STUDY OF SOLUBLE OR BIODEGRADABLE DEVICES FOR PROLONGED DRUG DELIVERY IN HOLLOW ORGANS

The present work was aimed to investigate the possibility to design and produce organ retentive systems for the delivery of drugs used in chronic treatments or in case of specific drug solubility or absorbability requirements. Attention was focused on three hollow organs: the urinary bladder, the stomach and the upper small intestine. Since development of drug delivery systems (DDS) is strictly connected to pharmaceutical technology used for their production, also this research area was deepened with a particular attention to innovative techniques such as 3D or 4D printing. For what concerns urinary bladder, a prototype of a DDS able to be administered through catheter was produced. Such system was made in a shape of a ring consisting of coated mini-matrices loaded with a drug tracer and connected by an absorbable suture thread. Drug release profile was studied in order to obtain a sustained release that lasted for some days. The purpose of the system was, in fact, to allow for catheter administration, acquire a sufficient special encumbrance to permit its retention in the organ for a few days releasing the drug, and be finally able to disassemble or dissolve once exhausted for leaving the organ physiologically with urination. Based on the need to treat topically diseases affecting the stomach or the upper small intestine or to improve absorption of drugs having narrow absorption windows in these anatomic districts, a novel Organ-Retentive Osmotically Driven System (ORODS) was studied. With the purpose to obtain a size increasing system that could eventually be retained in the stomach, a novel DDS exhibiting of one or two drug-containing units (HPMC matrices) promoting prolonged drug release, connected with osmotic units used as increasing volume compartments was prepared. The most important aspect that was taken into account while designing such a system, was that the device had to be able to gain encumbrance after administration for avoiding gastric-emptying, but also to disassemble and/or dissolve after a few hours. Preliminary studies were conducted by using paracetamol as the drug tracer and by assessing the expansion ability and mechanical resistance of osmotic units made of regenerated cellulose (dialysis membranes) containing sodium chloride as the osmotic agent. Based on these results the system was also exploited to deliver metformin, a drug used for type II diabetic patients, which needs frequent administrations of high doses, is characterized by high solubility, and exhibits a narrow absorption window in the upper intestine. The development of this system required granulation of the drug and application of external drug free layers to the matrices in order to obtain the desired drug release rate. Also, expanding osmotic units were better studied by using dialysis membranes having different cut-off (3.5-5 and 12-14 kD) and by filling them with two different osmotic agents (sodium chloride or mannitol) in different amounts. Considering the upper small intestine, the last organ taken into account, the development of a retentive system was conducted by applying 3D printing, which includes many different technologies from the mostly known fused deposition modeling (FDM) to the more recent stereolithography (SLA). The aim of this part of the work was to develop a retentive system meant to remain in situ for a few minutes, allowing for the contact of the drug containing units to the intestinal lumen membranes, eventually enabling a better absorption of the drug. The study was focused on the development of a device consisting in two drug containing units, or supports for a drug loaded dosage form, connected by a spring. Thanks to the design of the mentioned device, the system can have a space saving when the spring is compressed, eventually allowing for an oral administration, and a consequent expanded configuration when the spring is free to expand. The geometry, sizes and cross-section of the springs were evaluated in order to prepare systems able to withstand luminal pressure of small intestine. Triggering devices prepared by coating soluble thread with enteric polymers were studied for maintaining the systems in the compact configuration during oral administration and transit in the stomach, and for enabling a prompt expansion of the system when the upper intestine was reached.