Raimar Loebenberg

Percutaneous absorption of non-steroidal anti-inflammatory drugs from in situ gelling xyloglucan formulations in rats

The potential of gels formed in situ by dilute aqueous solutions of a xyloglucan polysaccharide derived from tamarind seed as sustained release vehicles for percutaneous administration of non-steroidal anti-inflammatory drugs has been assessed by in vitro and in vivo studies. Chilled aqueous solutions of xyloglucan that had been partially degraded by beta-galactosidase formed gels at concentrations of 1-2% w/w when warmed to 37 degrees C. The in vitro release of ibuprofen and ketoprofen at pH 7.4 from the enzyme degraded xyloglucan gels and the subsequent permeation of these fully ionized drugs through cellulose membranes followed root-time kinetics over a period of 12 h after an initial lag period. Diffusion coefficients were appreciably higher when the drugs were released from 1.5% w/w xyloglucan gels than when released from 25% w/w Pluronic F127 gels formed in situ under identical conditions. The difference in release rates was attributed to differences in the structure of the gels. The permeation rate of ibuprofen through excised skin was higher than that of ketoprofen when released from both gels, but of similar magnitude through cellulose membranes. Plasma concentrations of ibuprofen and ketoprofen from gels formed in situ following topical application of chilled aqueous solutions of xyloglucan and Pluronic F127 to the abdominal skin of rats were compared. The bioavailabilities of ibuprofen and ketoprofen were significantly higher when released from xyloglucan gels compared to Pluronic F127 gels. Occlusive dressing techniques had a greater enhancing effect on the bioavailability of ibuprofen when released from Pluronic gels.

Low Buffer Capacity and Alternating Motility along the Human Gastrointestinal Tract: Implications for in Vivo Dissolution and Absorption of Ionizable Drugs

In this study, we determined the pH and buffer capacity of human gastrointestinal (GI) fluids (aspirated from the stomach, duodenum, proximal jejunum, and mid/distal jejunum) as a function of time, from 37 healthy subjects after oral administration of an 800 mg immediate-release tablet of ibuprofen (reference listed drug; RLD) under typical prescribed bioequivalence (BE) study protocol conditions in both fasted and fed states (simulated by ingestion of a liquid meal). Simultaneously, motility was continuously monitored using water-perfused manometry. The time to appearance of phase III contractions (i.e., housekeeper wave) was monitored following administration of the ibuprofen tablet. Our results clearly demonstrated the dynamic change in pH as a function of time and, most significantly, the extremely low buffer capacity along the GI tract. The buffer capacity on average was 2.26 μmol/mL/ΔpH in fasted state (range: 0.26 and 6.32 μmol/mL/ΔpH) and 2.66 μmol/mL/ΔpH in fed state (range: 0.78 and 5.98 μmol/mL/ΔpH) throughout the entire upper GI tract (stomach, duodenum, and proximal and mid/distal jejunum). The implication of this very low buffer capacity of the human GI tract is profound for the oral delivery of both acidic and basic active pharmaceutical ingredients (APIs). An in vivo predictive dissolution method would require not only a bicarbonate buffer but also, more significantly, a low buffer capacity of dissolution media to reflect in vivo dissolution conditions.

Studying the compatibility of a metoclopramide-HCl–paracetamol mixture via IHCMC and establishing a validated RP-HPLC method for its determination in tablets

Currently metoclopramide hydrochloride (MCP-HCl) and paracetamol (PCM) are co-formulated together in a tablet form, which is widely used in relief of painful migraine. The purpose of this work was to investigate the physicochemical compatibility of this co-mixture in the solid form and in different media as well. A highly selective and sensitive RP-HPLC method was established to quantify MCP-HCl and PCM in the presence of their degradation products. Chromatographic separation was achieved on a C-8 column using phosphate buffer, acetonitrile and methanol (40 : 15 : 10, v/v/v, pH 3) as a mobile phase at a flow rate of 0.5 mL min−1 with UV detection at 220 nm. Isothermal Heat-Conduction Micro-Calorimetry (IHCMC) was used to investigate heat-flow caused by physico-chemical incompatibility. The method was linear within concentration ranges such as 20–80 μg mL−1 and 10–70 μg mL−1 for MCP-HCl and PCM, respectively. The LOD and LOQ of the method for determination of MCP-HCl and PCM were 0.501, 0.101, 1.67 and 3.39, respectively. Other analytical validation parameters such as accuracy, precision, selectivity and applicability of the method were evaluated using an external standard addition technique. The tablets containing MCP-HCl and PCM in the concentration ratio of 1 : 100 were analyzed by the method successfully via two concentration levels. Thermal analysis of solid mixtures of the drugs showed compatibility over short and long terms in contrast with their aqueous mixtures. So it is not recommended that this drug mixture be formulated in a liquid form.