INNOVATIVE MATERIALS FOR THE DESIGN OF OROMUCOSAL PREPARATIONS

The present Ph.D. thesis proposed to investigate the feasibility of using polymethylmethacrylates salts (XPPMs) as innovative materials for the production of oromucosal preparations. The overall experimental work carried out permitted to demonstrate the versatility of using these polymers, also in combination with maltodextrins (MDX), to obtain orodispersible films (ODFs) and mucoadehsive tablets obtained by freeze-drying technique. The goals have been accomplished by a preliminary deepening of ODFs characteristics. Films formulated by using MDX were used as a model, since their use for ODFs is already clearly established. Firstly, the advantageously use of amino acids (glycine, proline and lysine) as non-traditional plasticizers was evaluated (Chapter 1). The interest in this field is mainly due to one of the most critical attributes of orodispersible films, related to the development of dosage forms with tensile properties suitable for packaging and patient’s handling. Furthermore, since the dose is determined by cutting the polymeric film in the final shape, it is important to ensure the mechanical properties through all the manufacturing process. Aiming the same feature of Chapter 1, a strategy to reinforce tensile properties of MDX orodispersible films was investigated in Chapter 3 by adding an amorphous water insoluble nanofiller, known as polyvinylacetate (PVAc). Further in-depth analysis allowed to obtain MDX films loaded with quercetin nanocrystal, a poor soluble drug, enhancing its oral bioavailability (Chapter 2). Orodispersible films were successfully obtained without affecting the solid state of the drug, as evidenced from spectroscopic and calorimetric analyses, without modifying mechanical properties and dissolution properties of the matrix. Furthermore, the innovation was to formulate orodispersible films directly from the nanosuspensions, avoiding the intermediate step of lyophilisation and stability issues associated with nanoparticles. The obtained knowledge with MDX orodispersible films was used for the development of ODFs designed by using PMMs salts (Chapter 4). A novel film forming matrix, suitable for the manufacturing process, was successfully obtained. Indeed, film elongation was considered appropriate for the cutting procedure of the final dosage form. Considering the necessity to develop an exploiting matrix to load different active ingredients, the versatility of this system was demonstrated by loading ketoprofen as an example of plasticizing active ingredient. In order to prolong the oral residence time of the orodispersible films based on XPMMs, the feasibility of obtaining mucoadhesive tablets was also evaluated (Chapter 6). The freeze-drying technique was selected as a production method, even if it is usually exploited for orodispersible tablets (ODTs). As a preparatory phase, a deeper knowledge on the freeze-drying technique was gained, with an approach centred on the physical study of the process, and focusing on oromucosal preparations instead of the more common injectable freeze-dried formulations (Chapter 5). The project carried out is a preliminary evaluation on how the immediate packaging (in this case aluminium blisters) can affect the successful production of freeze-dried tablets. Heat transfer properties of blister (Kb) were evaluated, the knowledge of these properties can help to design and model freeze-drying cycles, also in the case of scalability issues. The work of Chapter 6 aims to point out the feasibility of developing XPMMs buccal adhesive tablets with the freeze-frying technique. Investigation on the effect of blending XPMMs with MDX with different molecular weight and in different ratio, in order to improve the flexibility of the matrix in terms of mucoadhesion and disaggregation, was also described. A novel composite material was successfully used to develop tablets with mucoadhesive properties and with a potentiality to obtain ODTs by combining the ratio and type between two polymers, by taking the advantage of different disaggregation behaviour.