Lipid drug delivery and rational formulation design for lipophilic drugs with low oral bioavailability, applied to cyclosporine

doi:10.1016/j.ejps.2003.08.005

European Journal of Pharmaceutical Sciences

Volume 20, Issues 4–5, December 2003, Pages 375-382

https://doi.org/10.1016/j.ejps.2003.08.005 Get rights and content

Abstract

By using a rational formulation approach, we have tried to find the general characteristics for promising self-emulsifying drug delivery systems (SEDDS) based on natural lipid components, for the oral delivery of lipophilic drugs. Galactolipids, which are polar lipids commonly found in the chloroplast membranes of green plants, and a natural part of the human diet, were the main surfactants in these formulations. This was done in three clinical studies: a screening study, followed by a prediction study and, finally, a confirmatory study; in all 17 experimental formulations were investigated. The clinical trials were performed in healthy volunteers. Cyclosporine, a well-known lipophilic peptide, was incorporated in different SEDDS, and administered orally, followed by the measurement of the blood concentration of the drug over time. The pharmacokinetic parameters, which describe the rate and extent of absorption, were estimated. We found that fractionated oat oil (FOO) and medium chain monoglycerides (60:30:10 mono-, di- and tri-glycerides) promoted absorption, and resulted in a formulation with absorption characteristics nearly equal to the commercial formulation of cyclosporine, Sandimmun Neoral^®.

Introduction

The use of lipid based drug formulations that enhance the bioavailability of poorly water-soluble drugs has gained much recent interest, because they utilize the well-known food effect of the ingested lipids (Humberstone and Charman, 1997). Lipid based formulations can reduce slow and incomplete dissolution, facilitate the formation of solubilized phases and, if very lipophilic, increase the amount of drug transported via the intestinal lymphatic system, thereby increasing absorption from the gastrointestinal tract (Humberstone and Charman, 1997, Porter and Charman, 2001).

Extensive research has been done in the area of self-emulsifying drug delivery systems (SEDDS), which are defined as homogeneous systems and are mixtures composed of natural or synthetic neutral lipids (triacylglycerol oils, etc.) and natural polar lipids (phospholipids, galactolipids, etc.), or synthetic surfactants with optional solvents and co-surfactants. The principal characteristic of this type of system is its ability to form fine oil-in water emulsions upon capsule disintegration and subsequent dilution in gastric fluids, with gastric motility supplying the necessary agitation. SEDDS are therefore good candidates for the oral delivery of hydrophobic drugs, provided they possess adequate solubility in oil or oil–surfactant blends (Gershanik and Benita, 2000). However, the development of a drug delivery system is a time-consuming process, requiring the matching of the appropriate delivery system components, and their relative levels, to the drug substance to obtain the desired absorption characteristics (Charman, 2000). Further, the complex interactions, which arise between the lipid based formulation, the digestive system and the co-administered drug, are not fully understood, and in vitro studies are not well correlated with absorption studies in vivo (Porter and Charman, 2001).

Various workers in the field have chosen to develop formulation design strategies of differing degree of complexity. From “single-use” applications solving a given problem, an example being the optimization of extended release tablets using statistical experimental design and multicriteria decision making (Sanchez-Lafuente et al., 2002), or more broader strategies using multivariate design and multivariate characterization to give an evolutionary system for excipient selection in tablet formulation (Gabrielsson et al., 2002, Rowe and Colbourn, 2002, Colbourn and Rowe, 2001).

Using a statistical experimental design and multivariate optimization strategy, would be an appealing approach when working with lipid based formulations for drug compounds, where several factors (lipid components, ratio in between, amount of drug incorporated) can be varied, each exerting differing impacts on the pharmacokinetic parameters describing the rate and extent of absorption.

Partial least square regression (PLS), a multivariate regression method, maximizes predictability rather than optimal fit of data, and has in this work been chosen for predictive model-building. We have performed three human absorption studies (a screening study followed by a predictive and a confirmatory study), using a statistical experimental design and multivariate optimization strategy, in the aim of evaluating and predicting the effect of different lipid combinations in self-emulsifying drug delivery systems on oral drug bioavailability.

