The design and manufacturing of oral colon drug delivery systems with improved targeting ability were undertaken after a preliminary literature survey highlighting the main issues of currently marketed drug products, intended for inflammatory bowel disease (IBD) treatment. First, a more consolidated time-based approach was applied, as technology transfer was faced for a 5-aminosalicylic acid prototype formulation evaluated in a human pharmacoscintigraphy study. Subsequently, an original combination strategy leveraging multiple physiological characteristics of the intestine was developed for enhanced site selectivity of drug release into the large bowel. Particularly, a double-coated delivery system was devised, wherein an enteric soluble outer film, containing a microbially-degradable polysaccharide as a channeling agent, and a water-swellable/erodible inner layer, composed of hydrophilic cellulose derivatives of broad use and availability, would act synergistically to prevent early release to the small intestine on the one hand, and release failure on the other. The experimental activities were mainly focused on the formulation and manufacturing of the enteric outer film, and particularly on the selection of a proper polysaccharide pore former out of naturally-occurring ones already described for colon delivery purposes. The screening encompassed high-amylose starch, high-methoxylated pectin, as such or as a polyelectrolyte complex with chitosan, and chondroitin sulfate sodium as a polyelectrolyte complex with chitosan. Fluid bed spray-coating technique was used, aqueous- or hydro-alcoholic-based when the former mode was proved unfeasible. Coating formulas were set by establishing the weight ratio between the enteric-soluble methacrylic acid copolymer (Eudragit® S) and the polysaccharide, as well as the nature and percentage amount of the excipients, i.e. plasticizer and anti-tacking agent. Minitablets, either as such or provided with the inner swellable/erodible layer, composed of low-viscosity hydroxypropyl methylcellulose, and hydroxypropyl cellulose capsular devices for modified-release, fabricated by injection-molding, were prepared and used as multiple- and single-unit cores, respectively. Process parameters were identified and adjusted on a case-by-case basis. The resulting coated systems underwent physico-technological characterization and in vitro release testing using compendial media. Based on release results, high-amylose starch, pectin and its polyelectrolyte complex with chitosan were shown potentially suitable polysaccharide candidates. On the other hand, chondroitin sulfate sodium was discarded on account of fast leaching from the coating layer, thus impairing the relevant barrier properties. The role of colonic bacterial strains on the release performance of the formulations developed so far was evaluated. To this end, a previously described method for preparation of simulated colonic fluid (SCF), consisting in culture medium of proper composition inoculated with fecal samples from IBD patients, was adapted and improved. Furthermore, a testing procedure was devised. Clear differences were thereby highlighted in the case of amylose- and pectin/chitosan-containing films depending on whether SCF or culture medium not inoculated with fecal samples, used as a control, was employed for the test.

DESIGN AND DEVELOPMENT OF A NOVEL PHYSIOLOGICALLY-BASED COMBINATION APPROACH TO ORAL COLON DELIVERY / S. Moutaharrik ; supervisor: A. MARONI ; coordinator: G. ALDINI. Università degli Studi di Milano, 2020 Jan 22. 32. ciclo, Anno Accademico 2019. [10.13130/moutaharrik-saliha_phd2020-01-22].

DESIGN AND DEVELOPMENT OF A NOVEL PHYSIOLOGICALLY-BASED COMBINATION APPROACH TO ORAL COLON DELIVERY

S. Moutaharrik
2020

Abstract

The design and manufacturing of oral colon drug delivery systems with improved targeting ability were undertaken after a preliminary literature survey highlighting the main issues of currently marketed drug products, intended for inflammatory bowel disease (IBD) treatment. First, a more consolidated time-based approach was applied, as technology transfer was faced for a 5-aminosalicylic acid prototype formulation evaluated in a human pharmacoscintigraphy study. Subsequently, an original combination strategy leveraging multiple physiological characteristics of the intestine was developed for enhanced site selectivity of drug release into the large bowel. Particularly, a double-coated delivery system was devised, wherein an enteric soluble outer film, containing a microbially-degradable polysaccharide as a channeling agent, and a water-swellable/erodible inner layer, composed of hydrophilic cellulose derivatives of broad use and availability, would act synergistically to prevent early release to the small intestine on the one hand, and release failure on the other. The experimental activities were mainly focused on the formulation and manufacturing of the enteric outer film, and particularly on the selection of a proper polysaccharide pore former out of naturally-occurring ones already described for colon delivery purposes. The screening encompassed high-amylose starch, high-methoxylated pectin, as such or as a polyelectrolyte complex with chitosan, and chondroitin sulfate sodium as a polyelectrolyte complex with chitosan. Fluid bed spray-coating technique was used, aqueous- or hydro-alcoholic-based when the former mode was proved unfeasible. Coating formulas were set by establishing the weight ratio between the enteric-soluble methacrylic acid copolymer (Eudragit® S) and the polysaccharide, as well as the nature and percentage amount of the excipients, i.e. plasticizer and anti-tacking agent. Minitablets, either as such or provided with the inner swellable/erodible layer, composed of low-viscosity hydroxypropyl methylcellulose, and hydroxypropyl cellulose capsular devices for modified-release, fabricated by injection-molding, were prepared and used as multiple- and single-unit cores, respectively. Process parameters were identified and adjusted on a case-by-case basis. The resulting coated systems underwent physico-technological characterization and in vitro release testing using compendial media. Based on release results, high-amylose starch, pectin and its polyelectrolyte complex with chitosan were shown potentially suitable polysaccharide candidates. On the other hand, chondroitin sulfate sodium was discarded on account of fast leaching from the coating layer, thus impairing the relevant barrier properties. The role of colonic bacterial strains on the release performance of the formulations developed so far was evaluated. To this end, a previously described method for preparation of simulated colonic fluid (SCF), consisting in culture medium of proper composition inoculated with fecal samples from IBD patients, was adapted and improved. Furthermore, a testing procedure was devised. Clear differences were thereby highlighted in the case of amylose- and pectin/chitosan-containing films depending on whether SCF or culture medium not inoculated with fecal samples, used as a control, was employed for the test.
22-gen-2020
Settore CHIM/09 - Farmaceutico Tecnologico Applicativo
MARONI, ALESSANDRA
MARONI, ALESSANDRA
ALDINI, GIANCARLO
Doctoral Thesis
DESIGN AND DEVELOPMENT OF A NOVEL PHYSIOLOGICALLY-BASED COMBINATION APPROACH TO ORAL COLON DELIVERY / S. Moutaharrik ; supervisor: A. MARONI ; coordinator: G. ALDINI. Università degli Studi di Milano, 2020 Jan 22. 32. ciclo, Anno Accademico 2019. [10.13130/moutaharrik-saliha_phd2020-01-22].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/701155
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