(315a) Chitosan-Based Anti-Malarial Oral Drug Delivery Systems Prepared Using A Green Supercritical Impregnation Process

Artemisinin (also known by the chinese name Quinghaosu) is a drug used to treat malaria which can synthesized or extracted from Artemisia annua L.. This substance is highly effective against the multidrug resistant strains of the Plasmodium falciparum and Plasmodium vivax malarial parasites. Artemisinin formulations are usually administrated to adults and children in tablets or in liquid dosage forms. Nevertheless, artemisinin has a very low aqueous solubility which reduces its bioavailability and thus limiting its use and efficiency. Therefore, researchers are presently trying to find new and more efficient administration forms for this drug, namely by the development of polymeric controlled drug release systems (CDR's). Chitosan and its derivatives are presently receiving great attention as supports for CDR's for several biomedical and pharmaceutical applications, because of their inherent biocompatibility, biodegradability, adsorption, transmucosal drug transport properties and the ability to interact with different substances (like hydrophilic and hydrophobic drugs). Chitosan functional and biological properties are related to its molecular weight, charge density and distribution, degree of deacetylation and to the pH value of the media in which it will be placed into. Consequently, these factors can restrain some biomedical chitosan applications as CDR's. Thus, there is a practical necessity to synthesize chitosan derivatives with improved solubility/non-solubility, at different pH values, taking in consideration the particular envisaged biomedical application. This is usually done by the introduction of some specific chemical modifications into the chitosan chain molecule. These ?tailored? modifications may change the polymeric solubility/non-solubility and biodegradability/biocompatibility nature, the polymeric ability to interact with drugs or with other biomolecules (enzymes, for example), and the kinetics of drug release for any new or particular envisaged CDR's application. The Supercritical Solvent Impregnation technique (SSI) already proved to be very valuable and to present several advantages for the development of drug impregnated polymeric materials which can be used as CDR's for many biomedical applications. Using this method some interesting hydrophobic drugs, which can not be impregnated by aqueous solution/suspension soaking, can be incorporated into polymeric materials. Drug loading and drug depth penetration can be considered as a ?tunable? process since it can be performed by controlling the depressurization step (which can be performed at several rates), the time of impregnation or by changing the solvent density (and consequently the drug solubility in it) by pressure and temperature control, in opposition of conventional impregnation processes. The main objective of this work was to study artemisinin impregnation into three synthetized chitosan derivatives (N-carboxymethylchitosan (CMC), N-carboxybutylchitosan (CBC) and succinylchitosan (SCC)), and using a CO2 SSI methodology, and in order to develop and prepare oral CDR's for malaria treatment. The effects of operational pressure and temperature on the prepared systems were investigated. The effect of pH on the swelling/dissolution behavior of these derivatives was also studied, in order to see how these polymeric samples behave in similar media to those found at the stomach and at intestine biological conditions. Swelling studies were performed at three different pH buffer media (2.0, 6.0 and 7.4). CO2 pressurized polymer samples were characterized by mercury porosimetry, helium gas picnometry, SEM and swelling/dissolution studies, to verify if high pressure CO2 affects polymeric structures, before and after the impregnation process. Impregnation experiments were performed from 10 MPa upto 18 MPa, and at 318 K, and for 1, 2.5 and 5 h. In order not to alter/damage the polymeric structures, slow depressurization rates were employed. The resulting CDR systems were characterized by FTIR-ATR spectroscopy, optical and SEM microscopy. Artemisinin was identified by TLC and was quantified by HPLC-UV and also gravimetrically. In pH 2.0 (similar to stomach conditions), CMC and CBC maximum swelling degree were found to be ~25 % and ~20 % (w/w), respectively. For these derivatives, and at pH's 6.5 and 7.4 (similar to intestine conditions) an almost constant and lower swelling degree was obtained (~7-10 %, w/w). SCC was a very sensitive polymer at pH 2.0, presenting a high dissolution rate while, at pH 7.4, its dissolution rate was low and presented a high swelling degree (~18 %, w/w). Considering that, at real biological conditions, these systems would stay for around 3 hours in the stomach (at low pH, 2.0) and then they would be transferred into the intestine (at higher pH's, 6.5 and 7.4), we may assume that it will be possible to keep polymer integrity and drug release at efficient levels and for long enough periods of time (from 0 to 8h). Thus, these results indicated that CMC and CBC can be considered as promising biomaterials for the release of artemisinin at the intestine. In addition, the SSI results indicated that it is possible to control the amount of impregnated drug just by changing the process pressure conditions, which reveals the feasibility of preparing chitosan derivatives-based drug delivery systems using this method.