Lymphatic Uptake of a Highly Lipophilic Protease Inhibitor Prodrug from a Lipid-Based Formulation is Limited by Instability in the Intestine.

Autor:	Xie Y; Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia., Lu Z; Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia., Styles IK; Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia., Reddiar SB; Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia., Phillips ARJ; Department of Surgery, The University of Auckland, Auckland, New Zealand., Windsor JA; Department of Surgery, The University of Auckland, Auckland, New Zealand., Porter CJH; Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia., Han S; Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia., Trevaskis NL; Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. Electronic address: natalie.trevaskis@monash.edu.
Jazyk:	angličtina
Zdroj:	Journal of pharmaceutical sciences [J Pharm Sci] 2024 Aug; Vol. 113 (8), pp. 2342-2351. Date of Electronic Publication: 2024 Apr 04.
DOI:	10.1016/j.xphs.2024.03.029
Abstrakt:	Dabigatran etexilate (DABE) is a lipophilic double alkyl ester prodrug of dabigatran (DAB) which is a serine protease inhibitor used clinically as an anticoagulant. Recently, translocation of serine protease enzymes, including trypsin, from the gut into the mesenteric lymph and then blood has been associated with organ failure in acute and critical illnesses (ACIs). Delivery of DABE into mesenteric lymph may thus be an effective strategy to prevent organ failure in ACIs. Most drugs access the mesenteric lymph in low quantities following oral administration, as they are rapidly transported away from the intestine via the blood. Here, we examine the potential to deliver DABE into the mesenteric lymph by promoting association with lymph lipid transport pathways via co-administration with a lipid-based formulation (LBF). A series of self-emulsifying LBFs were designed and tested in vitro for their potential to form stable DABE loaded emulsions and keep DABE solubilised and stable over time in simulated gastrointestinal conditions. The LBFs were found to form fine emulsions with a droplet size of 214 ± 30 nm and DABE was stable in the formulation. The stability of DABE in vitro in simulated intestinal conditions, plasma and lymph samples was also evaluated to ensure stability in collected samples and to evaluate whether the prodrug is likely to release active DAB. Ultimately, a highly uniform and stable self-emulsifying Type III A LBF of DABE was chosen for progression into in vivo studies in male Sprague Dawley rats to confirm the lymphatic uptake and plasma pharmacokinetics. Both in vitro and in vivo in plasma and lymph, DABE was rapidly converted to an intermediate and DAB. The main species present in vivo in both plasma and lymph was DAB and mass transport of DABE and DAB in lymph was minimal (∼0.5 % of dose). Importantly, the concentration of DABE in lymph was substantially (20-176 fold) higher than in plasma, supporting that if the prodrug were stable and did not convert to DAB in the intestine, it would be lymphatically transported. Future studies will therefore focus on optimizing the design of the prodrug and formulation to improve stability during absorption and further promote lymphatic uptake. Competing Interests: Declaration of competing interest N.L. Trevaskis is an Editorial Board Member for Journal of Pharmaceutical Sciences and was not involved in the editorial review or the decision to publish this article. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: N.L. Trevaskis, C.J.H. Porter, S. Han are inventors of a lymph-directing glyceride prodrug technology that has been patented and licensed to PureTech Health, Boston. The current work is not related to the glyceride prodrug technology. It evaluates and describe lymphatic uptake of a lipophilic ester prodrug of different molecular structure. (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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