The Action of the Human Small Intestine in Altering the Composition of Physiological Saline

Bucher, Gladys R.; Flynn, Joseph C.; Robinson, C. S.

doi:10.1016/s0021-9258(18)43200-0

Cited by 24 publications

(5 citation statements)

References 14 publications

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“…It is wellknown that, the pH of the stomach is below 2.0, 39 whereas the pH of the small intestine is above 7.0. 40 Based on the results from our study, it could be estimated that, a drug loaded in vesicles prepared from the PVPy/PNVP-COOH system could be released immediately when the vesicles enter the stomach, while a drug loaded in the vesicles prepared from the PABA/PNVP-NH 2 system would barely be released in the stomach, but could be totally released when the vesicles enter the small intestine.…”

Section: Resultsmentioning

confidence: 79%

Preparation of Supramolecular Graft Copolymers and the Subsequent Formation of pH-Sensitive Vesicles

Qian

2009

Chem. Mater.

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A feasible methodology for the preparation of vesicles through self-assembly of supramolecular graft copolymers (SGPs) was developed. Two types of polymeric vesicles were prepared through self-assembly of two SGPs. For the first SGP, hydrophobic poly(4-vinylpyridine) (PVPy) were used as main chains, and hydrophilic poly(N-vinylpyrrolidone) with carboxylic end groups (PNVP-COOH) were grafted onto the main chains through ionic interaction between the carboxylic groups and pyridine groups. For the second SGP, hydrophobic poly(4-acrylamidobenzoic acid) (PABA) were used as main chains, and poly(Nvinylpyrrolidone) with amino end groups were grafted onto the main chains through ionic interaction between the amino groups and carboxylic groups. Both SGPs could self-assemble to form vesicles in aqueous solution. The size of the vesicles prepared from the PVPy/PNVP-COOH (or PABA/PNVP-NH 2 ) system could be controlled through modulation of the mass ratio of PVPy and PNVP-COOH (or PABA and PNVP-NH 2 ). Both vesicles were sensitive to pH and could be deformed by changing pH. Drug-release studies showed that release rates of the loaded drug (sunset yellow) in the two vesicles could be well-controlled by the pH of the releasing solution.

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Section: Resultsmentioning

confidence: 79%

Preparation of Supramolecular Graft Copolymers and the Subsequent Formation of pH-Sensitive Vesicles

Qian

2009

Chem. Mater.

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“…The procedure used to introduce such a gradient also needs to be considered. This increase in pH appears, based on the findings of Bucher et al, to be mainly related to an aboral increase in intestinal fluid bicarbonate molarity, rather than to a decrease in carbon dioxide partial pressure, with the jejunal value being reported close to 8 mM , (coupled to a pH of 6.5) and the ileal value close to 30 mM . To check the significance of the pH increase mechanism, a run was performed where bicarbonate molarity was kept constant and the pH was increased by lowering the rate of carbon dioxide flow into the vessels.…”

