Oral administration of liposomes containing cyclosporine: a pharmacokinetic study

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Abstract

Liposomal formulation containing cyclosporine A (CSA) were prepared. The most stable liposomes with the composition of CSA, dipalmitoylphosphatidyl choline (DPPC) and cholesterol (Chol.) in molar ratio 1:0.2:1, respectively were administered orally to New Zealand rabbits. The pharmacokinetic of the administered CSA was compared with that of the commercially available oily oral formulation of CSA (Sandimmune) at dose of 15 mg/kg. Cyclosporine concentration in blood was monitored using a radioimmunoassay method (RIA). A change in the pharmacokinetic parameters of CSA due to liposomal encapsulation was observed. A peak concentration was reached in 50 min in case of liposomes compared with 225 min in case of Sandimmune. The rate of absorption (Cmax/AUC0–∞) was significantly faster following the liposome administration. A significant difference in the area under the concentration curve (AUC0–∞) was found and this was attributed to the difference in the terminal half-lives (t1/2β) which were 8.88±1.94 and 19.3±8.48 h for liposomes and Sandimmune preparations, respectively. The mean residence time (MRT) and the mean absorption time (MAT) were dramatically decreased following the administration of liposomal formulation. Generally, there was less inter-individual variation in the values of rate of absorption, t1/2β and MRT when CSA liposomes were orally administered compared to the administration of Sandimmune. Thus, an oral liposomal formulation for CSA can be developed to offer the advantages of low variability and fast onset of action.

Introduction

Cyclosporine A (CSA) is considered as one of the most effective immunosuppressive drugs used today for the prevention of allograft rejection after organ transplantation (Kahan, 1989). In spite of the great medical importance of the drug, some currently available dosage forms suffer several disadvantages. These include slow and high variability of CSA absorption following the oral administration of its oily solution (Ptachcinski et al., 1986). The polyoxyethylated castor oil (Cremophor EL) used to dissolve CSA in the intravenous (I.V.) formulation was reported to cause anaphylactic shock (Cavanak and Sucker, 1986) and to induce nephrotoxic effects similar to those produced by CSA (Luke et al., 1987). Due to the low solubility and the difficulty of solubilizing CSA in aqueous vehicles (Khidr, 1987), no safe commercial substitute to Cremophor has been yet identified. Several alternative dosage forms have been proposed to overcome these problems. Among these are a liposomal formulation for I.V. administration (Venkataram et al., 1990, Vadiei et al., 1989), and for aerosol delivery direct to the pulmonary tissue (Waldrep et al., 1993). A controlled release parenteral delivery system for CSA in biodegradable microspheres and nanospheres was also suggested (Sanchez et al., 1993). A lipophilic carrier for oral CSA administration was tried, but proved to have limited in vitro and in vivo stability (Yanagawa et al., 1989). Recently, a new oral formulation (Sandimmune Neoral) was developed which incorporated the drug in a microemulsion preconcentrate containing a surfactant, lipophilic and hydrophilic solvents, and ethanol (Muller et al., 1994). The greater toxicity from the currently I.V. CSA formulation than from the oral dosage form (Williams et al., 1986) and the need to have a rapid onset of the immunosuppressive effects in transplanted patients necessitate the search for an oral dosage form that might reduce the toxic effects and improve pharmacokinetics of CSA.

Although liposomes are expected to be unstable in the G.I.T., they have been found to improve the systemic absorption of labile compounds after oral administration (Fielding, 1991) and they may act as a non-toxic vehicle for insoluble drugs (Lidgate et al., 1988). In addition they can alter tissue distribution of drugs within the body. Thus, liposomes containing cyclosporine may help reduce the nephrotoxicity of CSA (Venkataram et al., 1990).

A number of liposomal CSA formulations have previously been developed and evaluated in our laboratory (Al-Angary et al., 1995). This included multilamellar vesicles composed of DPPC with and without cholesterol (Chol.) at different molar ratios. The purpose of the present work was to study the pharmacokinetics of CSA formulated in the most promising stable liposomal batch after oral administration to rabbits and to compare it to the commercially available oral Sandimmune® oily solution.

Section snippets

Materials

l-α-Dipalmitoylphosphatidyl choline (DPPC) and cholesterol (Chol.) were purchased from Sigma (St. Louis, MO, USA). Cyclosporine A (CSA) and cyclosporine D (CSD) were gifts from Sandoz Pharma, Switzerland. Commercially available Sandimmune® I.V. and oral formulations were purchased from the local market. Other solvents and materials were of analytical grade.

Preparation and in vitro evaluation of CSA liposomes

Multilamellar vesicles (MLV's) were prepared following the film method (Bangham et al., 1965). The method of preparation as well as the in

Results and discussion

Based on the in vitro evaluation and the in vivo targeting studies (Al-Angary et al., 1995), a liposomal formulation containing a high Chol-level was chosen for the bioavailability studies. Fig. 1 shows the mean blood CSA concentration versus time profiles after oral administration of CSA in two different dosage forms at 15 mg/kg to rabbits; namely: commercially available oily solution (Sandimmune®) and the selected liposomal formulation. The mean pharmacokinetic parameters of CSA following

Acknowledgements

This work was supported by the College of Pharmacy, Research Center (CPRC), King Saud University Project No: 45. The authors would like to thank Mr A. Abd-Al-Razik for his technical assistance.

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