Development of Enteric-coated Pectin-based Matrix Tablets for Colonic Delivery of Theophylline
´ ´ PAOLA MURAa,*, FRANCESCA MAESTRELLIa, MARZIA CIRRIa, M. LUISA GONZALEZ RODRIGUEZb and ANTONIO M. RABASCO ALVAREZb
a ` Universita degli Studi di Firenze, Dipartimento di Scienze Farmaceutiche, via Gino Capponi 9, 50121 Firenze, Italy; ` ´´ ´ ˜ Departamento de Farmacia y Tecnologıa Farmaceutica, Universidad de Sevilla, C/ Prof. Garcıa Gonzalez, s/n. 41012 Sevilla. Espana
Journal of Drug Targeting Downloaded from informahealthcare.com by University of Geneva on 04/08/13 For personal use only.
(Received 7 July 2003)
The present work was aimed at developing a new colonic drug delivery system which takes advantage of thecombined approaches of a speciﬁcally colon-biodegradable pectin matrix with a pH-sensitive Eudragitw S100 polymeric coating. The developed system was able to suitably retard the onset of drug release and to provide a colon-speciﬁc delivery, thus overcoming the problems of pectin solubility in the upper gastrointestinal tract and low site-speciﬁcity of simple pH-dependent systems. Due to the poorcompactability properties of pectin, it was used in mixture with Emdexw, a hydrophilic directlycompressible material, in order to make it possible to prepare tablets by direct compression. Theophylline (TP) was used as model drug due to its suitable pharmacokinetic properties for colonic delivery and good absorption in the large intestine. The effects of varying the type of pectin (low and highmethoxylated, or amidated), the pectin:Emdexw ratio and the level of the pH-dependent polymeric coating on drug release behavior were investigated. Release tests were performed using sequential liquids simulating the physiological variation of pH and the effect of the presence or not of pectinolytic enzymes into the simulated colonic medium was evaluated. Thirty percent (w/w) was the the minimumcontent of Emdexw for obtaining directly compressible tablets with sufﬁcient hardness to withstand the coating process and 27% (w/w) was the minimum coating amount for obtaining an adequate lag time before the onset of drug release. After lag time, linear nearly zero-order proﬁles were obtained whose slope (i.e. the drug release rate) depended on both the Emdexw content and the pectin type. Comparisonof the results obtained in the presence or not of pectynolitic enzymes allowed selection of the high methoxylated pectin as the most interesting candidate for speciﬁc colonic delivery since it was the least water-soluble and the most susceptible to enzymatic degradation, thus assuring a greater site-speciﬁcity of drug release. Finally, the importance of using appropriate dissolution testconditions to adequately characterize the drug release proﬁles from delivery systems endowed with a microﬂora-activated drug release triggering mechanism has been demonstrated. Keywords: Pectin; Colon drug delivery; Eudragit; Emdex; Theophylline
INTRODUCTION There is increasing interest in the development of colonspeciﬁc drug delivery systems, whose numerous opportunities and advantages have been wellrecognized and documented (Ashford and Fell, 1994; Rubinstein, 1995; Watts and Illum, 1997; Yang et al., 2002). The main approaches proposed to achieve colon-selective drug delivery include pH-sensitive (Ashford et al., 1993a), time-dependent (Pozzi et al., 1994) and microﬂoraactivated systems (Gliko-Kabir et al., 2000). However, high individual variability together with similarity in pH betweenthe small intestine and the colon make
the site-speciﬁcity of pH-dependent systems not very reliable (Ashford et al., 1993a; Yang et al., 2002). On the other hand, the potentially large variation in gastric emptying time can result in a spread of the initial release site in the gastrointestinal tract and therefore non-speciﬁc drug delivery in the colon from time-dependent systems (Yang et al.,...