Diego Caccavo

Modeling the Drug Release from Hydrogel-Based Matrices

In this work the behavior of hydrogel-based matrices, the most widespread systems for oral controlled release of pharmaceuticals, has been mathematically described. In addition, the calculations of the model have been validated against a rich set of experimental data obtained working with tablets made of hydroxypropyl methylcellulose (a hydrogel) and theophylline (a model drug). The model takes into account water uptake, hydrogel swelling, drug release, and polymer erosion. The model was obtained as an improvement of a previous code, describing the diffusion in concentrated systems, and obtaining the erosion front (which is a moving boundary) from the polymer mass balance (in this way, the number of fitting parameters was also reduced by one). The proposed model was found able to describe all the observed phenomena, and then it can be considered a tool with predictive capabilities, useful in design and testing of new dosage systems based on hydrogels.

Controlled drug release from hydrogel-based matrices: Experiments and modeling

Controlled release by oral administration is mainly achieved by pharmaceuticals based on hydrogels. Once swallowed, a matrix made of hydrogels experiences water up-take, swelling, drug dissolution and diffusion, polymer erosion. The detailed understanding and quantification of such a complex behavior is a mandatory prerequisite to the design of novel pharmaceuticals for controlled oral delivery. In this work, the behavior of hydrogel-based matrices has been investigated by means of several experimental techniques previously pointed out (gravimetric, and based on texture analysis); and then all the observed features were mathematically described using a physical model, defined and recently improved by our research group (based on balance equations, rate equations and swelling predictions). The agreement between the huge set of experimental data and the detailed calculations by the model is good, confirming the validity of both the experimental and the theoretical approaches.

Swellable Hydrogel-based Systems for Controlled Drug Delivery

The controlled delivery of drugs can be effectively obtained using systems based on hydrogels. Tablets, to be orally administered, represent the simplest and the most traditional dosage systems based on hydrogel. Their formulation and preparation require to mix and to compress, in proper ratios, various excipients, including a swellable polymer and a drug. Carriers for controlled release systems are usually cross-linked polymers able to form hydrogels that show peculiar release mechanisms, where both diffusion and tablet swelling play important roles. When a dry swellable hydrogel-based matrix is immersed in a physiological fluid, this starts to penetrate inside the polymeric hydrophilic matrix. When a certain solvent concentration is reached, the polymeric chains unfold due to a glass–rubber transition, and a gel-like layer is formed. In the swollen region, the drug molecules can easily diffuse toward the outer dissolution medium, once they are dissolved. The polymer network became extremely hydrated where the swollen matrix is in contact with the outer medium, and processes like chain disentanglement take place, “eroding” the matrix. This chapter is focused on the analysis of the state of the art about the uses of carriers for controlled release systems composed by hydrogel-based matrices. This analysis has been performed studying in deep both the experimental and the modeling techniques which have been investigated over the years to characterize all the phenomena involved during the drug release.

Drug delivery from hydrogels: A general framework for the release modeling

The controlled delivery of drugs, including siRNAs, can be effectively obtained using Hydrogel- Based Drugs Delivery Systems (HB-DDSs). Successful design of HB-DDSs requires the knowledge of the mechanisms that influence drug release. The modeling of the physical phenomena involved could help in the development and optimization of HB-DDS, sensibly reducing the time and costs required by a trial-and-error procedures. The modeling is rather complex because of the presence of several, synergistic and competing, transport phenomena. In this work a general framework useful for modeling the HB-DDS has been derived and it is proposed, coupling and homogenizing the literature models. It is shown that all of them can be traced back to two different approaches: multiphasic models and multicomponent mixture models. In the first one the hydrogel is seen as constituted by different phases, the behavior of each one being described by their own mass and momentum conservation equations. In the second approach, the hydrogel is considered as made of one phase composed by several components.

Effects of HPMC substituent pattern on water up-take, polymer and drug release: An experimental and modelling study

The purpose of this study was to investigate the hydration behavior of two matrix formulations containing the cellulose derivative hydroxypropyl methylcellulose (HPMC). The two HPMC batches investigated had different substitution pattern along the backbone; the first one is referred to as heterogeneous and the second as homogenous. The release of both the drug molecule theophylline and the polymer was determined. Additionally, the water concentrations at different positions in the swollen gel layers were determined by Magnetic Resonance Imaging. The experimental data was compared to predicted values obtained by the extension of a mechanistic Fickian based model. The hydration of tablets containing the more homogenous HPMC batch showed a gradual water concentration gradient in the gel layer and could be well predicted. The hydration process for the more heterogeneous batch showed a very abrupt step change in the water concentration in the gel layer and could not be well predicted. Based on the comparison between the experimental and predicted data this study suggests, for the first time, that formulations with HPMC of different heterogeneities form gels in different ways. The homogeneous HPMC batch exhibits a water sorption behavior ascribable to a Ficḱs law for the diffusion process whereas the more heterogeneous HPMC batches does not. This conclusion is important in the future development of simulation models and in the understanding of drug release mechanism from hydrophilic matrices.

