Pharmacokinetic aspects and in vitro-in vivo correlation potential for lipid-based formulations

Abstract

Lipid-based formulations have been an attractive choice among novel drug delivery systems for enhancing the solubility and bioavailability of poorly soluble drugs due to their ability to keep the drug in solubilized state in the gastrointestinal tract. These formulations offer multiple advantages such as reduction in food effect and inter-individual variability, ease of preparation, and the possibility of manufacturing using common excipients available in the market. Despite these advantages, very few products are available in the present market, perhaps due to limited knowledge in the in vitro tests (for prediction of in vivo fate) and lack of understanding of the mechanisms behind pharmacokinetic and biopharmaceutical aspects of lipid formulations after oral administration. The current review aims to provide a detailed understanding of the in vivo processing steps involved after oral administration of lipid formulations, their pharmacokinetic aspects and in vitro in vivo correlation (IVIVC) perspectives. Various pharmacokinetic and biopharmaceutical aspects such as formulation dispersion and lipid digestion, bioavailability enhancement mechanisms, impact of excipients on efflux transporters, and lymphatic transport are discussed with examples. In addition, various IVIVC approaches towards predicting in vivo data from in vitro dispersion/precipitation, in vitro lipolysis and ex vivo permeation studies are also discussed in detail with help of case studies.

Keywords: ADME, absorption/distribution/metabolism/elimination; AUC, area under the curve; BCS, biopharmaceutics classification system; BDDCS, biopharmaceutics drug disposition classification system; CACO, human epithelial colorectal adenocarcinoma cells; CMC, critical micellar concentration; CYP, cytochrome; Cmax, maximum plasma concentration; DDS, drug delivery systems; Efflux transporters; FaSSGF, fasted-state simulated gastric fluid; FaSSIF, fasted-state simulated intestinal fluid; FeSSIF, fed-state simulated intestinal fluid; Food effect; GIT, gastrointestinal tract; IVIVC; IVIVC, in vitro in vivo correlation; LCT, long chain triglyceride; LFCS, lipid formulation classification system; Lipolysis; Lymphatic delivery; MCT, medium chain triglyceride; MDCK, Madin–Darby canine kidney cells; NCE, new chemical entity; P-app, apparent permeability; P-gp, permeability glycoprotein; Pharmacokinetics; SCT, short chain triglyceride; SEDDS, self-emulsifying drug delivery system; SIF, simulated intestinal fluid; SMEDDS, self-microemulsifying drug delivery system; SNEDDS, self-nanoemulsifying drug delivery system; Vit E, vitamin E; log P, n-octanol/water partition coefficient.

Graphical abstract

Figure 1

General process flow for development of microemulsions indicating the pharmacokinetic importance of each step.

Figure 2

Mechanisms by which lipid formulations can enhance bioavailability.

Figure 3

In vitro lipid digestion experiment indicating the critical process parameters that can influence the prediction of in vivo data. (1) Composition of lipid digestion media-pancreatin source, bile salts concentration, pH and volume of media and amount of lipid in the formulation. (2) Rate of calcium chloride addition-faster the rate faster the digestion. (3) pH of the media – optimize between 5.5 and 7.5. (4) Temperature – representing biological conditions at 37 °C. (5) Molarity of NaOH – low molarity leads to higher end volume of media and higher molarity leads to titrator overshooting and experimental error. (6) Stirring speed – higher speed to mix the components thoroughly.

Figure 4

Different ways to achieve IVIVC for lipid based formulations.