Self-emulsifying lipid vehicles based on dietary lipids alone, are expected to be well tolerated in humans, thereby being good candidates for long term clinical use. In this study, we focused on drug formulations containing natural lipids, mainly the galactolipids, which have been proposed as suitable for pharmaceutical formulation work because of their physicochemical properties (Blom et al., 1996). Good sources for galactolipids are certain grains, such as oats, which are common in the human diet. Galactolipids, like phospholipids have good emulsifying properties, but one major difference is that phospholipids are charged, while the galactolipids are non-ionic and regarded as more safe for long term use (Gren et al., 2002). However, the properties of galactolipids as excipients in lipid based pharmaceutical formulations for human use have not been fully investigated before.

We have chosen the poorly water soluble immunosuppressive cyclic peptide drug cyclosporine (Ritschel, 1996) as the model drug. As the comparator Sandimmun Neoral^®, a pharmaceutical formulation of cyclosporine which is a micro emulsion and one of the few successful lipid based oral pharmaceutical products on the market today, was used (Pouton, 2000). In this work, by using a rational formulation approach, we have tried to find the general characteristics for promising self-emulsifying drug delivery systems, SEDDS, based on natural lipid components, for the oral delivery of lipophilic drugs.

Section snippets

Reference drug

The drug cyclosporine, Sandimmun Neoral^® was used as the reference. Cyclosporine, Sandimmun Neoral^® is a micro emulsion containing corn oil mono-, di- and tri-glycerides, polyoxyl 40 hydrogenated castor oil, propylene glycol and DL-α-tocopherol according to the product information from Novartis. The older formulation Sandimmun^® have been reported to have a bioavailability around 20–50%. Neoral has a more uniform and slightly increased bioavailability compared to the former formulation, but the

Adverse event

No serious or unexpected events occurred in any of the studies. The most commonly reported event was a feeling of heat in different parts of the body, especially hand, feet, face and groins, which started when the maximum concentration in the blood was achieved (about 1–2 h after dose) and lasted about 1–2 h.

Screening study

The relative bioavailability for the formulations, compared to the reference, is illustrated in Fig. 1. It is obvious that the composition of the lipid formulation can exert a profound effect

References (18)

T. Andrysek
Impact of physical properties of formulations on bioavailability of active substance: current and novel drugs with cyclosporine
Mol. Immunol.
(2003)
W.N. Charman
Lipids, lipophilic drugs, and oral drug delivery-some emerging concepts
J. Pharm. Sci.
(2000)
T. Gershanik et al.
Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs
Eur. J. Pharm. Biopharm.
(2000)
A.J. Humberstone et al.
Lipid-based vehicles for the oral delivery of poorly water soluble drugs
Adv. Drug Deliv. Rev.
(1997)
J.M. Kovarik et al.
Reduced inter- and intra-individual variability in cyclosporine pharmacokinetics from a microemulsion formulation
J. Pharm. Sci.
(1994)
L. Ohlsson et al.
Orally fed digalactosyldiacylglycerol is degraded during absorption in intact and lymphatic duct cannulated rats
J. Nutr.
(1998)
C.J. Porter et al.
In vitro assessment of oral lipid based formulations
Adv. Drug Deliv. Rev.
(2001)
C.W. Pouton
Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and ‘self-microemulsifying’ drug delivery systems
Eur. J. Pharm. Sci.
(2000)
M. Blom et al.
Pharmacokinetics, tissue distribution and metabolism of intravenously administered digalactosyldiacylglycerol and monogalacosyldiacylglcyerol in the rat
J. Liposome Res.
(1996)

There are more references available in the full text version of this article.

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Lipid drug delivery and rational formulation design for lipophilic drugs with low oral bioavailability, applied to cyclosporine

Abstract

Introduction

Section snippets

Reference drug

Adverse event

Screening study

Mol. Immunol.

J. Pharm. Sci.

Eur. J. Pharm. Biopharm.

Adv. Drug Deliv. Rev.

J. Pharm. Sci.

J. Nutr.

Adv. Drug Deliv. Rev.

Eur. J. Pharm. Sci.

Pharmacokinetics, tissue distribution and metabolism of intravenously administered digalactosyldiacylglycerol and monogalacosyldiacylglcyerol in the rat

J. Liposome Res.