Incorporation of cyclosporin A in solid lipid nanoparticles (SLN)

https://doi.org/10.1016/S0378-5173(02)00268-5Get rights and content

Abstract

The cyclic undecapeptide cyclosporin A (CyA) a potent immunosuppressive drug used in many therapies, is extremely hydrophobic. Commercial products employ solubilising agents to improve gastrointestinal absorption. In the present study CyA solid lipid nanoparticles (SLN) are prepared from warm o/w microemulsion, dispersed in cold water. The matrix chiefly consists of stearic acid, phosphatidylcholine and taurocholate; up to 13% of CyA can be incorporated. The average diameter of CyA-loaded SLNs is below 300 nm and transmission electron microscopy (TEM) analysis shows them to be spherical. In vitro release of CyA from SLNs is low. CyA-loaded SLNs can be proposed for most administration routes, in particular for the duodenal route.

Introduction

Cyclosporin A (CyA) is an extremely hydrophobic cyclic undecapeptide that is practically insoluble in water, used as first-line therapy in the prevention of xenograft rejection following organ transplantation. Many delivery systems have been proposed, such as liposomes (Venkataram et al., 1990), a commercial microemulsion such as Neoral®, lecithin vesicular carriers (Guo et al., 2000); the drug has been incorporated in solid lipid nanoparticles (SLN) (Zhang et al., 2000, Radtke and Müller, 2001a, Radtke and Müller, 2001b) obtained by high pressure homogenisation; Ford and co-workers (Ford et al., 1999) prepared spherical solid nanospheres, obtained by a precipitation method, constituted of the drug alone, to improve its bioavailability. Müller and co-workers obtained two patent applications (Müller et al., 1998, Penkler et al., 1999).

We prepare SLN from warm microemulsions: in laboratory we have monitored the administration of SLNs incorporating different drugs, by the parenteral, intravenous, ocular and duodenal routes, obtaining AUCs higher than those of the respective solutions, as well as sustained releases (Gasco, 1997, Gasco, 2001).

The aim of the present study was to investigate whether it was possible to incorporate a lipophilic peptide as CyA in SLNs obtained from warm o/w microemulsion and to verify its in vitro release.

Section snippets

Materials

CyA was obtained from Fluka (Buchs, Switzerland). Stearic acid and butyric acid were purchased from Merck (Darmstadt, Germany). Epikuron 200® (containing about 95% soya phosphatidylcholine) was a kind gift from Lucas Meyer Co. (Hamburg, Germany), taurocholic acid sodium salt (TC) was kindly provided by PCA (Basaluzzo, Italy). The other chemicals were of analytical reagent grade. Water from a Millipore Milli-Q® ultrapure water purification unit was used.

Preparation of solid lipid nanospheres

Two different amounts of CyA were added to

Size analysis

The average diameters and the polydispersity indices of SLNs prepared with two different amounts of CyA and dispersed in water are reported in Table 2. The results showed that increasing the amount of drug incorporated the sizes of SLNs increase; similar results were obtained in the isotonic glycerol solution (data not shown).

TEM analysis confirmed the spherical shape and colloidal sizes of the SLNs (Fig. 1).

Percentage of cyclosporin A incorporated

The amounts of CyA incorporated in the SLNs determined by HPLC analysis are reported in

Discussion

The bioavailability of CyA by the oral route is always low, about 30% (Fahr, 1993, Noble and Markham, 1995). Furthermore, the rate and extent of absorption is dependent on many factors, including food intake, bile production and gastrointestinal motility. Many attempts have been made over time to enhance the drug's bioavailability using different dosage forms. The commercial microemulsion Neoral®, commonly administered in many therapies, is a microemulsion concentrate and consist of oil,

Acknowledgements

The work has been supported by University of Turin (ex 60%).

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