A computerized artificial stomach model to assess sodium alginate-induced pH gradient

Vatier, J; Celice-Pingaud, C.; Farinotti, Robert

doi:10.1016/s0378-5173(97)00372-4

Cited by 14 publications

(9 citation statements)

References 4 publications

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“… 40 In the absence of vigorous mixing, the raft can be sustained for several hours 40 , . 49 , 50 The in vitro acid neutralization capacity of Gaviscon has been evaluated using both standard and modified Rossett and Rice tests, a test of the ability of an antacid to sustain neutralization in the presence of continuous acid influx 51 . In the standard test application, Washington et al 52 .…”

Section: Alginate Preparations: Properties and Mechanism Of Actionmentioning

confidence: 99%

Review article: alginate‐raft formulations in the treatment of heartburn and acid reflux

Mandel

Daggy

Brodie

et al. 2000

Aliment Pharmacol Ther

204

126

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Alginate-based raft-forming formulations have been marketed word-wide for over 30 years under various brand names, including Gaviscon. They are used for the symptomatic treatment of heartburn and oesophagitis, and appear to act by a unique mechanism which differs from that of traditional antacids. In the presence of gastric acid, alginates precipitate, forming a gel. Alginate-based raft-forming formulations usually contain sodium or potassium bicarbonate; in the presence of gastric acid, the bicarbonate is converted to carbon dioxide which becomes entrapped within the gel precipitate, converting it into a foam which floats on the surface of the gastric contents, much like a raft on water. Both in vitro and in vivo studies have demonstrated that alginate-based rafts can entrap carbon dioxide, as well as antacid components contained in some formulations, thus providing a relatively pH-neutral barrier. Several studies have demonstrated that the alginate raft can preferentially move into the oesophagus in place, or ahead, of acidic gastric contents during episodes of gastro-oesophageal reflux; some studies further suggest that the raft can act as a physical barrier to reduce reflux episodes. Although some alginate-based formulations also contain antacid components which can provide significant acid neutralization capacity, the efficacy of these formulations to reduce heartburn symptoms does not appear to be totally dependent on the neutralization of bulk gastric contents. The strength of the alginate raft is dependant on several factors, including the amount of carbon dioxide generated and entrapped in the raft, the molecular properties of the alginate, and the presence of aluminium or calcium in the antacid components of the formulation. Raft formation occurs rapidly, often within a few seconds of dosing; hence alginate-containing antacids are comparable to traditional antacids for speed of onset of relief. Since the raft can be retained in the stomach for several hours, alginate-based raft-forming formulations can additionally provide longer-lasting relief than that of traditional antacids. Indeed, clinical studies have shown Gaviscon is superior to placebo, and equal to or significantly better than traditional antacids for relieving heartburn symptoms. Alginate-based, raft-forming formulations have been used to treat reflux symptoms in infants and children, and in the management of heartburn and reflux during pregnancy. While Gaviscon is effective when used alone, it is compatible with, and does not interfere with the activity of antisecretory agents such as cimetidine. Even with the introduction of new antisecretory and promotility agents, alginate-rafting formulations will continue to have a role in the treatment of heartburn and reflux symptoms. Their unique non-systemic mechanism of action provides rapid and long-duration relief of heartburn and acid reflux symptoms.

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Section: Alginate Preparations: Properties and Mechanism Of Actionmentioning

confidence: 99%

Review article: alginate‐raft formulations in the treatment of heartburn and acid reflux

Mandel

Daggy

Brodie

et al. 2000

Aliment Pharmacol Ther

204

126

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“…The results of in vivo studies have not been successfully correlated with in vitro findings. Nevertheless, the measurement of esophageal pH in response to GavisconB in healthy subjects 1401 and in patients with gastroesophageal reflux [8] gave pH values comparable to those obtained in vitro at the surface of the gastric contents in the computerized artificial stomach capable of controlling the position of the surface electrode in regard to gastric volume variations by means of a surface detector system [57]. In these conditions, GavisconB induced a pH gradient close to 4,O pH units instead to 2,O pH units as shown in a previous study based on the manual adjustment of surface electrode position [46, 471 and in another study according to Rossett and Rice method [36] by modifiying the electrode position Some differences between in vivo and i n vitro assays could be related to different parameters:…”

Section: Are In Vivo Studies Still Necessary?mentioning

confidence: 99%

“…( 2 ) A slight decrease of pH gradient has been observed with Gaviscon throughout the assays, evidencing a raft permeability to H+ ions corresponding to a decrease of the raft strength [57].…”

mentioning

confidence: 94%

Interests of the ‘artifical stomach’ techniques to study antacid formulations: Comparison with in vivo evaluation

