supercritical fluid technology for gastroretentive formulations

Supercritical fluid technology for gastroretention formulations Brief description of proposed project: The project applies supercritical fluid technology to the design of highly porous micron-sized particles capable of gastric retention. The process parameters and microparticles properties required to achieve gastroretention, and improve oral delivery of 'problematic' drugs, will be investigated. Background Drugs with an absorption window in the upper small intestine have limited bioavailability when applied as conventional oral dosage forms, as the residence time of these formulations in the stomach and upper intestine is short, hence limiting extend of the drug absorption. To increase the bioavailability of the 'absorption window' drugs, formulations which the prolong residence time have been suggested, including (i) systems that adhere to the mucosal surface, (ii) systems that rapidly increase in size and thus cannot leave the stomach and (iii) systems with optimized density to float on gastric fluids (1-2). These systems are usually based on the 'one unit' approach but their reliability (due to such a design) has been questioned and application of 'multiple unit systems' (3) such as floating capsules with granules of gas generating agents (3) or hollow microparticles (4) has been suggested. We believe that the application of supercritical fluid (SCF) technology will make a step change in the hollow particles technology, compared to the current double emulsion (eg. 1,4) as, via changes in the kinetics of carbon dioxide depressurisation, one can generate formulations of variable densities, sizes and morphologies. The technology is generic and potential applications are in eg. systemic therapy of Alzhemier disease (L-dopa), CNS therapy (diazepam), cardiovascular therapy (propranolol), pulmonary oedema (furosemid) or local therapy of eg Helicobacter pylori (5). Project plan Task1. Preparation of hollow microparticles by SCF technology Initially the project will select materials and conditions to produce microparticles with controlled size ranges, densities and morphologies. Materials will initially be based on lactic acid and polyethhylne oxide polymers and their combinations, as established within the company. Processing of other materials will also be investigated, such as combinations of phospholipids and fatty acids. Task 2. In vitro characterization and drug incorporation The in vitro characterization aims to establish a fundamental understanding of a correlation between the buoyancy of microparticles (in simulated gastric conditions) and their physicochemical properties: size, density (and internal structure) and morphology (eg roundness). The drug loading potential of the microparticles for model drug compounds (L-dopa, furosemid and indomethacin) will be investigated and correlated to the nature of the material and the processing conditions. The release profile of incorporated compounds will be determined and optimized to correlate with the potential gastric retention time. Task 3. In vivo performance A limited number of selected systems will be investigated for their in vivo performance. These will include a dosing of experimental animals (pig) to determine plasma concentration profiles (bioavailability). The studies will be conducted in collaboration Prof. J Wiseman, School of Biosciences, Univ. of Nottingham. There is a current established collaboration in animal experimentation on the mucosal delivery and a DTI Technology Programme project (D Gray) to which both J Wiseman and S Stolnik are contributors. References 1. Streubel A et al. Current Opinion in Pharmacology 6 (2006) 501 2. Brahma N et al. Journal Controlled Release 63 (2000) 235. 3 Shweta Arora et al. AAPS PharmSciTech 6 ( 2005) Art. 47 (http://www.aapspharmscitech.org). 4 Yasunori Satoa et al, Journal of Pharmaceutics and Biopharmaceutics 55 (2003) 297. 5 Bardonnet PL et al. Journal Controlled Release 111 (2006)