Loratadine, chemically known as ethyl 4-(8-chloro-5,6-dihydro-11H-benzo [5,6]-cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate, is a weak base with a pK a value of ca. 6 (calculated in our laboratories). It is absorbed rapidly following oral administration in humans giving maximum plasma concentration (C max ) in about 1-1.5 h when administered under fasting conditions, but the degree of inter-subject variability in the pharmacokinetic parameters was reported to be very high. The C max and plasma concentration-time (AUC t ) data obtained following oral administration of 10 mg, 20 mg, and 40 mg loratadine capsules were found to have a dose-proportional relationship. 3)Following oral dosing 80% of the total dose administered was found equally distributed between urine and faeces in the form of metabolic products within 10 d.4) The kinetics of loratadine observed during a multiple dose study were found comparable to those reported from single dose studies, but the mean plasma concentration-time data were approximately 90% greater than that reported for single dose data, and the steady state plasma concentrations were apparent by the fifth day of dosing. 5)The objective of the studies reported here was two fold; firstly, to classify loratadine according to the biopharmaceutics drug classification scheme, 6,7) and secondly, to compare plasma time profiles predicted from in vitro dissolution data with experimental plasma time data in order to select the most appropriate conditions for in vitro assessment of loratadine solid dosage forms. Furthermore, attempts have been made to investigate factors responsible for the high inter-subject variability in pharmacokinetic parameters of the drug. MATERIALS AND METHODS MaterialsLoratadine of European Pharmacopoeia (EP) quality was purchased from Chemo Iberica S.A. (Lugano, Switzerland). Standard pharmacopoeial grade excipients were used in the tablet formulation. Egg lecithin used for dissolution studies under biorelevant conditions was a gift from Lipoid AG (Cham, Switzerland). Crude sodium taurocholate (batch no. 386645/1, standardised against a lot of the pure substance containing above 97%) was purchased from Sigma Chemical Co. (St. Louis, U.S.A.). Sodium lauryl sulphate, hydrochloric acid and all other chemicals used for evaluation of the tablets were of analytical grade. The tablets were prepared in-house (by wet granulation technology using starch paste as a binder).For permeability testing, Caco-2 cells were obtained from the European Collection of Cell Cultures (U.K.) at passage 20. Dulbecco's Eagles medium (DMEM) containing glucose (4500 mg/ml) was purchased from Imunološki Zavod, Zagreb (Croatia). Fetal bovine serum (FBS), glutamax I, nonessential amino acids (NEAA), penicillin/streptomycin, fungizone and 0.25% trypsin-EDTA were obtained from Gibco, Life Technologies (U.K.). Hanks balanced salt solution (HBSS) and dimethylsulphoxide (DMSO) were purchased from Sigma-Aldrich (Germany). Tert-butyl methyl ether (TBME) was supplied by Merck (Germany).Solubili...

The objective of this study was to identify the factors controlling the arrival of amlodipine into the systemic circulation after oral administration in the fasting state. Dissolution data were collected with the rotating paddle and the flow-through apparatus. Caco-2 cell lines were used to assess the intestinal permeability characteristics. Actual in-vivo data were collected in 24 fasted healthy subjects after single-dose administration of the same amlodipine besylate tablet formulation used in the in-vitro dissolution studies. Regardless of the hydrodynamics, dissolution of amlodipine besylate tablets was rapid and complete in media simulating the contents of the upper gastrointestinal tract in the fasting state. Permeability of amlodipine through Caco-2 cell lines was lower than propranolol's and higher than ranitidine's, indicating that transport through the intestinal mucosa may be one process that limits the arrival into the systemic circulation. Indeed, the de-convoluted profile indicated that arrival into portal blood occurs at rates much slower than gastric emptying or dissolution rates. However, prediction of amlodipine's mean plasma profile after oral administration became possible only after additionally assuming excretion of amlodipine into the bile and a reasonable gastrointestinal residence time. Interestingly, in-vitro permeability data collected in this or in previous studies were inappropriate for simulating the mean actual plasma profile.