Gastrointestinal Tracking and Gastric Emptying of Coated Capsules in Rats with or without Sedation Using CT imaging

Following oral administration, gastric emptying is often a rate-limiting step in the absorption of drugs and is dependent on both physiological and pharmaceutical factors. To guide translation into humans, small animal imaging during pre-clinical studies has been increasingly used to localise the gastrointestinal transit of solid dosage forms. In contrast to humans, however, anaesthesia is usually required for effective imaging in animals which may have unintended effects on intestinal physiology. This study evaluated the effect of anaesthesia and capsule size on the gastric emptying rate of coated capsules in rats. Computed tomography (CT) imaging was used to track and locate the capsules through the gastrointestinal tract. Two commercial gelatine mini-capsules (size 9 and 9h) were filled with barium sulphate (contrast agent) and coated using Eudragit L. Under the effect of anaesthesia, none of the capsules emptied from the stomach. In non-anaesthetised rats, most of the size 9 capsules did not empty from the stomach, whereas the majority of the smaller size 9h capsules successfully emptied from the stomach and moved into the intestine. This study demonstrates that even with capsules designed to empty from the stomach in rats, the gastric emptying of such solid oral dosage forms is not guaranteed. In addition, the use of anaesthesia was found to abolish gastric emptying of both capsule sizes. The work herein further highlights the utility of CT imaging for the effective visualisation and location of solid dosage forms in the intestinal tract of rats without the use of anaesthesia.This research was funded by the Engineering and Physical Sciences Research Council (EPSRC) UK, grant number EP/L01646XS

Visualizing disintegration of 3D printed tablets in humans using MRI and comparison with in vitro data

Three-dimensional (3D) printing is revolutionising the way that medicines are manufactured today, paving the way towards more personalised medicine. However, there is limited in vivo data on 3D printed dosage forms, and no studies to date have been performed investigating the intestinal behaviour of these drug products in humans, hindering the complete translation of 3D printed medications into clinical practice. Furthermore, it is unknown whether conventional in vitro release tests can accurately predict the in vivo performance of 3D printed formulations in humans. In this study, selective laser sintering (SLS) 3D printing technology has been used to produce two placebo torus-shaped tablets (printlets) using different laser scanning speeds. The printlets were administered to 6 human volunteers, and in vivo disintegration times were assessed using magnetic resonance imaging (MRI). In vitro disintegration tests were performed using a standard USP disintegration apparatus, as well as an alternative method based on the use of reduced media volume and minimal agitation. Printlets fabricated at a laser scanning speed of 90 mm/s exhibited an average in vitro disintegration time of 7.2 ± 1 min (measured using the USP apparatus) and 25.5 ± 4.1 min (measured using the alternative method). In contrast, printlets manufactured at a higher laser scanning speed of 130 mm/s had an in vitro disintegration time of 2.8 ± 0.8 min (USP apparatus) and 18.8 ± 1.9 min (alternative method). When tested in humans, printlets fabricated at a laser scanning speed of 90 mm/s showed an average disintegration time of 17.3 ± 7.2 min, while those manufactured at a laser scanning speed of 130 mm/s exhibited a shorter disintegration time of 12.7 ± 6.8 min. Although the disintegration times obtained using the alternative method more closely resembled those obtained in vivo, no clear correlation was observed between the in vitro and in vivo disintegration times, highlighting the need to develop better in vitro methodology for 3D printed drug products

