Nicholas Lowther

In Vitro and In Situ Permeability of a 'Second Generation' Hydroxypyridinone Oral Iron Chelator: Correlation with Physico-Chemical Properties and Oral Activity

AbstractPurpose. The in vitro and in situ transport of CGP 65015 ((+)-3-hydroxy-1-(2-hydroxyethyl) -2-hydroxyphenyl-methyl-1 H-pyridin-4-one), a novel oral iron chelator, is described. The predictive power of these data in assessing intestinal absorption in man is described. Methods. Caco-2 epithelial monolayer and in situ rat jejunum perfusion intestinal permeability models were utilized. In vivo iron excretion and preliminary animal pharmacokinetic experiments were described, lonization constants and octanol/aqueous partition coefficients were measured potentiometrically. Solubilities and intrinsic dissolution rates were determined using standard procedures. Results. Caco-2 cell (Papp ∼ 0.25 X 10−6 cm.s−1) and rat jejunum (Pw ∼ 0.4) permeabilities of CGP 65015 were determined. The log D(pH 7.4) of CGP 65015 was 0.58 and its aqueous solubility was > 0.5 mg.ml−1 (pH 3−9). The intrinsic dissolution rate of CGP 65015 in USP simulated intestinal fluid was 0.012 mg.min−1.cm−2. CGP 65015 promotes iron excretion effectively and dose dependently in animals. Conclusions. Caco-2 and rat intestinal permeabilities predict incomplete oral absorption of CGP 65015 in man. Preliminary rat pharmacokinetics support this. Physico-chemical data are, also, in line and suggest that CGP 65015 may, in addition, be solubility/dissolution rate limited in vivo. Nevertheless, early animal pharmacological data demonstrate that CGP 65015 is a viable oral iron chelator candidate.

Hybrid (BDBB) interferon-α: preformulation studies

Abstract A number of techniques, including RP-HPLC, HP-SEC and SDS-PAGE have been used in the delineation of degradative mechanisms of recombinant hybrid (BDBB) interferon-α (IFN-α) in the solution phase. Different degradation profiles are found according to medium pH. At pH 4.0 the major routes of degradation are via chemical transformation of the monomeric protein to a species which retains antiviral activity, and by self-proteolytic hydrolysis. At pH 7.6, methionine-oxidation is the major chemical degradative process. Protein aggregation is also a significant route of degradation at the higher pH. The results have assisted in a targeted preformulation screen of potentially stabilising excipients and possible parenteral solution dosage forms have been identified. Preliminary ‘real-time’ storage data confirm excellent chemical and physical stability of IFN-α in vehicles formulated at pH 7.6 or, especially, pH 4.0 under the proposed shelf conditions.

Crystallisation of carbamazepine in tablets stored at elevated temperatures

Abstract Carbamazepine crystals were shown to grow on the surfaces of tablets containing stearic acid if the tablets were stored at 50 ° C or 80 ° C. This effect was not observed at 35 ° C or in tablets not containing stearic acid. The phenomenon was due to recrystallisation of carbamazepine probably from solution in molten stearic acid and illustrates an alternative crystal growth mechanism to the more common water-mediated phenomenon.

A Novel Depot Preparation of Desferrioxamine-B: Development of Formulation Principles

This report describes the feasibility of simple oil-based depot formulations of a novel n-decanesulfonate salt of the iron chelator desferrioxamine-B. After subcutaneous administration in rodents, desferrioxamine-B n-decanesulfonate depot induces both (a) prolonged release of drug and (b) an increase of at least threefold to fourfold in iron excretion efficiency compared with the parent compound Desferal (desferrioxamine-B mesylate). Optimization experiments probing vehicle composition, surfactant loading, drug loading, and particle size distribution of the depot preparation are described, and the physiochemical stability of an identified pilot formulation is assessed.