Sandimmun Neoral Research Articles

Physicochemical characterization and evaluation of a microemulsion system for oral delivery of cyclosporin A

The purpose of this study was to improve the solubility and enhance the bioavailability of poorly water-soluble cyclosporin A loaded in o/w microemulsion systems. Microemulsions with varying weight ratios of surfactant to cosurfactant were prepared using caprylic/capric triglyceride (Captex 355 ®) as an oil, polyoxyethylated castor oil (Cremophor EL ®) as a surfactant, Transcutol ® as a cosurfactant and saline. The area of o/w microemulsion region in pseudo-ternary phase diagram was increased with increasing ratio of Cremophor EL ® to Trancutol ®. The solubility of cyclosporin A in microemulsion systems reached the maximum with 2:1 mixture of Cremophor EL ® and Trancutol ®. The dispersion rate of oil–surfactant–cosurfactant mixture with varying ratios of Cremophor EL ® to Trancutol ® in aqueous media assuming the condition of gastric fluid decreased with the increase of Cremophor EL ® to Trancutol ® weight ratio. The droplet size of microemulsion without cyclosporin A was decreased with the increase of Cremophor EL ® content. The droplet size increased on increasing the incorporation of cyclosporin A. The droplet size of cyclosporin A loaded microemulsion was minimized with microemulsions prepared with 2:1 mixture of surfactant to cosurfactant (Cremophor EL ®:Transcutol ®:Captex 355 ®, 10:5:4). The maximal blood concentration ( C max) of cyclosporin A and the area under the drug concentration-time curve (AUC) after oral administration of this cyclosporin A loaded microemulsion was 3.5 and 3.3 fold increased compared with Sandimmun ®. No significant difference of C max and AUC was observed between this microemulsion system and Sandimmun Neoral ®. The absolute bioavailability of cyclosporin A loaded in this microemulsion system was increased about 3.3 and 1.25 fold compared with Sandimmun ® and Sandimmun Neoral ®. The enhanced bioavailability of cyclosporin A loaded in this microemulsion system might be due to the reduced droplet size of microemulsion systems.

Conversion of Psoriasis Patients from the Conventional Formulation of Cyclosporin A to a New Microemulsion Formulation: A Randomized, Open, Multicentre Assessment of Safety and Tolerability

Objective: To assess the safety, tolerability and efficacy of a new cyclosporin A (CyA) microemulsion formulation, Sandimmun Neoral^® (Neoral), in patients with severe psoriasis that was stable on CyA administered as Sandimmun^® (SIM). Methods: In this 24-week, open, randomized, prospective, multicentre trial, 28 patients continued on the same dosage of SIM, while 30 converted to Neoral at 2.5 mg/kg/day or a dosage equivalent to their pre-conversion SIM dosage. During the study, dosages could be adjusted to maintain efficacy, because of adverse events or after disease stabilization. The maximum permitted dosage for either formulation was 5.0 mg/kg/day. Primary efficacy criteria were change in Psoriasis Area and Severity Index (PASI) from baseline and time to relapse. Results: The dosage was increased to maintain efficacy in 22 patients (Neoral 13; SIM 9) and 20 dose reductions for safety were required (Neoral 14, SIM 6). In both groups, PASI scores remained stable throughout and relapses were primarily a result of dosage reduction after disease stabilization. No significant difference was found between groups in the proportion of patients remaining relapse-free. Adverse events were recorded in 20 patients receiving Neoral and 14 receiving SIM. Most drug-related events were of mild or moderate severity and reflected the known CyA side-effect profile. Dose titration guidelines ensured that mean blood pressure and serum creatinine concentrations remained stable in both groups. Conclusions: If the guidelines for CyA use are followed and the Neoral dosage does not exceed 5 mg/kg/day, conversion of stable patients with severe psorisasis from SIM to Neoral should present no clinically relevant safety or tolerability problems and efficacy of treatment is maintained.

A Pharmacokinetic Study of Cyclosporin (Sandimmune??)

In this study, we have investigated the absorption and elimination kinetics of cyclosporin (CsA) at once-daily and twice-daily (at 0800h and 2000h) dosage intervals from the 2 earlier dosage forms, Sandimmune® Oral Solution (OS) and Sandimmune® Soft Gel Capsules (SGC), in 11 stable renal transplant patients. Our objective was to illustrate and explain the factors that are responsible for the poor performance of trough levels in the prediction of CsA exposure and to show how these problems may be overcome in the future by the administration of a new dosage form of CSA, Sandimmune Neoral® (Neoral®). Predose trough levels for OS and SGC in the 0800- and 2000-hour intervals, and for SGC in the once-daily interval, were not significantly different. In the 0800-hour interval, the time to maximum drug concentration for the OS dosage form was significantly longer than for SGC. Analysis of the data from all patients showed no significant difference in dose-adjusted area under the concentration-time curve from zero to 12 hours (AUC0–12h) between 0800-hour and once-daily intervals; however, those results were affected by high intrasubject variability in absorption rate exhibited by a few individuals. Analysis of the data from 7 individuals with very uniform blood CsA concentration profiles revealed a significant dose-dependent effect on CsA absorption. Diurnal fluctuations in SGC absorption rate and extent had significant effects on postdose trough levels: in the 2000-hour interval, postdose trough concentration (Cmin12) was significantly higher than predose trough concentration (Cmin0). This change reflected both delays in absorption as well as increases in absorption extent. The assessment of the predictive potential of CsA trough levels from SGC 12- (0800-hour) and 24-hour (once-daily) intervals revealed poor correlations between: (1) dose vs AUC0–12h (r = 0.17) and AUC0–24h (r = 0.21), (2) dose vs pre- and postdose 12-hour trough concentrations (r < 0.2 in all cases), and (3) AUC0–12hvs predose (r = 0.16) and postdose (r = 0.49) 12-hour trough concentrations. Better correlations were observed with AUC0–24hvs 24-hour predose (r = 0.85) and postdose (r = 0.88) trough concentrations. The results in this study thus serve to illustrate the complexity underlying the use of predose trough concentrations to either predict the AUC, or calculate a dose, for a subsequent dosage interval.

