IN-VITRO IN-VIVO CORRELATION OF DRUG LIBERATION WITH AN EXTENDED-RELEASE PERORAL DOSAGE FORM FOR ILOPROST IN MAN

Iloprost is a chemically stable prostacyclin analogue for which therapeutic efficacy was demonstrated after i.v. infusion treatment in several vascular diseases. In order to facilitate drug therapy and to enlarge therapeutic usability an peroral dosage form for non-hospitalized patients was developed on the basis of an extended release (ER) pellet formulation mimicking therapeutic plasma levels as obtained after i.v. infusion in man. Modified drug liberation was pH-independent and showed an in-vitro release of 75 to 95 % of dose over 3 h at pH 7.4 using the basket method. In 12 PAOD-patients the pharmacokinetic profile of the ER-formulation in capsules (SH K 529 I/M) was characterized after repeated administration of 150 mu g iloprost as compared to a standard i.v. infusion treatment with iloprost (Ilomedin(R)). Peroral treatment resulted in highly reproducible plasma level profiles in the therapeutic range (> 50 pg/ml) for approx. 6 h, i.e. a similar time period as obtained after i.v. infusion. Half-value duration was approx. 4 h. AUC accounted for 0.8 +/- 0.2 ng ng . h/ml as compared to 1.0 +/- 0.2 ng . h/ml (i.v.), bioavailability was 19 +/- 5 %. A level A correlation (1:1 correlation) of in-vitro liberation and in-vivo absorption could be set up based upon individual plasma level data by means of the Wagner-Nelson method. Linear correlations with a slope of approx. 1 were obtained when plotting dose fraction released in-vitro vs. dose fraction absorbed in-vivo. Half-lives of liberation in-vitro and in-vivo were similar. A lag-time for the onset of in-vivo absorption was observed caused by disintegration of the dosage form and liquid mediated formation of ER diffusion membrane on the pellets. The present ER-dosage form of iloprost provides long-lasting plasma levels of iloprost in the therapeutic range and thus might be a clinically effective equivalent of i.v. infusion, which can easily be used by ambulant patients. The intraindividual reproducibility and the correlation of in-vitro and in-vivo performance of the modified release preparation are prerequisites for efficacy, safety and patient compliance.