DEVELOPMENT OF AN ORAL MULTIPLE-UNIT DOSAGE FORM CONTAINING A HIGH LOAD OF 5-AMINOSALICYLIC ACID
Creators: name: DI PRETORO, GIUSTINO
Publisher: name: Universit� degli Studi di Milano
Year: 2010

description: DEVELOPMENT OF AN ORAL MULTIPLE-UNIT DOSAGE FORM CONTAINING A HIGH LOAD OF 5-AMINOSALICYLIC ACID Introduction 5-aminosalicylic acid (5-ASA) is the first-line drug therapy for mild to moderate acute exacerbations of IBD (Inflammatory Bowel Disease). 5-ASA is generally administered at the dosage regimen of 2.4 g/day, even though recent clinical trials have convincingly demonstrated that by doubling the standard dose of 5-ASA, both safety and efficacy and hence cost-effectiveness can be improved. However, most of the oral formulations currently available on the market are associated with a number of limitations, mainly a relatively low drug dosage (generally 500 mg 5-ASA/unit). Frequent daily dosing and a high number of tablets/capsules are therefore required at the expense of patient acceptability and adherence to therapy [1]. Purpose The aim of the research project was to develop a high-strength multiple-unit dosage form containing more than 1000 mg 5-ASA, in order to achieve once/twice-a-day administration, improving compliance. In addition, in order to meet the therapeutic IBD needs, the formulation is intended to prevent gastric breakdown and systemic absorption in the upper part of the small intestine, thus minimising unwanted absorption and potential risk of side-effects while maximising the therapeutic effective dose delivered to the affected regions of the gastrointestinal (GI) tract. Multiparticulates, based on high density pellets, have been sought as promising alternatives for the administration of 5-ASA, both for their biopharmaceutical (e.g. more even and predictable distribution and transportation in the GI tract) and technological (e.g. high drug loading and density) advantages [2]. Extrusion-spheronisation (E-S) was investigated as the manufacturing technique, as it offers the potential to produce highly-loaded pellets [3]. Experimental A ram extruder apparatus (capillary rheometer) was initially employed to investigate, systematically, the rheological behavior of highly-loaded 5-ASA pastes undergoing extrusion. In particular, the effect of the chemical (acidity) and physical (particle size and shape) characteristics of 5-ASA were studied. The influence of an E-S aid in the extrusion process of highly-loaded 5-ASA pastes, was also assessed. The water retention ability, quantified by centrifuge testing and supported by ram extrusion, as well as the rheological performance of a standard microcrystalline cellulose (MCC) grade (i.e. Avicel PH101) and colloidal ones (i.e. Avicel RC591 and CL611) containing sodium carboxymethylcellulose were therefore investigated. Moreover, ram extrusion of solid-liquid paste formulations through multi-holed square-ended dies was used to assess the extrudability of different 5-ASA/MCC paste formulations. Extrudates were spheronised using a benchtop spheronisation device (Caleva) and the quality of extrudates monitored via visual and automated shape analyses. The research activity pertaining to the rheological studies and feasibility of processing highly-loaded 5-ASA paste formulations was performed in collaboration with the ?Department of Chemical Engineering and Biotechnology? of the University of Cambridge (UK). Promising formulations, as identified in the preliminary study performed in the ram apparatus, were afterwards tested on a pilot scale screen extruder and spheroniser (Nica). Considered the complexity and the multifactoriality of the E-S process, an investigation of both formulation and process parameters, in the pilot-scale apparatus, was also performed. A factorial approach, namely a mixed fractional factorial design, was employed for this purpose. In particular, the effect of three formulation components (5-ASA:MCC ratio, PVP and water amount) and two process parameters (extrusion speed and spheronisation time) on the process yield and on the final characteristics of pellets, i.e. size, shape, mechanical resistance, bulk density and dissolution properties, was investigated. The independent variables and the relevant experimental space investigated were selected on the base of preliminary trials. In particular, a batch of 5-ASA with specific characteristics of particle size and shape and the Avicel RC591 grade of MCC were selected for paste preparation. 