Predicting pharmaceutical inkjet printing outcomes using machine learning

[Abstract]: Inkjet printing has been extensively explored in recent years to produce personalised medicines due to its low cost and versatility. Pharmaceutical applications have ranged from orodispersible films to complex polydrug implants. However, the multi-factorial nature of the inkjet printing process makes formulation (e.g., composition, surface tension, and viscosity) and printing parameter optimization (e.g., nozzle diameter, peak voltage, and drop spacing) an empirical and time-consuming endeavour. Instead, given the wealth of publicly available data on pharmaceutical inkjet printing, there is potential for a predictive model for inkjet printing outcomes to be developed. In this study, machine learning (ML) models (random forest, multilayer perceptron, and support vector machine) to predict printability and drug dose were developed using a dataset of 687 formulations, consolidated from in-house and literature-mined data on inkjet-printed formulations. The optimized ML models predicted the printability of formulations with an accuracy of 97.22%, and predicted the quality of the prints with an accuracy of 97.14%. This study demonstrates that ML models can feasibly provide predictive insights to inkjet printing outcomes prior to formulation preparation, affording resource- and time-savings.The research was partially supported by MCIN (PID 2020-113881RB-I00/AEI/10.13039/501100011033), Spain, Xunta de Galicia (ED431C 2020/17), and FEDER.L.R.P. acknowledges the predoctoral fellowship provided by the Ministerio de Universidades (Formación de Profesorado Universitario (FPU 2020). I.S.V. acknowledges Consellería de Cultura, Educación e Universidade for her Postdoctoral Fellowship (Xunta de Galicia, Spain; ED481B-2021-019). L.R.P. acknowledges the predoctoral fellowship provided by the Ministerio de Universidades (Formación de Profesorado Universitario (FPU 2020) .Xunta de Galicia; ED431C 2020/17Xunta de Galicia; ED481B-2021-01

Intravitreal implants manufactured by supercritical foaming for treating retinal diseases

Chronic retinal diseases, such as age-related macular degeneration (AMD), are a major cause of global visual impairment. However, current treatment methods involving repetitive intravitreal injections pose financial and health burdens for patients. The development of controlled drug release systems, particularly for biological drugs, is still an unmet need in prolonging drug release within the vitreous chamber. To address this, green supercritical carbon dioxide (scCO2) foaming technology was employed to manufacture porous poly(lactic-co-glycolic acid) (PLGA)-based intravitreal implants loaded with dexamethasone. The desired implant dimensions were achieved through 3D printing of customised moulds. By varying the depressurisation rates during the foaming process, implants with different porosities and dexamethasone release rates were successfully obtained. These implants demonstrated controlled drug release for up to four months, surpassing the performance of previously developed implants. In view of the positive results obtained, a pilot study was conducted using the monoclonal antibody bevacizumab to explore the feasibility of this technology for preparing intraocular implants loaded with biologic drug molecules. Overall, this study presents a greener and more sustainable alternative to conventional implant manufacturing techniques, particularly suited for drugs that are susceptible to degradation under harsh conditions

Novel approaches in local drug delivery systems for the treatment of Inflammatory Bowel Disease

La enfermedad inflamatoria intestinal (EII) es una afección inmunitaria crónica del intestino que alterna periodos de actividad o brotes con periodos de remisión o inactividad. Los dos tipos principales de enfermedad inflamatoria intestinal son la colitis ulcerosa y la enfermedad de Crohn. Los tratamientos convencionales son poco específicos, no siempre son efectivos y muy frecuentemente, están acompañados de serios efectos adversos, por lo que resultaría interesante encontrar alternativas y tratamientos más tolerables. Dado que diversos estudios sugieren que la EII está relacionada con el estrés oxidativo, en este trabajo se ha investigado el posible efecto terapéutico de la melatonina y el resveratrol en el tratamiento de esta enfermedad en ratas, dadas las propiedades antioxidantes e anti-inflamatorias de ambas moléculas. Para ello se recurrió a la técnica de imagen no invasiva conocida como PET/CT. Además, se utilizó la tecnología de impresión 3D para fabricar supositorios de tacrolimus con propiedades autoemulsionantes como alternativa a los supositorios convencionales preparados de forma manual en los servicios de farmacia hospitalaria, el cual es un proceso tedioso no exento de errores de pesada que podrían causar severos efectos adversos a los pacientes. Finalmente, la misma técnica de impresión 3D se utilizó para preparar pequeños lotes de supositorios con tacrolimus, para evaluar la viabilidad de esta técnica como forma de producción de formas de dosificación para estudios preclínicos en animales

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 areaThis research was funded by Xunta de Galicia grant number GRC2013/015 and GPC2017/015. A.F.-F. acknowledges the support of Instituto de Salud Carlos III (Juan Rodés research grant JR18/00014). P.A. acknowledges the support of RYC-2015/17430 (Ramón y Cajal). X.G.-O. acknowledges the financial support of the IDIS (Health Research Institute of Santiago de Compostela)S