Classification of Loratadine Based on the Biopharmaceutics Drug Classification Concept and Possible in Vitro-in Vivo Correlation

Abstract

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...

Development of a Discriminating Dissolution Method for Immediate-Release Soft Gelatin Capsules Containing a BCS Class II Compound

“…Unlike most classical antihistamines, it lacks central nervous system depressing effects such as drowsiness (10). Loratadine is a Biopharmaceutics Classification System (BCS) Class II drug, with dissolutionor solubility-limited absorption (11). It is a weak base, with a pK a value at 25 °C reported to be 4.85-6.00 (10)(11)(12).…”

“…Loratadine is a Biopharmaceutics Classification System (BCS) Class II drug, with dissolutionor solubility-limited absorption (11). It is a weak base, with a pK a value at 25 °C reported to be 4.85-6.00 (10)(11)(12). The pH-dependent solubility of loratadine has been described at different pH ranges by Frizon et al (13) and Khan et al (11) and was 484.27 µg/mL, 4.32 µg/mL, and 3.16 µg/mL at pH 2 0.1 N HCl, pH 6.8 phosphate buffer, and pH 12.5 tris(hydroxymethyl)aminomethane buffer, respectively.…”

Formulation of Novel Glycerin Nanoparticles for Enhancement the Solubility of Loratadine; Application to Transdermal Hydrogel Delivery System

“…It is used to prevents the seasonal and perennial allergic rhinitis, allergic dermatitis, idiopathic urticaria and ocular allergy [2]. LOR belongs to biopharmaceutical classification system class II with low solubility and high permeation drug [3]. Accordingly, LOR is used in a high dose (10 mg/Tablet) to reach the desirable therapeutic blood concentration [4].…”

Investigating the Use of Liquisolid Compacts Technique to Minimize the Influence of pH Variations on Loratadine Release

“…It is used for the symptomatic relief of allergic conditions including rhinitis and chronic urticaria (1,2). According to the Biopharmaceutics Classification System and based on its poor water solubility and high permeability, loratadine is classified as a class II drug (3). As a member of this class of drugs, the rate of oral absorption of loratadine is controlled by its dissolution rate in the gastrointestinal (GI) tract and, as a result, no more than 80% of the total dose administered is absorbed (3).…”