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Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs

Key Points

  • Highly potent but poorly water-soluble drug (PWSD) candidates are common outcomes of contemporary drug discovery programmes. These lipophilic compounds often exhibit poor systemic exposure following oral administration.

  • Lipid-based formulations can significantly enhance the absorption of PWSDs following oral delivery. The three main mechanisms by which lipids and lipophilic excipients affect PWSD absorption are outlined below.

  • First, by enhancing drug solubilization in the intestinal milieu. Drug dissolution is a prerequisite for drug absorption from the small intestinal lumen into the intestinal absorptive cells (enterocytes), and the rate and extent of drug dissolution can be a limiting factor in the absorption of PWSDs. Lipid-based formulations enhance drug solubilization both by initially presenting the drug in a solubilized form and by preventing drug precipitation by altering the nature of both exogenous (formulation-derived) and endogenous solubilizing species in the intestinal milieu.

  • Second, by recruitment of intestinal lymphatic drug transport (and reduced first-pass metabolism). Highly lipophilic drugs (Log P > 5, triglyceride solubility >50 mg per g) can be transported to the systemic circulation by the intestinal lymphatic system rather than the portal vein blood following oral delivery. This transport is mediated by association of the lipophilic drug with lymphatic lipids. Lipid-based formulations (in particular, those that contain long-chain and unsaturated lipids) recruit endogenous and exogenous lipid transport and stimulate intestinal lymphatic transport of co-administered lipophilic drugs. By enhancing lymphatic transport, lipid-based formulations might protect PWSDs from first-pass metabolism.

  • Third, by altering enterocyte-based drug transport and disposition. Lipids and lipophilic excipients can interact with apical membrane lipid transporters, alter the expression of intracellular lipid-binding proteins and change the intracellular pooling of lipids within the enterocyte. In this way, lipid-based formulations can alter enterocyte lipid trafficking, which leads to an indirect effect on PWSD absorption and cellular disposition.

Abstract

Highly potent, but poorly water-soluble, drug candidates are common outcomes of contemporary drug discovery programmes and present a number of challenges to drug development — most notably, the issue of reduced systemic exposure after oral administration. However, it is increasingly apparent that formulations containing natural and/or synthetic lipids present a viable means for enhancing the oral bioavailability of some poorly water-soluble, highly lipophilic drugs. This Review details the mechanisms by which lipids and lipidic excipients affect the oral absorption of lipophilic drugs and provides a perspective on the possible future applications of lipid-based delivery systems. Particular emphasis has been placed on the capacity of lipids to enhance drug solubilization in the intestinal milieu, recruit intestinal lymphatic drug transport (and thereby reduce first-pass drug metabolism) and alter enterocyte-based drug transport and disposition.

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Figure 1: Potential effect of lipids and lipidic excipients on drug absorption.
Figure 2: Lipid digestion and drug solubilization in the small intestine.
Figure 3: Lipid digestion models for in vitro assessment of lipidic formulations.
Figure 4: Lipid and drug transport by the mesenteric lymph or portal blood following oral delivery.
Figure 5: Pathways of lipid absorption and pooling within the enterocyte.

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Correspondence to Christopher J. H. Porter.

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Department of Pharmaceutics, Monash University

Glossary

Enterocyte

The absorptive cells lining the small intestine.

Dissolution rate

The rate at which a solute (for example, a drug) dissolves in a solvent.

Polymorphs

A specific crystalline form of a compound (for example, a drug) that exhibits polymorphism, that is the ability to crystallize in different forms.

Solid dispersion

A solid-dose formulation that comprises a molecular mixture of a drug and a highly water-soluble excipient (commonly polyethylene glycol or polyvinylpyrrolidone).

Post-prandial

After a meal.

Post-prandial response

The physiological response that occurs after ingestion of a meal (in particular, a fatty meal) including delayed gastric emptying, release of bile and pancreatic secretions, and alterations in gastrointestinal motility and secretions.

Bile

A fluid secreted from hepatocytes in the liver and stored in the gall bladder before release into the small intestine. The primary constituents of bile are water, bile salt, cholesterol, phospholipid, bicarbonate, bile pigments and organic wastes. Bile salt, cholesterol and phospholipid are co-secreted in bile in the form of mixed micellar complexes in a molar ratio of approximately 16:4:1.

Critical micelle concentration

The minimum concentration of a surfactant in a bulk solution that leads to spontaneous formation of surfactant micelles. Also, the concentration of free surfactant in solution that is in equilibrium with surfactants in a micellar (aggregated) form.

First-pass metabolism

Drugs administered orally are typically taken up into the enterocytes lining the upper small intestine and transported by the mesenteric vessels to the hepatic portal vein and then to the liver before reaching the systemic circulation. First-pass metabolism refers to the metabolism of a drug within the liver and enterocytes before the drug first reaches the systemic circulation.

Lipoproteins

Colloidal particles synthesized in the liver and small intestine that consist of a hydrophobic core (containing triglyceride and cholesteryl esters) and a hydrophilic surface (containing phospholipids, cholesterol and apolipoproteins). Lipoproteins facilitate the transport of lipids and lipophilic substances around the body.

Chylomicrons

Chylomicrons are larger (50–500 nM) and less dense (Sf > 400) lipoproteins than very low-density lipoproteins, and are formed exclusively in the small intestine following the ingestion of lipids (dietary-derived or formulation-derived).

VLDL

Very low-density lipoproteins (VLDL) are small (20–50 nM) and more dense (Sf = 20–400) lipoproteins than chylomicrons, and are formed in the liver and the small intestine (where they are the predominant lipoproteins secreted in the fasted state).

Log D7.4

Log10 of the octanol–water partition co-efficient of a molecule (for example, a drug) at pH 7.4.

Pluronic L-81

A hydrophobic surfactant that blocks intestinal chylomicron secretion at the pre-Golgi level without affecting triacylglycerol uptake into the enterocytes, or triglyceride re-esterification in the smooth endoplasmic reticulum.

Colchicine

Clinically used to treat gout and has also been shown to cause accumulation of lipoproteins in the smooth endoplasmic reticulum and Golgi, thereby blocking chylomicron exit from the enterocytes.

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Porter, C., Trevaskis, N. & Charman, W. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat Rev Drug Discov 6, 231–248 (2007). https://doi.org/10.1038/nrd2197

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