International Journal of Pharmaceutics 334 (2007) 35–41 Development and evaluation of new multiple-unit levodopa sustained-release floating dosage forms J. Goole a , F. Vanderbist b , K. Amighi a,∗ a Laboratory of Pharmaceutics and Biopharmaceutics, Universit´ e Libre de Bruxelles, Campus de la Plaine, CP 207, Boulevard du Triomphe, Brussels 1050, Belgium b Laboratoires SMB S.A., Rue de la Pastorale, Brussels 1080, Belgium Received 7 July 2006; received in revised form 4 October 2006; accepted 9 October 2006 Available online 13 October 2006 Abstract This work relates to the development and the in vitro evaluation of sustained-release minitablets (MT), prepared by melt granulation and subsequent compression, which are designed to float over an extended period of time. Levodopa was used as a model drug. The importance of the composition and manufacturing parameters of the MT on their floating and dissolution properties was then examined. The investigation showed that MT composition and MT diameter had the greatest influence on drug release, which was sustained for more than 8 h. By using the same formulation, the best floating properties were obtained with 3 mm MT prepared at low compression forces ranging between 50 and 100 N. Their resultant-weight (RW) values were always higher than those obtained with a marketed HBS dosage form within 13h. When they were filled into gelatin capsules, no sticking was observed. By evaluating the dissolution profiles of levodopa at different pH values, it was found that dissolution profiles depend more on the prolonged-release ability of Methocel ® K15M than on the pH-dependent solubility of levodopa. Finally, the robustness of the floating MT was assessed by testing the drug release variability in function of the stirring conditions during dissolution tests. © 2006 Elsevier B.V. All rights reserved. Keywords: Minitablets; Floating; Sustained-release; Melt granulation; Levodopa 1. Introduction Oral sustained-drug-delivery formulations show some limita- tions connected with the gastric emptying time (GET). In partic- ular, unpredictable GET leads to variations in the amount of drug absorbed. Moreover, a too rapid gastrointestinal transit can result in incomplete drug release from the device above the absorption zone, leading to diminish effectiveness of the administered dose when the drug presents an absorption window. A prolongation of gastric residence time (GRT) of a rate-controlled oral drug delivery system can overcome these problems by reducing the inter-subject variability, the so called “peak and trough” effect, and leads to a more predictable effect with increased bioavail- ability, especially for drugs with a narrow absorption window (NAW) in the upper part of the gastrointestinal tract (Hoffman et al., 2004). Moreover, extended-release dosage forms with pro- longed residence time in the stomach are also highly desirable ∗ Corresponding author. Tel.: +32 2 650 5252; fax: +32 2 650 5269. E-mail address: kamighi@ulb.ac.be (K. Amighi). for drugs (i) that are locally active in the stomach, (ii) that are unstable in the intestinal or colonic environment, and/or (iii) have low solubility at higher pH values (Streubel et al., 2003). As the total gastrointestinal transit time is also prolonged, the number of doses in the regimen can be reduced and so the patient compliance is improved. Among the various attempts made to increase the retention of an oral dosage form (Mo¨ es, 1993; Iannucelli et al., 1998a; Talwar et al., 2001; Klausner et al., 2003; Sato et al., 2004), it seems that the floating drug delivery systems offer the most effective and rational protection against early and random gastric emp- tying compared to the other methods proposed for prolonging the GRT of solid dosage forms (Mo¨ es, 1993). In this way, Seth and Tossounian (1978, 1984) have developed a Hydrodynam- ically Balanced capsule System (HBS TM ) based on a mixture of drugs and hydrocolloid. Upon contact with gastric fluids, the capsule shell dissolves and the hydrocolloid begins to swell, maintaining a relative integrity of shape, a bulk density lower than 1 g/ml and regulating the drug release. Unfortunately, most single-unit floating systems are generally unreliable and non- reproducible in prolonging the GRT. They also show a higher 0378-5173/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2006.10.018