Biomedical subjects

N Lowther

Publications and source records attributed to N Lowther.

5 recordsLinked to original sources

PubMed1999

Hybrid (BDBB) interferon-alpha: preformulation studies.

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-alpha (IFN-alpha) 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-alpha in vehicles formulated at pH 7.6 or, especially, pH 4.0 under the proposed shelf conditions.

Chemistry, Pharmaceutical↗

PubMed1999

In vitro and in situ permeability of a 'second generation' hydroxypyridinone oral iron chelator: correlation with physico-chemical properties and oral activity.

PURPOSE: The in vitro and in situ transport of CGP 65015 ((+)-3-hydroxy-1-(2-hydroxyethyl)-2-hydroxyphenyl-methyl-1H-pyridin-4-on e), 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. Ionization constants and octanol/aqueous partition coefficients were measured potentiometrically. Solubilities and intrinsic dissolution rates were determined using standard procedures. RESULTS: Caco-2 cell (Papp approximately 0.25 x 10(-6) cm x s(-1)) and rat jejunum (Pw approximately 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 x ml(-1) (pH 3-9). The intrinsic dissolution rate of CGP 65015 in USP simulated intestinal fluid was 0.012 mg x min(-1) x 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.

Administration, Oral↗

PubMed1999

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.

Animals↗

PubMed1998

Caco-2 cell permeability of a new (hydroxybenzyl)ethylenediamine oral iron chelator: correlation with physicochemical properties and oral activity.

This study describes the transport of CGP 75254A, a novel oral iron chelator, across Caco-2 cells in an attempt to model intestinal epithelial cell permeability in man. CGP 75254A was dosed to the apical side of Caco-2 cell monolayers, together with [14C]mannitol as an internal permeability standard. The apparent permeability (Papp) was calculated from the cumulative appearance of drug in the basolateral fluid with time. The [14C]mannitol Papp indicated that the Caco-2 monolayers remained intact and that the iron chelator was not toxic to the cells. Permeabilities of CGP 75254A were compared with the Caco-2 permeabilities of compounds of known absorption in man. The results predict that absorption of CGP 75254A is likely to be virtually complete at pH values between 5.5 and 7.0. However, at pH 8.0 permeability is predicted as negligible. Cell permeability data are in full accordance with key physicochemical properties of CGP 75254A and suggest that the drug is passively absorbed. The results, which suggest likely quantitative absorption in vivo, are supported by preliminary pharmacological experiments in marmosets.

Administration, Oral↗

PubMed1995

The transmucosal absorption of recombinant human interferon-alpha B/D hybrid in the rat and rabbit.

For therapeutic proteins such as interferon-alpha B/D, a non-parenteral route of delivery is desirable. Possible sites of administration include the various regions of the gastrointestinal tract and airways, and this paper reports the bioavailability of interferon-alpha B/D via these routes in the rat and rabbit. Apart from the stomach, detectable levels of interferon-alpha B/D in the serum were achieved via all routes. Bioavailabilities were less than 1%, except from the lung (6.8% in the rat) and nasal cavity (2.9% in the rabbit). Absorption from the gastrointestinal tract was similar for both species, but in the nasal cavity of the rabbit was sixfold that of the rat, and in the lung of the rat was tenfold that in the rabbit. Absorption from all routes, except the buccal cavity, resulted in detectable biochemical changes in the liver of the rabbit. Comparison with reports from other groups show differences in the extent of absorption of interferon-alpha B/D and of natural or homologous recombinant interferon-alpha. The non-parenteral delivery of biochemically active amounts of interferon-alpha B/D is thus demonstrated.

Absorption↗