TUNING THE MECHANICAL AND ADHESIVE PROPERTIES OF TRANS-DERMAL DRUG DELIVERY SYSTEMS

Drugs are usually applied onto the skin either for the treatment of localized diseases or systemic pathologies. Among the available dosage forms transdermal patches and the newest film-forming systems are considered the most attractive dosage forms. Firmly adhering to the skin, they assure a prolonged release of the drug predetermining the administered dose and the area of application. Film-forming systems are composed by a polymeric solution or suspension which contains the active substance(s). Patches in their simplest configuration consist of a flexible backing layer, an adhesive matrix in which the active substance(s) are dissolved or dispersed and a removable release liner. Both such dosage forms must comply peculiar technological features. Film-forming systems should quickly dry on the skin and the formed film should be almost invisible and non-sticky. Furthermore, their mechanical properties should overcome the stresses caused by body movements. Transdermal patches have to be sticky and exhibit an optimal balance between adhesion and cohesion. Indeed, a patch should strongly adhere to the skin and be easily removed with no or little trauma. Moreover, a certain cohesiveness is necessary so that the patch will not move when applied in vivo and can be peeled away without living any residues. To satisfy the requirements of flexibility necessary to assure a proper skin/dosage form contact, a material should have an elastic modulus lower than that of the skin and, in the case of a patch, a viscoelastic pattern. Despite many products are currently available on the market, some critical issues, such as adhesive and mechanical properties, which affect the residence time of the dosage form onto the skin and subsequently its therapeutic efficacy, are still scarcely investigated. Hence, there is the need to study the overall relevant issues involved in designing film-forming systems and transdermal patches and clarify the possible relationships between their features. This kind of relationship could provide useful information to design and optimize both such dosage forms. This doctoral thesis aimed to evaluate the effect of the formulation compositions on rheological, adhesive and mechanical properties as well as on the in vitro biopharmaceutical performances of different polymeric matrices in order to design film forming systems and transdermal patches. In particular, the experimental work was focused on: (i) the design of film-forming systems based on an ammonium methacrylate copolymer (Eudragit RL) solubilized in a mixture of solvents in different ratios and plasticized by different amounts of plasticizer; the effects of solvent systems as well as the addition of the plasticizer were evaluated on drying time, outward stickiness, mechanical properties and in vitro biopharmaceutical performances; (ii) the design of transdermal patches based on differently plasticized ammonium methacrylate copolymer (Eudragit RL) and the evaluation of their rheological and tack properties, primarily to better understand their debonding mechanisms and adhesive characteristics; moreover, the main technological and in vitro biopharmaceutical properties were tested; (iii) the design of transdermal patches based on a styrenic copolymer (styrene-block-(ethylene-co-butylene)-block-styrene, SEBS); the effects of tackifiers and SEBS molecular weights on the rheological and adhesive properties of the materials were investigated. In particular, the debonding behavior under different operative conditions were evaluated and the technological as well as the in vitro biopharmaceutical performances of the formulated patches were studied. The overall results allowed to confirm the versatility of the ammonium methacrylate copolymer (Eudragit RL), opportunely plasticized, in the design of both transdermal patches and film-forming systems. The study of rheological, adhesive and mechanical properties as well as the thermic behavior was crucial to identify the formulative window for the design of both the dosage forms. The relevance of the rheological behavior on the matrix adhesive properties and in vitro drug release from the patches was further confirmed by the results obtained by SEBS-based formulations. Highlights The thermic characterization of differently plasticized Eudragit RL allowed to define the suitable formulative windows to design both film-forming systems (Par. 1.3.1, pp. 30-31) or transdermal patches (Par. 2.3.1, pp. 58). The composition of the solvent mixture influenced both the outward stickiness and tensile properties of in situ formed films (Par. 1.3.1, pp. 31-34). The drug release studies from film-forming systems evidenced, for the first time, that not only the drug thermodynamic activity, but also the evaporation rate of the vehicle significantly influenced the drug skin permeation from film-forming systems (Par. 1.3.2, pp. 35-39). The rheological studies performed in the range of frequency suitable for predicting the adhesive performances (0.01-100 rad/s) and at the in vivo skin temperature (i.e. 32 °C), allowed identify the most suitable formulations having the required viscoelastic pattern (Par. 2.3.1, pp. 58-61; Par. 3.3.1, pp.93-95). As expected, the rheological data were in agreement with the failure mechanisms observed during the debonding process of the adhesive matrices (Par. 2.3.1, pp. 63-67), cold flow (Par. 2.3.2, pp. 68; Par. 3.3.2, pp. 99), tackiness (Par. 3.3.2, pp. 99) and shear adhesion (Par. 2.3.2, pp. 67, Par 3.3.2, pp. 98-99) of the formulated patches. Moreover, the drug loading, influencing the extent of viscoelasticity, can affect the overall adhesive properties of the patches (Par. 2.3.3, pp. 69-70, Par 3.3.3, pp. 100-101). Interestingly, a relationship among matrix fluidity and in vitro drug release rate from the patch was evidenced (Par. 2.3.3, pp. 71-72; Par 3.3.3, pp. 101-102).