RESUMEN
Successful treatment of ulcerative colitis (UC) is highly dependent on several parameters, including dosing regimen and the ability to deliver drugs to the disease site. In this study two strategies for delivering mesalazine (5-aminosalicylic acid, 5-ASA) to the colon were compared in an advanced in vitro model of the human gastrointestinal (GI) tract, the SHIME® system. Herein, a prodrug strategy employing bacteria-mediated drug release (sulfasalazine, Azulfidine®) was evaluated alongside a formulation strategy that utilised pH and bacteria-mediated release (5-ASA, Octasa® 1600 mg). SHIME® experiments were performed simulating both the GI physiology and colonic microbiota under healthy and inflammatory bowel disease (IBD) conditions, to study the impact of the disease state and ileal pH variability on colonic 5-ASA delivery. In addition, the effects of the products on the colonic microbiome were investigated by monitoring bacterial growth and metabolites. Results demonstrated that both the prodrug and formulation approaches resulted in a similar percentage of 5-ASA recovery under healthy conditions. On the contrary, during experiments simulating the GI physiology and microbiome of IBD patients (the target population) the formulation strategy resulted in a higher proportion of 5-ASA delivery to the colonic region as compared to the prodrug approach (P < 0.0001). Interestingly, the two products had distinct effects on the synthesis of key bacterial metabolites, such as lactate and short chain fatty acids, which varied according to disease state and ileal pH variability. Further, both 5-ASA and sulfasalazine significantly reduced the growth of the faecal microbiota sourced from six healthy humans. The findings support that the approach selected for colonic drug delivery could significantly influence the effectiveness of UC treatment, and highlight that drugs licensed for UC may differentially impact the growth and functioning of the colonic microbiota.
Asunto(s)
Antiinflamatorios no Esteroideos , Colon , Microbioma Gastrointestinal , Mesalamina , Sulfasalazina , Mesalamina/administración & dosificación , Mesalamina/farmacología , Humanos , Colon/microbiología , Colon/metabolismo , Colon/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Sulfasalazina/administración & dosificación , Profármacos/administración & dosificación , Sistemas de Liberación de Medicamentos , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/microbiología , Concentración de Iones de Hidrógeno , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/microbiología , Liberación de FármacosRESUMEN
Targeted drug delivery to the colon offers a myriad of benefits, including treatment of local diseases, direct access to unique therapeutic targets and the potential for increasing systemic drug bioavailability and efficacy. Although a range of traditional colonic delivery technologies are available, these systems exhibit inconsistent drug release due to physiological variability between and within individuals, which may be further exacerbated by underlying disease states. In recent years, significant translational and commercial advances have been made with the introduction of new technologies that incorporate independent multi-stimuli release mechanisms (pH and/or microbiota-dependent release). Harnessing these advanced technologies offers new possibilities for drug delivery via the colon, including the delivery of biopharmaceuticals, vaccines, nutrients, and microbiome therapeutics for the treatment of both local and systemic diseases. This review details the latest advances in colonic drug delivery, with an emphasis on emerging therapeutic opportunities and clinical technology translation.