Systemic availability and metabolism of colonic-derived short-chain fatty acids in healthy subjects: a stable isotope study

The short-chain fatty acids (SCFAs), acetate, propionate and butyrate, are bacterial metabolites that mediate the interaction between the diet, the microbiota and the host. In the present study, the systemic availability of SCFAs and their incorporation into biologically relevant molecules was quantified. Known amounts of 13C-labelled acetate, propionate and butyrate were introduced in the colon of 12 healthy subjects using colon delivery capsules and plasma levels of 13C-SCFAs 13C-glucose, 13C-cholesterol and 13C-fatty acids were measured. The butyrate-producing capacity of the intestinal microbiota was also quantified. Systemic availability of colonic-administered acetate, propionate and butyrate was 36%, 9% and 2%, respectively. Conversion of acetate into butyrate (24%) was the most prevalent interconversion by the colonic microbiota and was not related to the butyrate-producing capacity in the faecal samples. Less than 1% of administered acetate was incorporated into cholesterol and <15% in fatty acids. On average, 6% of colonic propionate was incorporated into glucose. The SCFAs were mainly excreted via the lungs after oxidation to 13CO2, whereas less than 0.05% of the SCFAs were excreted into urine. These results will allow future evaluation and quantification of SCFA production from 13C-labelled fibres in the human colon by measurement of 13C-labelled SCFA concentrations in blood

Combination of (M)DSC and surface analysis to study the phase behaviour and drug distribution of ternary solid dispersions

Purpose: Miscibility of the different compounds that make up a solid dispersion based formulation play a crucial role in the drug release profile and physical stability of the solid dispersion as it defines the phase behaviour of the dispersion. The standard technique to obtain information on phase behaviour of a sample is (modulated) differential scanning calorimetry ((M)DSC). However, for ternary mixtures (M)DSC alone is not sufficient to characterize their phase behaviour and to gain insight into the distribution of the active pharmaceutical ingredient (API) in a two-phased polymeric matrix. Methods: MDSC was combined with complementary surface analysis techniques, specifically time-of-flight secondary ion mass spectrometry (ToF-SIMS) and atomic force microscopy (AFM). Three spray-dried model formulations with varying API/PLGA/PVP ratios were analyzed. Results: The distribution of the API in the ternary solid dispersions depended on formulation parameters. The extent of API surface coverage and therefore the distribution of the API over both polymeric phases differed significantly for the three formulations. Conclusions: Combining (M)DSC and surface analysis rendered additional insights in the composition of mixed phases in complex systems, like ternary solid dispersions

The phage therapy paradigm: prêt-à-porter or sur-mesure?

The present opinion is the result of discussions on the future of phage therapy (personalized or large-scale uniform therapy?) during the first International Congress on Viruses of Microbes, held at the Institut Pasteur in Paris on June 21–25, 2010

Evaluation of sesamum gum as an excipient in matrix tablets

In developing countries modern medicines are often beyond the affordability of the majority of the population. This is due to the reliance on expensive imported raw materials despite the abundance of natural resources which could provide an equivalent or even an improved function. The aim of this study was to investigate the potential of sesamum gum (SG) extracted from the leaves of Sesamum radiatum (readily cultivated in sub-Saharan Africa) as a matrix former. Directly compressed matrix tablets were prepared from the extract and compared with similar matrices of HPMC (K4M) using theophylline as a model water soluble drug. The compaction, swelling, erosion and drug release from the matrices were studied in deionized water, 0.1 N HCl (pH 1.2) and phosphate buffer (pH 6.8) using USP apparatus II. The data from the swelling, erosion and drug release studies were also fitted into the respective mathematical models. Results showed that the matrices underwent a combination of swelling and erosion, with the swelling action being controlled by the rate of hydration in the medium. SG also controlled the release of theophylline similar to the HPMC and therefore may have use as an alternative excipient in regions where Sesamum radiatum can be easily cultivated

Synthesis and evaluation of new linear azo-polymers for colonic targeting

Copolymers of 4-[4-[(6-hydroxyhexyl)oxy]phenylazo] benzoic acid and 16-hydroxyhexadecanoic acid were prepared by polycondensation and evaluated as materials for colonic targeting. The in vitro degradation of the azo-polymers was performed in sonicated rat coecal content (cell-free extract) containing nicotinamide adenine dinucleotide phosphate, glucose-6-phosphate, glucose-6-phosphate dehydrogenase, and benzyl viologen as the redox mediator. The degradation of the azo-polymers was examined using UV absorption spectrometry and solution viscosimetry. The results of this study clearly demonstrate that the polymers can be degraded by rat bacterial azo-reductase to polymers with lower molecular weight, and may offer opportunities to develop colon-specific drug delivery systems.status: publishe

