A Kinetic Model To Explain the Zero-Order Release of Drugs from Ionic Polymeric Drug Conjugates: Application to AMPS-Triflusal-Derived Polymeric Drugs Alberto Gallardo,* Gema Rodrı ´guez, Marı ´a Rosa Aguilar, Mar Ferna ´ ndez, and Julio San Roma ´ n Instituto de Ciencia y Tecnologı ´a de Polı ´meros, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain Received February 26, 2003; Revised Manuscript Received July 11, 2003 ABSTRACT: The microstructural characterization of metacryloyloxyethyl [2-(acetyloxy)-4-(trifluorom- ethyl)]benzoate (THEMA) and 2-acrylamido-2-metylpropanesulfonic acid (AMPS) copolymers (THA) is described. Both monomers presented a high differential reactivity in copolymerization (the reactivity ratios have been determined, rTHEMA ) 4.54 and rAMPS ) 0.32), and the monomer incorporation to the copolymer chains is quite heterogeneous: the more reactive THEMA is incorporated preferentially in the first steps of the reaction and AMPS in last stages. Two rich THEMA copolymers (0.60 and 0.80 THEMA feed molar fraction), as well as the homopolymer, have been used for in vitro Triflusal (Disgren) release experiments, giving rise to zero-order profiles. A kinetic model called the “progressive accessibility model” has been developed in order to explain the zero-order kinetics of Triflusal release from AMPS- THEMA copolymers in different media, at pH ) 2.0, 7.4, and 10.0. The experimental results fit adequately the model, which considers the accessibility of the hydrolyzable THEMA units controlled by the microstructural distribution of these units in copolymer sequences. Introduction The ability to inhibit thrombus formation on surfaces is an important aim for polymers used to make small- diameter vascular grafts and any other devices coming in contact with blood. In this sense, the synthesis of polymers with good haemocompatibility has permitted a reduction of the administration of heparin associated with the use of blood contact devices and, therefore, the reduction of the side effects derived from it, mainly thrombocytopenia and haemorrhage. Different strate- gies have been developed to improve the long-term efficacy of these vascular substitutes, being one of the most important the modification of the blood contact surfaces with active polymeric coatings. It has been recently described by our group that the application of specific polymeric drugs derived from acetylsalicylic acid on the inner surface of small diameter vascular grafts improves the prevention of adhesion and aggregation of platelets on the surface. 1-4 Polymeric drugs are simply insoluble prodrugs that can be converted to their active, soluble form through hydrolysis. Copolymers are a well-known approach to altering the physical proper- ties of polymers and to obtaining a specific physico- chemical and biological behavior. Their properties are controlled by the monomers incorporated in the mac- romolecules and by the chains microstructure. Our group has recently described the synthesis of statistical copolymers based on a methacrylic derivative of an antiaggregant drug, Triflusal (methacryloyloxyethyl[2- (acetiloxy)-4-(trifluoromethyl)] benzoate), and 2-acryla- mido-2-methylpropanesulfonic acid (AMPS), a biocom- patible monomer which incorporates biologically active sulfonic groups in its side chains. In this kind of system the drug is polymerized to form an insoluble matrix, and it permits the drug loading of up to 100% and ensure its long-term stability, activity, and bioavailability. THEMA-rich copolymers were formulated in the range of water insolubility and therefore in the range of compositions useful for vascular grafty coating applica- tion. These insoluble polymeric formulations bearing Triflusal covalently attached as well as sulfonic groups prevented adhesion and activation of platelets. 4 These effects are due to the antiaggregant properties of Triflusal and, in addition, to the presence of the sulfonic groups which can mimic the antiacoagulant action of heparin. 5,6 Figure 1 shows the release mechanism. Once Triflusal is released from the system, the HEMA-AMPS back- bone becomes hydrosoluble, and on the other hand, free Triflusal is rapidly deacetylated and converted into the metabolite [2-hydroxy-4-trifluoromethyl]benzoic acid (HTB), which is the residue we analyze in the release experiments. This article is devoted to the analysis of the poly- (THEMA-co-AMPS) microstructure and to the study of the in vitro controlled Triflusal release at different pH. The in vitro drug release presented long-term zero-order kinetics, very interesting for this application owing to * Corresponding author: fax 34-915644853; e-mail gallardo@ ictp.csic.es. Figure 1. Scheme of the THEMA-AMPS copolymer structure and of the mechanism of hydrolysis and solubilization of the copolymer chains. 8876 Macromolecules 2003, 36, 8876-8880 10.1021/ma034248v CCC: $25.00 © 2003 American Chemical Society Published on Web 10/22/2003