In vitro study of cyclosporin absorption: Vehicles and intestinal immaturity

The intestinal absorption of the immunosuppressant cyclosporin-A (CsA) has been studied in vitro using the Grass chamber technique applied to the proximal small bowel of rat. CsA concentration in the donor-phase was 100 mg/1 for either 2-weeks or 6-weeks-old rat intestine. CsA was dissolved in different vehicles, including the oily solution Sandimmun® (CsA-S) and the new microemulsion Sandimmun Neoral ® (CsA-SN) together with bile salts and pancreatic lipase. The limit of tissue viability was set at 90 min by monitoring the transepithelial electric resistance. Mucosal histology was studied by both optical and transmission electron microscopy. CsA was determined in the receptor-phase. CsA was partially metabolised by the 6-weeks-old rat intestine. In these experiments no difference was observed between CsA-S and CsA-SN absorption. On the contrary, the 2-weeks-old rat intestine did not allow CsA absorption from CsA-SN. This was related to intestinal immaturity and brush border erosion, as shown by electron microscopy. Hence, CsA absorption from microemulsion may require a mature and viable intestine. Microvilli of absorptive cells may play a role in CsA capture from the microemulsion-modified-micelles, in which CsA concentration is lower than in oily droplets. CsA absorption was not impaired by oily vehicles. Complete lipolysis of olive oil (CsA-S) induced an important decrease in CsA absorption, related to free oleic acid production.

Cholestasis-Related Cyclosporin Malabsorption Overcome by Administration of Sandimmun Neoral®

Cholestasis-Related Cyclosporin Malabsorption Overcome by Administration of Sandimmun Neoral®

CYCLOSPORINE PHARMACOKINETICS AND VARIABILITY FROM A MICROEMULSION FORMULATION—A MULTICENTER INVESTIGATION IN KIDNEY TRANSPLANT PATIENTS

The steady-state pharmacokinetics and tolerability of a microemulsion formulation of cyclosporine (Sandimmune Neoral) were compared with the commercial formulation (Sandimmune) in 55 clinically stable renal allograft recipients. In study period I (2 weeks' duration), patients entered the study on a stable, individualized twice-daily dosage regimen of the commercial formulation. In period II (2 weeks), they were changed over to the microemulsion formulation at the same dose as at study entry. In period III (2 weeks), dose titration was subsequently allowed if necessary to provide comparable steady-state trough concentrations as at study entry. The commercial formulation was reinstituted during period IV (2 weeks). Safety and tolerability were assessed at weekly clinic visits, and the steady-state pharmacokinetics of cyclosporine in whole blood were characterized at the end of each study period. A milligram-to-milligram dose conversion was adequate when making the initial change between formulations in order to maintain steady-state trough concentrations in the target therapeutic range. Concomitant with this conversion, the steady-state peak concentration and area under the curve increased on average by 59% and 30%, respectively, due to absorption-related differences between the formulations. These increases were not associated with an increase in adverse experiences or changes in blood pressure or clinical laboratory parameters over the first four weeks after the change-over. Trough concentrations were more stable and were more strongly correlated with systemic exposure (area under the curve) during treatment with the microemulsion formulation. Intraindividual coefficients of variation in steady-state peak concentration, time to attain the peak, area under the curve, and percent peak-trough fluctuation ranged from 18% to 74% from the commercial formulation. Variability from the microemulsion formulation was significantly less, ranging from 10% to 22%.

Reduced Inter- and Intraindividual Variability in Cyclosporine Pharmacokinetics from a Microemulsion Formulation

The inter- and intraindividual variability of cyclosporine pharmacokinetics from a microemulsion formulation were compared with the currently marketed formulation In a sequential bioreplication study. Twenty-four healthy male volunteers were randomized to receive each formulation on two separate occasions; the reference treatment was a single oral dose of 300mg of Sandimmune and the test treatment was a single oral dose of 180mg of Sandimmune Neoral, both given as soft gelatin capsules. Serial venous blood samples were obtained over a period of 48h after each administration, and cyclosporine concentrations were measured in whole blood by a specific monoclonal RIA method. Between- and within-subject variabilities were quantified from the appropriate sums of squares from analysis of variance and statistically compared between formulations. Both inter- and intraindividual variation for the peak concentration, time to reach the peak, area under the curve, and terminal half-life of the test formulation were significantly reduced (p < 0.05) with two exceptions. For area under the curve between subjects (p < 0.2) and peak concentration within subjects (p < 0.1), trends toward reduced variability for the test formulation were evident. These results were further reflected in the inter- and intraindividual coefficients of variation of the pharmacokinetic parameters that ranged from 3 to 22% for the test formulation comparedwith 19to41 % for the reference formulation. Incomparison with the currently marketed formulation, reduced variability in the pharmacokinetics of cyclosporine following oral administration of Sandimmune Neoral provides a more predictable and consistent concentration-time profile.

Pharmacokinetic studies of sandimmune neoral in liver transplant recipients

Pharmacokinetic studies of sandimmune neoral in liver transplant recipients