Sublingual permeability of model drugs in New Zealand White Rabbits: In Vitro-In vivo correlation

Introduction

Sublingual drug delivery refers to the administration of a drug product by placing it under the tongue. The drug dosage form disintegrates and dissolves underneath the tongue due to the presence of saliva. The sublingual area stands out as a favorable site for drug delivery, as drug absorbed through the mucosal membrane empties directly into systemic circulation via the internal jugular vein bypassing the liver and resulting in an increased rate and extent of drug absorption. Depending on the design of delivery systems, after sublingual absorption, the remaining drug absorption occurs through the oral route by swallowing saliva. Ease of administration, site accessibility, and short cellular turnover time (4–14 days) are additional advantages of the sublingual route. (Hearnden et al., 2012, Rathbone et al., 2015) Despite numerous benefits, only 31 FDA-approved sublingual drug products, in dosage forms such as films, aerosols, tablets, sprays, and powders, are currently available.(US Food and Drug Administration, 2022) Despite the numerous benefits of sublingual drug delivery, there is a significant gap between the extensive research conducted in this field and the number of drug molecules that have entered the sublingual drug market. This gap underscores the need for further research, particularly in understanding the in-vivo translation of in-vitro data in the preclinical stage.

Several investigators studied the sublingual permeation of drugs in vitro using cell lines or artificial membranes. (Bayrak et al., 2011, Wang et al., 2009), dissected tissues(Franz-Montan et al., 2016, Majid et al., 2021, Ong and Heard, 2009, Squier and Hall, 1985, Wang et al., 2009, 2010), and in vivo using animals (Al-Furaih et al., 1991, Bayrak et al., 2011, Claus et al., 2007, Dali et al., 2006, John et al., 1992, Qiu et al., 1999, Wang et al., 2010) Most of these investigations use single-model drug molecules. Comparison pharmacokinetics between sublingual and oral administration have also been conducted to understand the differences between these two routes and the contribution of sublingual delivery to systemic absorption using a single-model drug molecule. (Berthold et al., 1997, Gunja et al., 2004, Price et al., 1997) The results are inconclusing with variability in pharmacokinetic parameters, with sublingual administration resulting in either an enhancement, equivalence, or reduction of these parameters compared to the oral route.

Dali et al. studied the pharmacokinetic parameters, such as Cmax, Tmax, AUC, and F, obtained from the intraoral absorption of propranolol and compared them between rabbits and humans.(Dali et al., 2006a). The permeability of molecules among different tissue and cell models such as porcine sublingual, porcine buccal, Epioral®, and Caco-2 cells were compared and correlated (Yang et al., 2016). The permeability values were compared between tissues and cells from two different species, pig and human, following intra-oral administration. However, no researchers have studied the in vitro and in vivo permeabilities of several model compounds in the same animal species to understand the viability of in vitro studies. The novelty of this study is to determine the sublingual permeability of five model compounds with varying physicochemical properties in vitro using a Franz diffusion cell with sublingual mucosa and unidirectional devices applied in vivo. The new insights obtained from this study help enhance the basic understanding of sublingual drug delivery. Ultimately, this will result in the development of innovative sublingual drug products that help treat new patient populations.

The current study aims to discern the difference between in vitro and in vivo systems and establish a correlation by assessing sublingual absorption parameters such as permeability and lag time using New Zealand white rabbits. In vitro studies were done in a Franz-type diffusion apparatus using excised sublingual mucosa, while in vivo sublingual pharmacokinetic study was conducted by placing a unidirectional cotton pad containing a model drug reservoir.

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Navdeep Kaur, Pramila Sharma, Xiaoling Li, Bhaskara Jasti, Sublingual permeability of model drugs in New Zealand White Rabbits: In Vitro-In vivo correlation, International Journal of Pharmaceutics, Volume 668, 2025, 124998, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124998.

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