Vatier

Celice-Pingaud

Farinotti

1998

Fundamemntal Clinical Pharma

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In this overview, the methods for assessing antacid activity in vitro are surveyed, and the problems of their comparison with in vivo methods of evaluation are discussed. In vitro assessment is based on two types of method: static and dynamic. The static method of titration, with end-of-titration pH values ranging between 3.0 and 1.0, has been used to quantify the number of sites capable of binding H+ ions at each end-of-titration pH, and to identify certain chemical mechanisms involved in this binding; in other words, this approach provides the pharmacological characteristics of the drugs tested. In contrast, it does not take into account physiological factors modulating antacid activity, such as gastroduodenal fluxes (including gastric emptying), drug adherence to the mucosa, and acid secretion. The dynamic method was initially based on an artificial stomach model, which has gradually been upgraded to a computer-controlled artificial stomach-duodenum model. This model overcomes certain weaknesses of the static method by simulating flux and pH conditions in the gastroduodenal tract, by taking into account interactions with the gastric mucosa and thereby reproducing the in vivo medium encountered by antacids. It is therefore capable of reflecting the characteristics of antacids, namely their effect on gastric pH and resistance to acidification, at the same time helping to identify the underlying chemicophysical mechanisms. In vivo, the antacid effect can be assessed qualitatively by means of pH-meter studies in healthy volunteers, both in baseline conditions and during secretory stimulation, and also quantitatively by methods based on intragastric titration in response to a liquid meal (IGT). pH-meter studies in baseline conditions come up against the variability of the basal pH and antacid homogenization with gastric contents, which results in a wide range of individual values. This variability is found in pH-meter studies during pentagastrin infusion and, to a lesser degree, in response to a meal. Close correlations have, however, been established between results obtained with the artificial stomach model and in healthy volunteers submitted to pH-metric or IGT studies, with several antacids. It seems that the artificial stomach method is sufficiently reproducible to make it the method of choice for investigating the antacid activity of all drugs aimed at treating acid hypersecretion disorders. In contrast, in vivo studies may be warranted for precise therapeutic indications, such as treatment of duodenal ulcer or gastro-esophageal reflux, in which the therapeutic effect is judged on the basis of an improvement in symptoms and endoscopic criteria, without the need to demonstrate the antacid effect itself.

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“…For instance, multicompartment dissolution models, represented by artificial stomach-duodenum model (ASD), find some use in evaluating the effect of gastric emptying on drug dissolution, and the propensity for supersaturation-precipitation of weak bases upon transfer from an acidic gastric compartment to a separate duodenal compartment. Supersaturation could enhance the apparent solubility of the basic drug in the intestine when it moves from a more soluble environment with lower pH (i.e., typical fasted stomach) to a less favorable environment with higher pH (i.e., intestine) (16)(17)(18). Coupled with high permeability for a Biopharmaceutical Classification System (BCS) II drug, supersaturation may greatly reduce the limit of solubility on its absorption (19).…”

Section: Introductionmentioning

confidence: 99%

Assessment of In Vivo Clinical Product Performance of a Weak Basic Drug by Integration of In Vitro Dissolution Tests and Physiologically Based Absorption Modeling

Ding

Gueorguieva

Wesley

et al. 2015

AAPS J

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Abstract. Effective integration of in vitro tests and absorption modeling can greatly improve our capability in understanding, comparing, and predicting in vivo performances of clinical drug products. In this case, we used a proprietary drug candidate galunisertib to describe the procedures of designing key in vitro tests, analyzing relevant experimental and trial data, and integrating them into physiologically based absorption models to evaluate the performances of its clinical products. By simulating the preclinical study result, we estimated high in vivo permeability for the drug. Given the high sensitivity of its solubility to pH, supersaturation may play an important role in the absorption of galunisertib. Using the dynamic dissolution test, i.e., artificial stomach-duodenum (ASD) model and simulation, we concluded galunisertib in solution or tablet products could maintain supersaturation during the transit in the gastrointestinal tract (GIT). A physiologically based absorption model was established by incorporating these key inputs in the simulation of Trial 1 results of galunisertib solution. To predict the performance of three tablet products, we developed z-factor dissolution models from the multi-pH USP dissolution results and integrate them into the absorption model. The resultant biopharmaceutical models provided good prediction of the extent of absorption of all three products, but underestimated the rate of absorption of one tablet product. Leveraging the ASD result and optimization with the dissolution model, we identified the limitation of the model due to complexity of estimating the dissolution parameter z and its in vitro-in vivo correlation.

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A computerized artificial stomach model to assess sodium alginate-induced pH gradient

Cited by 14 publications

References 4 publications

Review article: alginate‐raft formulations in the treatment of heartburn and acid reflux

Review article: alginate‐raft formulations in the treatment of heartburn and acid reflux

Interests of the ‘artifical stomach’ techniques to study antacid formulations: Comparison with in vivo evaluation

Assessment of In Vivo Clinical Product Performance of a Weak Basic Drug by Integration of In Vitro Dissolution Tests and Physiologically Based Absorption Modeling

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