Nanoparticle oral absorption and its clinical translational potential

Oral administration of pharmaceuticals is the most preferred route of administration for patients, but it is challenging to effectively deliver active ingredients (APIs) that i) have extremely high or low solubility in intestinal fluids, ii) are large in size, iii) are subject to digestive and/or metabolic enzymes present in the gastrointestinal tract (GIT), brush border, and liver, and iv) are P-glycoprotein substrates. Over the past decades, efforts to increase the oral bioavailability of APIs have led to the development of nanoparticles (NPs) with non-specific uptake pathways (M cells, mucosal, and tight junctions) and target-specific uptake pathways (FcRn, vitamin B12, and bile acids). However, voluminous findings from preclinical models of different species rarely meet practical standards when translated to humans, and API concentrations in NPs are not within the adequate therapeutic window. Various NP oral delivery approaches studied so far show varying bioavailability impacted by a range of factors, such as species, GIT physiology, age, and disease state. This may cause difficulty in obtaining similar oral delivery efficacy when research results in animal models are translated into humans. This review describes the selection of parameters to be considered for translational potential when designing and developing oral NPs.

Introduction

Oral dosage form occupies a major fraction (∼53%) of all therapeutic medicines in the global market [1]. In addition to the specific uses of injectables, such as patient unconsciousness, urgent plasma levels in an emergency, and precise dosing of a drug within its narrow therapeutic window, studies have indicated a clear patient preference for orally administered drugs over injectables [2]. The pharmaceutical industry, however, keeps producing injectables because a significant fraction of newly discovered drug candidates with novel targets is often large-small molecules (>MW 500 Da) and have challenges in oral formulations because of poor solubility in intestinal fluids. This often violates more than two of Lipinski’s rule of 5, which has been formulated from a long empirical industrial experience, resulting in poor permeability of the intestinal epithelial cell layer (absorptive enterocyte) and poor oral bioavailability (oBA) [3].

Peptide and protein drugs have been traditionally formulated as injectables due to various hurdles in the gastrointestinal tract (GIT), including gastric pH, digestive enzymes, large sizes, and hydrophilicity, despite some examples of drug administration via the nasal and pulmonary routes. Insulin was first discovered in 1922, and oral insulin delivery was first reported in 1923 [[4], [5], [6]]. Oral insulin delivery research has since been regarded as the “Holy Grail” in pharmaceutical science and represents a history of continuous ambition and failure [7,8]. This ambition has been growing because biologics occupy a significant portion of the pharmaceutical market (USD 188 billion in 2017) [9].

Most oral delivery approaches for biologics rely on protease inhibitors and permeation enhancer technologies for either transcellular or paracellular pathways. Combinations of these two technologies, temporal disturbance of tight junctions (TJs), and mucoadhesion approaches have been extensively employed. This technology has been applied to relatively small polypeptides, such as insulin and exendin-4, and yielded relative oBA up to 32% in rodent models [10]. This success has encouraged entrepreneurial activities and collaboration with major pharmaceutical companies. However, when translated into clinical trials, such as oral semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, oral biologics still suffer from extremely low oBA, leading to the conclusion that there is a serious gap in oBA between preclinical models and human patients, and preclinical results do not endorse translational success.

Recent successful cases of injectable nanomedicine have been mRNA/lipid nanoparticle (NP) vaccines against COVID-19 infection developed after considerable efforts in nanomedicine research [11,12]. Most nanomedicines, whether therapeutics, diagnostics, or theranostics are introduced into the body by parenteral administration [[13], [14], [15]]. Various studies have been conducted to create oral NPs, exploring passive and active transport mechanisms [[16], [17], [18]]. Considering oral delivery of NPs is probably not impossible, the delivery efficiency and significance are not fully justified for practical applications. Once oral NP can meet pharmacological needs, its impact will become broad and significant. Besides providing oBA, the transport pathways to the systemic circulation are entirely different from those of orally absorbed small molecules, as exemplified by chylomicrons (fat NPs formed after absorption in the small intestine) [[19], [20], [21]]. The absorbed NPs can be transported through the intestinal lymphatic system, which is rich in immune cells, the thoracic duct, and then to the heart for systemic circulation before reaching the liver. This opens a new direct pathway to the immune system, unlike other routes.

Existing oral NP delivery technology hardly meets practical standards, and it suggests the need for exploring new approaches to achieve the high absorption necessary to reach therapeutic doses of NP and to locate within the therapeutic windows of given active ingredients (APIs) of interest. This review aims to provide an overview and critiques, wherever possible, of various approaches to NP oral delivery and absorption and to address their potential as a stepping stone for future oral drug delivery systems.

Kyoung Sub Kim, Kun Na, You Han Bae, Nanoparticle oral absorption and its clinical translational potential, Journal of Controlled Release, Volume 360, 2023, Pages 149-162, ISSN 0168-3659,
https://doi.org/10.1016/j.jconrel.2023.06.024.