DEVELOPMENT OF AN ORAL MULTIPLE-UNIT DOSAGE FORM CONTAINING A HIGH LOAD OF 5-AMINOSALICYLIC ACID
Tesi di Dottorato
Data di Pubblicazione:
2010
Citazione:
DEVELOPMENT OF AN ORAL MULTIPLE-UNIT DOSAGE FORM CONTAINING A HIGH LOAD OF 5-AMINOSALICYLIC ACID / G. Di Pretoro ; Coordinatore: Carlo De Micheli ; Docente guida: Lucia Zema. Universita' degli Studi di Milano, 2010 Dec 15. 23. ciclo, Anno Accademico 2010. [10.13130/di-pretoro-giustino_phd2010-12-15].
Abstract:
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
Tipologia IRIS:
Tesi di dottorato
Keywords:
5-aminosalicylic acid ; extrusion-spheronisation ; pellets ; multiple-unit dosage form
Elenco autori:
G. DI PRETORO
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