Section: Discussionmentioning

confidence: 99%

Toward Biopredictive Dissolution for Enteric Coated Dosage Forms

2016

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The aim of this work was to develop a phosphate buffer based dissolution method for enteric-coated formulations with improved biopredictivity for fasted conditions. Two commercially available enteric-coated aspirin products were used as model formulations (Aspirin Protect 300 mg, and Walgreens Aspirin 325 mg). The disintegration performance of these products in a physiological 8 mM pH 6.5 bicarbonate buffer (representing the conditions in the proximal small intestine) was used as a standard to optimize the employed phosphate buffer molarity. To account for the fact that a pH and buffer molarity gradient exists along the small intestine, the introduction of such a gradient was proposed for products with prolonged lag times (when it leads to a release lower than 75% in the first hour post acid stage) in the proposed buffer. This would allow the method also to predict the performance of later-disintegrating products. Dissolution performance using the accordingly developed method was compared to that observed when using two well-established dissolution methods: the United States Pharmacopeia (USP) method and blank fasted state simulated intestinal fluid (FaSSIF). The resulting dissolution profiles were convoluted using GastroPlus software to obtain predicted pharmacokinetic profiles. A pharmacokinetic study on healthy human volunteers was performed to evaluate the predictions made by the different dissolution setups. The novel method provided the best prediction, by a relatively wide margin, for the difference between the lag times of the two tested formulations, indicating its being able to predict the post gastric emptying onset of drug release with reasonable accuracy. Both the new and the blank FaSSIF methods showed potential for establishing in vitro-in vivo correlation (IVIVC) concerning the prediction of Cmax and AUC0-24 (prediction errors not more than 20%). However, these predictions are strongly affected by the highly variable first pass metabolism necessitating the evaluation of an absorption rate metric that is more independent of the first-pass effect. The Cmax/AUC0-24 ratio was selected for this purpose. Regarding this metric's predictions, the new method provided very good prediction of the two products' performances relative to each other (only 1.05% prediction error in this regard), while its predictions for the individual products' values in absolute terms were borderline, narrowly missing the regulatory 20% prediction error limits (21.51% for Aspirin Protect and 22.58% for Walgreens Aspirin). The blank FaSSIF-based method provided good Cmax/AUC0-24 ratio prediction, in absolute terms, for Aspirin Protect (9.05% prediction error), but its prediction for Walgreens Aspirin (33.97% prediction error) was overwhelmingly poor. Thus it gave practically the same average but much higher maximum prediction errors compared to the new method, and it was strongly overdiscriminating as for predicting their performances relative to one another. The USP method, despite not being overdiscriminating, provided poor pr...

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“…(11)(12)(13)(14) Using the pCO 2 /pH method, the bicarbonate concentration in the upper intestine (duodenum and jejunum) of fasted adults has been measured to range between 2 and 20 mM, and the influx of hydrochloric acid into the upper small intestine has been shown to result in a significant increase in bicarbonate secretion rates. (6,(15)(16)(17)(18) Here it should be mentioned that pCO 2 /pH measurements have been criticized as sometimes leading to an underestimation of bicarbonate concentration, (19) in which case values at the upper end of the reported ranges for the stomach and upper intestine are likely to be closer to the true intraluminal values.…”

Section: Introductionmentioning

confidence: 97%

Measuring pH and Buffer Capacity in Fluids Aspirated from the Fasted Upper Gastrointestinal Tract of Healthy Adults

et al. 2020

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Purpose: The design of biorelevant conditions for in vitro evaluation of orally administered drug products is contingent on obtaining accurate values for physiologically relevant parameters such as pH, buffer capacity and bile salt concentrations in upper gastrointestinal fluids. Methods:The impact of sample handling on the measurement of pH and buffer capacity of aspirates from the upper gastrointestinal tract was evaluated, with a focus on centrifugation and freeze-thaw cycling as factors that can influence results. Since bicarbonate is a key buffer system in the fasted state and is used to represent conditions in the upper intestine in vitro, variations on sample handling were also investigated for bicarbonate-based buffers prepared in the laboratory.Results: Centrifugation and freezing significantly increase pH and decrease buffer capacity in samples obtained by aspiration from the upper gastrointestinal tract in the fasted state and in bicarbonate buffers prepared in vitro. Comparison of data suggested that the buffer system in the small intestine does not derive exclusively from bicarbonates.Conclusions: Measurement of both pH and buffer capacity immediately after aspiration are strongly recommended as "best practice" and should be adopted as the standard procedure for measuring pH and buffer capacity in aspirates from the gastrointestinal tract. Only data obtained in this way provide a valid basis for setting the physiological parameters in physiologically based pharmacokinetic models.

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The Action of the Human Small Intestine in Altering the Composition of Physiological Saline

Cited by 24 publications

References 14 publications

Preparation of Supramolecular Graft Copolymers and the Subsequent Formation of pH-Sensitive Vesicles

Preparation of Supramolecular Graft Copolymers and the Subsequent Formation of pH-Sensitive Vesicles

Toward Biopredictive Dissolution for Enteric Coated Dosage Forms

Measuring pH and Buffer Capacity in Fluids Aspirated from the Fasted Upper Gastrointestinal Tract of Healthy Adults

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