3D Printed Tacrolimus Rectal Formulations Ameliorate Colitis in an Experimental Animal Model of Inflammatory Bowel Disease

The aim of this study was to fabricate novel self-supporting tacrolimus suppositories using semisolid extrusion 3-dimensional printing (3DP) and to investigate their efficacy in an experimental model of inflammatory bowel disease. Blends of Gelucire 44/14 and coconut oil were employed as lipid excipients to obtain suppository formulations with self-emulsifying properties, which were then tested in a TNBS (2,4,6-trinitrobenzenesulfonic acid) induced rat colitis model. Disease activity was monitored using PET/CT medical imaging; maximum standardized uptake values (SUVmax), a measure of tissue radiotracer accumulation rate, together with body weight changes and histological assessments, were used as inflammatory indices to monitor treatment efficacy. Following tacrolimus treatment, a significant reduction in SUVmax was observed on days 7 and 10 in the rat colon sections compared to non-treated animals. Histological analysis using Nancy index confirmed disease remission. Moreover, statistical analysis showed a positive correlation (R2 = 71.48%) between SUVmax values and weight changes over time. Overall, this study demonstrates the effectiveness of 3D printed tacrolimus suppositories to ameliorate colitis and highlights the utility of non-invasive PET/CT imaging to evaluate new therapies in the preclinical area.

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or continue reading here: Seoane-Viaño, I.; Gómez-Lado, N.; Lázare-Iglesias, H.; García-Otero, X.; Antúnez-López, J.R.; Ruibal, Á.; Varela-Correa, J.J.; Aguiar, P.; Basit, A.W.; Otero-Espinar, F.J.; González-Barcia, M.; Goyanes, A.; Luzardo-Álvarez, A.; Fernández-Ferreiro, A. 3D Printed Tacrolimus Rectal Formulations Ameliorate Colitis in an Experimental Animal Model of Inflammatory Bowel Disease. Biomedicines 2020, 8, 563.

Conclusions
The versatility of semisolid extrusion 3DP allowed the preparation of small self-emulsifying suppositories containing an exact dose of the drug with a size and shape adapted for their rectal administration in rats. The combination of Gelucire 44/14 and coconut oil showed adequate printability, and the disaggregation of the suppositories and subsequent release of the drug from the formed emulsion occurred within an acceptable period of time (more than 50% of tacrolimus released within the first hour). Moreover, the remission of the disease was achieved in five days, compared to the 9 days required for the non-treated animals to recover. Moreover, [18F]FDG PET/CT imaging was shown to be a useful tool for the assessment of the disease over time and CT imaging allowed for a better in vivo characterization of the suppositories. The quantification of inflammation using the SUVmax parameter, commonly used in clinical practice, helps the translation into humans of this new therapeutic approach. The combination of semisolid extrusion 3DP with medical imaging offered a new approach for the development and assessment of novel IBD therapies in the preclinical area.

Materials
Tacrolimus was purchased from Guinama S.L.U., Valencia, Spain. Coconut oil was obtained from Acofarma, Madrid, Spain. Barium sulphate Reagent Grade, 99%, was obtained from Honeywell, London, UK. Gelucire 44/14 was kindly donated by Gattefosse España SA, Madrid, Spain. TNBS (2,4,6-trinitrobenzenesulfonic acid) was purchased from Sigma-Aldrich Company Ltd., Madrid, Spain. Ethanol absolute was obtained from VWR International S.A.S., Briare, France. NaCl 0.9% B. Braun was purchased from Braun Medical Inc. Barcelona, Spain. Ultravist® 300 mg/mL was purchased from Bayer Hispania S.L., Barcelona, Spain.