Determination of the release mechanism of Theophylline from pellets coated with Surelease®—A water dispersion of ethyl cellulose

The aim of this study was to investigate the water transport over free standing films based on the aqueous ethyl cellulose (EC) coating Surelease® and the drug (Theophylline) release mechanism from coated pellets. It was found that the main drug release rate from pellets was controlled by a diffusion mechanism. However, the drug release rate was altered by addition of sodium chloride to the external release medium. A decrease in the drug release rate when sodium chloride is added to the release medium has traditionally been used to indicate an osmotic drug release mechanism. However, our findings that the release rate decreased by sodium chloride addition could be explained by sodium chloride diffusing through the coating layer into the inner parts of the pellets, decreasing the solubility of Theophylline. This gave a reduced drug concentration gradient over the coating layer and thus a slower release rate. Furthermore, this study shows, as expected, that the transport of water through Surelease® films into the pellets was faster than the transport out of Theophylline (approx. seven times), which was the reason why the pellets were swelling during the release. It was also shown that the drug release rate, determined for both whole dose release and for single pellets, decreased with increasing thickness (from 16 to 51μm) of the coating layer controlling the drug release rate.

Modeling capillary formation in calcium and copper alginate gels

Alginate solutions in the presence of bivalent ions can form ionic cross-linked gels. In particular gelation conditions the gel structure can be characterized by great anisotropy with the presence of straight capillaries along a preferential direction. These materials can find applications mainly in high-tech sectors, like tissue engineering, where the gel characteristics play a crucial role. Despite the need of mastering the capillary formation and properties, the process remains a poorly known problem, and its development is left to trial and error procedures. In this work a quantitative approach to the description of the capillary formation process has been developed. The theory proposed by Treml et al. (2003) has been implemented and extended to an alginate different from the one used in that study and two different ions (calcium and copper). Some of the model parameters have been derived through simple measurements; others have been scaled using proper scaling equations. Experiments have been performed in different gelation conditions, varying alginate and ionic solution concentrations, to highlight the effects of these parameters on the anisotropic structure and to validate the model. In all the analyses done, the model has performed nicely showing a good reliability in the prediction of gel characteristics like capillary formation, capillary length and process time.

Mathematical modelling of the drug release from an ensemble of coated pellets

Coated pellets are widely used as oral drug delivery systems, being highly accepted by patients and with several advantages compared to single unit devices. However, their behaviour needs to be elucidated so as to improve the effectiveness of the formulations and reduce production costs. In spite of this important issue, few mathematical modelling studies have been attempted, mostly due to the complexities arising from the systems polydispersity (non‐homogeneous multiple‐unit particulate systems), which has been scarcely investigated using mechanistic models.

Hydrogel-Based Granular Phytostrengtheners for Prolonged Release: Production and Characterization

Soil wellness is an indispensable requirement to obtain fruits and vegetables with finest quality and with high yields. To the purpose, periodical administrations of nutrients, as well as phytostrengtheners could be required. Crucial goals to maximize the economic and environmental sustainability of the whole cultivation are the decrease of the dosages number together with the increase of the active substance availability within the soil. With these aims a controlled release phytostrengtheners encapsulated in a granular Hydroxypropyl methylcellulose matrix has been developed exploiting the wet granulation process. The granular product has been analyzed in terms of Particle Size Distribution (PSD), morphology and flowability. The results showed the effectiveness of the granulation process and the good flowability of the granules, highly desirable features for the product handling and commercialization.

Understanding the adhesion phenomena in carbohydrate-hydrogel-based systems: Water up-take, swelling and elastic detachment.

The bio-adhesion is a complex phenomenon which takes place when two materials (at least one of biological nature, the other usually is a polymeric one) are held together for extended periods of time, usually for local drug delivery purposes. Despite bio-adhesion is widely exploited in commercial pharmaceuticals such as the buccal patches, the underlying phenomena of the process are not completely clarified yet. In this study experimental tests, in which the role of biological membranes is played by a water-rich agarose gel whereas patches are mimicked by hydrogel tablets (made of Carbopol or of Carbopol added with NaCl), have been used to analyze the behavior of the model system above described. Tablets have been forced to adhere on the agarose gel, and after a given contact time they have been detached, recording the required forces. Furthermore weight gain of the tablets (the water transported from the agarose gel toward the tablet) has been quantified. Water transport (during the time in which the contact between tablet and agarose gel is held) and elastic part of mechanical response during the detachment are modelled to achieve a better understanding of the adhesion process. Both the two sub-models nicely reproduce, respectively, the weight gain as well as the swelling of the Carbopol tablets, and the point at which the mechanical response ceases to be purely elastic.