Nasal mucoadhesive delivery systems of the anti-parkinsonian drug, apomorphine: influence of drug-loading on in vitro and in vivo release in rabbits

Lyophilized polyacrylic acid powder formulations loaded with apomorphine HCl were prepared and the influence of drug loading on in vitro release and in vivo absorption studied after intranasal administration in rabbits. These formulations prepared with Carbopol 971P, Carbopol 974P and polycarbophil sustained apomorphine release both in vitro and in vivo. The in vitro release rate and mechanism were both influenced by the drug loading. There was no large influence of drug loading on the time to achieve the peak (Tmax) for a particular polymer, but Tmax differed between different polymers. For a particular drug loading, the Tmax from Carbopol 971P was the slowest compared with that for Carbopol 974P and polycarbophil; however, only the Tmax from Carbopol 971P loaded with 15% w/w of apomorphine was significantly longer than polycarbophil of similar drug loading (P=0.0386). The trend further observed was that increasing drug loading led to increased peak plasma concentration and area under the curve (AUC). In the second part of this study, a mixture containing an immediate release component and sustained release formulation was administered in an attempt to increase the initial plasma level, as this could be therapeutically beneficial. Only one peak plasma concentration was observed and the initial plasma concentrations were no higher than those obtained with solely sustained release formulation. The Tmax, the peak plasma drug concentration (Cmax) and AUC from the lactose-containing formulation were lower than the formulation without lactose but the differences were only marginally statistically significant for Cmax (P=0.0911) and AUC (P=0.0668), but not Tmax (P=0.2788).status: publishe

Simulated intestinal fluid as transport medium in the Caco-2 cell culture model

The Caco-2 model is widely used as a predictive tool for the oral absorption of drug candidates. Presently. transport experiments in the Caco-2 system are usually performed in 'HBSS-like' buffers. In this paper, we investigate the possibility of using simulated intestinal buffers as donor solvent during Caco-2 experiments. Toxicity assessment of these buffers on the monolayer showed that FASSIF was compatible with the Caco-2 model for at least 2 h. On the other hand, FESSIF was toxic to the monolayer. The functionality of the Caco-2 cells was assessed by determination of the transport of model compounds and the metabolic activity of hydrolases in presence of these buffers. Similar P-app values for the (passive) theophyllin transport as well as for the (active) phenylalanine transport were obtained in TM and FASSIF It was demonstrated that NaTC (present in FASSIF) had a P-gp inhibitory activity, as inclusion of NaTC in the apical compartment resulted in an increased absorptive and decreased secretory transport of CsA. The activity of the aminopeptidase enzyme was similar in both models. These results suggest that FASSIF can be used as an apical medium in the Caco-2; system. Since bile salts are also present in physiological conditions, the use of FASSIF may increase the relevance for the prediction of oral absorption using Caco-2 experiments. (C) 2002 Elsevier Science B.V. All rights reserved

Simulated intestinal fluid as transport medium in the Caco-2 cell culture model

The Caco-2 model is widely used as a predictive tool for the oral absorption of drug candidates. Presently, transport experiments in the Caco-2 system are usually performed in 'HBSS-like' buffers. In this paper, we investigate the possibility of using simulated intestinal buffers as donor solvent during Caco-2 experiments. Toxicity assessment of these buffers on the monolayer showed that FASSIF was compatible with the Caco-2 model for at least 2 h. On the other hand, FESSIF was toxic to the monolayer. The functionality of the Caco-2 cells was assessed by determination of the transport of model compounds and the metabolic activity of hydrolases in presence of these buffers. Similar P(app) values for the (passive) theophyllin transport as well as for the (active) phenylalanine transport were obtained in TM and FASSIF. It was demonstrated that NaTC (present in FASSIF) had a P-gp inhibitory activity, as inclusion of NaTC in the apical compartment resulted in an increased absorptive and decreased secretory transport of CsA. The activity of the aminopeptidase enzyme was similar in both models. These results suggest that FASSIF can be used as an apical medium in the Caco-2 system. Since bile salts are also present in physiological conditions, the use of FASSIF may increase the relevance for the prediction of oral absorption using Caco-2 experiments.status: publishe