Innovative systems for drug delivery: pharmacokinetic and technological aspects

Nowadays, the main objective of pharmaceutical companies is to develop innovative oral dosage forms for both prolonged and immediate drug releases. In fact, oral delivery has the peculiar advantage of being highly versatile dosage-wise. However, actives suffering from low oral bioavailability may not always be administered by using traditional dosage forms or common controlled release devices, due to the bioavailability's strict dependence on both drug solubility in gastrointestinal fluids and on drug permeability through the cellular membranes. Recently, both conventional and modified release oral dosage forms have been developed by applying innovative technologies such as a) melt extrusion, and b) solid-state mechanochemistry. a) Melt extrusion Melt extrusion is a viable technology since it allows the production of a final dosage form having the desired shape and dimension. This is achieved by means of suitable thermoplastic polymeric carriers or by using non-polymeric carriers capable of softening or melting during the process. The loaded drug can be dissolved or dispersed in both crystalline and amorphous forms. Despite the efforts of the scientific community, this process still requires an adequate technology transfer, due to the high number of physical, chemical, physicochemical, mechanical and pharmacokinetics variables influencing the melt extruded product. In this context, the first part of the thesis (Chapter 2) presents an innovative contribution, i.e., the production of unconventional melt helical shaped extrudates with a ram extruder. These extrudates, based on mixtures of microcrystalline wax and theophylline, were characterized in terms of morphology (by Scanning Electron Microscopy (SEM)), of in vitro dissolution, of solid- state (by means of Differential Scanning Calorimetry (DSC) and X-Ray Powder Diffraction (XRPD)) and by checking the presence of the drug on the surface (by Photoelectron Spectroscopy (XPS)). Finally, an ad hoc in vitro-vivo modeling, suitably describing, and predicting the drug release and absorption from such kind of systems, was designed. b) Mechanochemistry Mechanochemical activation has been successfully employed to ameliorate the oral performance of drugs having scarce solubility, and therefore, low bioavailability. Through this solvent-free solid-state process, drug-carrier composites containing the drug in a highly available form are obtained thanks to the modification of its physicochemical properties (e.g. in an amorphous or nanocrystalline drug). This is the objective of the first part of Chapter 3, where mechanochemical process has been applied to improve dissolution performance, and therefore, absorption, of two scarcely soluble highly crystalline actives, namely, vinpocetine and vincamine. The drugs were subjected to mechochemical treatment in a lab scale planetary mill, using crosslinked polyvinylpyrrolidone as a carrier for vinpocetine, and sodium crosscarmellose or crosslinked polyvinylpyrrolidone as carriers for vincamine. These studies demonstrated the suitability of these materials to the mechanochemical process, the influence of these carriers on the disruption of the crystalline lattice, and the positive influence of the carriers on the dissolution performances and in vivo absorption. The drug-carrier coground composites were then characterized by means of transmission electron microscopy (TEM), solid-state nuclear magnetic resonance (SSNMR), DSC, PXRD, and Raman spectroscopy/imaging. A second possibility of application of the mechanochemical process is the mechanochemical synthesis: this is the focus of the second part of Chapter 3, where the mechanochemical synthesis is employed, under suitable experimental conditions, to promote the solid-state salification of both vinpocetine and vincamine. Citric acid was selected as a reagent, while crosslinked polyvinylpyrrolidone and sodium cross carmellose were chosen as fillers and process adjuvants in the case of vinpocetine and vincamine, respectively. In both cases, several cogrounds (differing from one another in terms of grinding time, active†"to-citric acid molar ratio, presence, or absence of the filler) were prepared. This way, by means of a proper experimental design, the influence of the above mentioned formulation and process variables were studied. XPS and high-resolution TEM were used to obtain qualitative and quantitative information about the produced salt forms and to get some insight into the salification mechanism.