27 runs, including 3 replicates of the central point, were performed. An optimisation study, based on the desirability function approach [4], was finally undertaken, to identify the combination of factors that would provide the optimal response values to be obtained. The drug release of highly-loaded 5-ASA pellets was accordingly tailored to meet specific IBD therapeutic needs. To achieve modular sustained- and pH-independent release profiles, pellets were coated with a polyvinyl acetate polymeric dispersion, up to different theoretical weight gains. An outer, additional, acrylate polymeric layer was applied to avoid/minimise 5-ASA loss from pellets during the gastric residence time. Coating process was performed in an pilot-scale fluidized bed apparatus (Glatt� Process Technology GmbH, Binzen, Germany). The drug release performance was tested in-vitro (USP 29 paddle apparatus) in a III buffer stage pH to simulate gastric, small and large intestinal fluid conditions [5]. Finally, preliminary attempts to realise a final DDS based on a capsule dosage form were made. The drug release performance of the final DDS was afterwards compared to that of two commercially available products. Results and discussion A systematic study of 5-ASA/MCC paste formulations was performed. When undergoing ram extrusion, liquid phase migration (LPM) within the paste and hence variation in water content of extrudates and reproducibility of the final E-S product, was generally observed. The extent of LPM was found to be related to both the drug loading and its physical properties, particularly the particle morphology (needle-like). This was confirmed by extruding calcium sulphate/MCC pastes, where the sulphate polymorph was selected to match the 5-ASA shape. A reduction in particle size, combined with a change in the morphology of 5-ASA particles, allowed LPM to be reduced considerably or sometimes eliminated. Accordingly, a micronisation step was adjusted and the milled 5-ASA used in the final formulations. Colloidal MCC grades were identified as promising alternatives to the standard Avicel PH101 for the extrusion of highly-loaded 5-ASA pastes, due to their ability to hinder water migration. By combining a micronised 5-ASA batch, with the appropriate characteristics of particle size and shape, and colloidal MCC grades, an E-S route for the development of a multiparticulate formulation containing up to 90 wt% 5-ASA was identified. The promising 5-ASA/MCC formulations were successfully processed in the pilot-scale apparatus and the MFFD allowed the most affecting process and formulation parameters to be identified. In particular, the 5-ASA:MCC ratio, the PVP and the water amount were found to have a significant effect (p&lt;0.05) on most of the response variables evaluated. As for the process parameters, the extrusion speed was identified as having a considerable effect on the bulk density and shape of pellets, whereas the spheronisation time only showed a significant influence on the size parameter. An optimisation step was successfully performed and allowed pellets with 95 wt% 5-ASA, with satisfactory characteristics (e.g. high bulk density, low friability and good sphericity), to be obtained. The optimised combination of parameters was: extrusion speed, 40 rpm; spheronisation time, 2 min; water and PVP contents, 35% and 0.2% (w/w%, dry mass), respectively. The drug release of highly-loaded 5-ASA pellets was successfully tailored in conformity of the IBD needs. A prolonged- and pH-independent release of 5-ASA, over 12-h dissolution testing was achieved. In addition, no drug release occurred under simulated gastric conditions. The final DDS developed proved to be superior in-vitro to the reference mesalamine products tested. Conclusion The particle size and the morphology (needle-like) of 5-ASA were identified as critical parameters in E-S processing of MCC-based pastes. Particle size reduction combined with change in particle shape allowed highly-loaded 5-ASA pastes to be extruded. Modified MCC grades containing NaCMC were identified as promising alternatives to the standard MCC grade for the extrusion of highly-loaded 5- pastes. A combination of an appropriate micronised batch of 5-ASA and a colloidal MCC type allowed a promising formulation for highly-loaded multi-particulate dosage form to be identified. The feasibility of scaling up this formulation from a ram extruder to a pilot scale apparatus (basket type) was demonstrated. The optimisation step was successfully performed and allowed 95wt% 5-ASA loaded pellets to be achieved. The possibility of customizing drug release of 5-ASA, accordingly to the IBD therapeutic needs, was also demonstrated, as well as the possibility of realising a final DDS containing more than 1000 mg 5-ASA, and with improved in-vitro release performance to that of current reference products.