, while in USP intestinal fluid a very marked improvement in drug dissolution was observed. Hydrophilic matrices containing the drug with the smoothed dissolution rate characteristics were prepared via mixing the granules with a gelling polymer (cellulose ether) and then tabletting the resulting mixture. In vitro release tests performed both at constant pH and with pH variation showed that the matrices are capable of providing extended drug release in both acidic and neutral/basic media.

Linear extended release of a water-insoluble drug, carbamazepine, from erodible matrices

Abstract The preparation and in vitro characterization of extended release erodible hydrophilic matrices containing a water insoluble drug (carbamazepine) are described. The matrices are obtained by tabletting mixtures of the drug with a water swellable polymer (cross-linked sodium carboxymethylcellulose) and a water gelling polymer (hydroxypropylmethylcellulose). These matrices appear to be subject, during in vitro tests, both to a gelation and to an erosion process and they are capable of releasing the drug at a nearly constant rate, until almost the entire drug content is released. The influence of the technological parameters of the formulation (weight ratios of polymers used, compression forces, etc.) and of the gelation and erosion processes of the matrices during the in vitro tests, on drug release are investigated.

Carbamazepine Modified Release Dosage Forms

AbstractThe preparation of sustained release dosage forms of Carbamazepine (anti-epileptic drug characterized by a very low water solubility and by a short half life on chronique dosing) was carried out.These formulations were obtained in two different steps:a) modified release granules were prepared by the loading of cross-linked sodium carboxymethylcellulose (swellable polymer), with the drug and an enteric polymer. Cellulose acetate phthalate, methacrylic acid – methacrylic acid methyl ester copolymer (usually employed as enteric coating agents) and cellulose acetate trimellitate (a new enteric polymer) were used in different weight ratios.b) some sustained release dosage forms were prepared tabletting physical mixtures of the modified release granules with different weight ratios of hydroxypropylmethylcellulose.In vitro dissolution tests of modified release granules in gastric fluid (USP XXI) showed a modulation of the drug release, while in intestinal fluid (USP XXI) a quick drug dissolution was obse...