New modules and assembled systems for the controlled release of drugs in combination

Abstract Dome matrix technology is a module assembly technology for construction of delivery systems for time and space controlled release of drugs[1]. The objective of this work was the development via the use of Dome matrix technology of a floating dosage forms, useful for drugs administration with a very narrow absorption window or not soluble at intestinal pH, or the manufacture of a multi-drugs and multi-kinetics dosage form[2-4]. The first part of this thesis will focus on the realization of a double pulse release of esomeprazole in combination with sucralfate assembled system for the delivery of active substances into the stomach for the treatment of gastric ulcer and gastro-esophageal reflux. The delivery system should release the first pulse of esomeprazole in the stomach and the second, after 4 to 6 hours, in the upper part of the intestine. The first pulse of esomeprazole will not be coated, but it will contain an alkalizing agent to protect the drug from gastric content. The alkalizing agent should stabilize the acid sensitive esomeprazole allowing a direct absorption into gastric mucosa where lie the target of the drug.[5-7] The second pulse of esomeprazole is delayed being the drug protected by an impermeable coating during its permanence into the stomach. For the delivery purpose, this Dome Matrix assembled system consist of five modules (4 female modules and 1 male module), assembled and partially coated. The second part will focus on the manufacture of a floating system for the controlled release of norfloxacin using alginate as the polymer of interest for controlled release Norfloxacin has been selected as the model drug, because of its high solubility in gastric environment and low bioavalability at higher pH values.[2] Dome matrix technology will be used to assemble a floating dosage form in order to increase the bioavalability of the norfloxacin. [2] Physiochemical interaction of excipients in the matrix will be also investigated to determine the extent of the crosslinkage between calcium and alginate in the matrix and therefore its efficiency in drug release control.[8] Pharmacokinetic study on rats will be also performed to assess the bioavailability of the drug thanks to the floating dosage form.[9] 1. Losi, E., et al., Assemblage of novel release modules for the development of adaptable drug delivery systems. Journal of Controlled Release, 2006. 111(1†"2): p. 212-218. 2. Oliveira, P.R., et al., Assembled modules technology for site-specific prolonged delivery of norfloxacin. International Journal of Pharmaceutics, 2011. 405(1-2): p. 90-96. 3. Strusi, O.L., et al., Artesunate-clindamycin multi-kinetics and site-specific oral delivery system for antimalaric combination products. Journal of Controlled Release, 2010. 146(1): p. 54-60. 4. Strusi, O.L., et al., Module assemblage technology for floating systems: In vitro flotation and in vivo gastro-retention. Journal of Controlled Release, 2008. 129(2): p. 88-92. 5. Carmelo, S., New drugs to suppress acid secretion: current and future developments. Drug Discovery Today: Therapeutic Strategies, 2007. 4(3): p. 155-163. 6. Howden, Immediate-release proton-pump inhibitor therapy: potential advantages. Aliment Pharmacol Ther, 2005. 7. Schellekens, R.C.A., et al., Pulsatile drug delivery to ileo-colonic segments by structured incorporation of disintegrants in pH-responsive polymer coatings. Journal of Controlled Release, 2008. 132(2): p. 91-98. 8. Bajpai, S.K. and S. Sharma, Investigation of swelling/degradation behaviour of alginate beads crosslinked with Ca2+ and Ba2+ ions. Reactive and Functional Polymers, 2004. 59(2): p. 129-140. 9. Stein, G.E., Review of the bioavailability and pharmacokinetics of oral norfloxacin. The American Journal of Medicine, 1987. 82(6, Supplement 2): p. 18-21.