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.

Hot-melt coating process (HMCP) was applied to develop a lipid based oral controlled release matrix system (tablet) to deliver highly aqueous soluble drugs using paracetamol as a model drug. Granules prepared from paracetamol and particular filler were coated with different levels of lipid and then compressed into tablets to get controlled/sustained delivery of the drug over an optimum period. Process parameters were optimized with particular focus on fluidization pattern during HMCP proposing a 'design space' with 'Quality by Design' (QbD) concept in mind. The results demonstrated that the granule composition influenced the drug release pattern, and the rate of release could be manipulated by varying the amount of lipid in the formulation. The in vitro release profile of the drug was pH-independent and the most promising release profile was obtained from tablets prepared from granules with the water-soluble filler, lactose, and coated at 9% (w/w) level with a lipid, glyceryl behanate. In vivo plasma profiles of the drug were predicted from the in vitro release profile data by convolution analysis which confirmed that the lactose based formulation with 9% (w/w) lipid coating on the granules would be suitable for controlled delivery of the drug over a period of 12 h making the formulation suitable for highly water soluble drug candidates like paracetamol with twice daily dose regimen. Moreover, the dissolution data adequately fitted into Higuchi model suggesting that the drug release occurred predominantly by diffusion.

The biopharmaceutical properties of an in-house developed new crystal modification of torasemide (Torasemide N) were investigated in comparison with the most well known crystal modification form of torasemide (Torasemide I) in order to classify the drug according to the Biopharmaceutics Classification System (BCS), and to evaluate the data in line with current US Food and Drug Administration (FDA) guidance (with biowaiver provision for Class I drugs) to determine if the biowaiver provision could be improved. The solubility profiles of Torasemide I and Torasemide N were determined, and tablets prepared from both forms of the drug were studied for in-vitro release characteristics in media recommended by the current FDA guidance for biowaiver of generic products, and in other media considered more appropriate for the purpose than the ones recommended by the FDA. Two separate bioequivalence studies in healthy humans (following oral administration) were performed with two test products (both prepared from Torasemide I) against a single reference product (prepared from Torasemide N). The absorption profiles of the drug from the tablets were determined by deconvolution for comparison with the in-vitro release profiles to determine the appropriateness of some dissolution media for predicting in-vivo performance and to determine the comparative rate and extent of absorption. The drug was absorbed from the tested products quickly and almost completely (about 95% within 3.5 h of administration). However, one test product failed to meet the bioequivalence criteria and had a significant initial lower absorption rate profile compared with the reference product (P< or =0.05), whereas the other product was bioequivalent and had a similar absorption profile to the reference product. A dissolution medium at pH 5.0, in which torasemide has minimum solubility, was found to be more discriminatory than the media recommended by the FDA. Torasemide has been classified as a Class I drug according to the BCS up to a maximum dose of 40 mg and the data suggest that the current FDA guidance could be improved by giving more emphasis to selection of appropriate dissolution media than is given in its current form for approving biowaiver to generic products of Class I drugs.