Ultrasound cavitation agent mediated gastrointestinal drug delivery

Thesis

In 1923, Harrison, a chemical pathologist in King’s College Hospital, published a paper entitled “Insulin in alcoholic solution by the mouth”. 100 years of chemical and formulation research later, formulation scientists still struggle to deliver biopharmaceuticals via the most convenient administration route due to the physiological barriers posed by the gastrointestinal tract which result in poor stability and permeability of biopharmaceuticals. Ultrasound mediated gastrointes-tinal drug delivery was inspired by the success of physical approaches in transdermal drug de-livery research. This DPhil aims to explore the feasibility of ultrasound cavitation agent mediat-ed gastrointestinal drug delivery (UCAMGIDD) in pursuit of the goal to deliver biopharmaceu-ticals via the oral route. A less thermogenic and faster manufacturing method for lipid-shelled microbubbles was optimised with design of experiment; the resultant microbubbles were com-pared to sonication and displayed a smaller mean diameter, a narrower size distribution, a high-er concentration, a higher stability, and similar acoustic response. The stability of lipid-shelled microbubbles was demonstrated in fasted and fed state simulated gastrointestinal media. The acoustic response of microbubbles was examined in simulated gastrointestinal media, and re-sults showed that fed state media diminished the acoustic response (0.5 and 1.1 MHz, 0.5, 1, 2 MPa peak negative pressure). A high intensity focused ultrasound (HIFU) Franz diffusion cell was developed that was compatible with transepithelial electrical resistance (TEER) probes, submergible to facilitate HIFU stimulation and passive cavitation detection, with minimal dis-tortion of the sound field. The HIFU Franz facilitated the assessment of a standard microbubble formulation co-administered with Fluorescein Isothiocyanate dextran 70 kDa (FITC-dextran 70 kDa) and found no alteration of the tissue integrity or no promotion of FITC-dextran 70 kDa uptake in porcine ileal or caecal tissues covered with biosimilar mucus. These results imply that microbubbles stimulated with the examined ultrasound parameters did not alter permeability or improve delivery of a model biopharmaceutical. This thesis lays the foundation for future re-search to investigate new ultrasound parametric design spaces and new formulations to further progress towards ultrasound cavitation agent mediated gastrointestinal drug delivery.

Authors: O'Reilly, CS

• DOI: 10.5287/ora-7rgao8epk
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: cavitation agents; oral biopharmaceutical delivery; ultrasound; gastrointestinal drug delivery; microbubbles
• Subjects: Pharmaceutics; Engineering