Clinical and laboratory studies of the antacid and raft-forming properties of Rennie alginate suspension

Abstract

Summary

Background

Acid pockets at the gastro-oesophageal junction escape buffering from meals in the stomach. Combining high-dose antacid with alginate may therefore be of benefit in gastro-oesophageal reflux disease.

Aim

To characterize the antacid and raft-forming properties of Rennie alginate suspension (containing high-dose antacid and alginate; Bayer Consumer Care, Bladel, the Netherlands).

Methods

The in vitro acid-neutralizing capacity of Rennie algniate was compared with Gaviscon (Reckitt Benckiser, Slough, UK) by pH-recorded HCl titration. Alginate raft weight formed in vitro at different pH was used to evaluate the pH dependency of raft formation with each product. A double-blind, placebo-controlled, randomized crossover study also compared the antacid activity of Rennie alginate vs. placebo in vivo using continuous intragastric pH monitoring in 12 healthy fasting volunteers.

Results

Compared with Gaviscon, Rennie alginate had a higher acid-neutralizing capacity, greater maximum pH and longer duration of antacid activity in vitro. However, the two products produced comparable alginate rafts at each pH evaluated. In vivo, Rennie alginate provided rapid, effective and long-lasting acid neutralization, with an onset of action of <5 min, and duration of action of almost 90 min.

Conclusions

The dual mode of action of Rennie alginate offers an effective treatment option for mild symptomatic gastro-oesophageal reflux disease particularly considering recent findings regarding ‘acid pockets’.

Introduction

Mild gastro-oesophageal reflux disease (GERD) affects millions of people worldwide, reducing quality of life.¹ The prevalence of reflux has been reported to be as high as 29% in people of 20–69 years of age,² with the characteristic symptom being heartburn, the burning sensation which results from the flow of acidic gastric contents into the distal oesophagus.

The vast majority of individuals with mild GERD self-treat with over-the-counter medications,¹ only seeking professional help if symptoms persist or complications arise. A wide range of liquid and tablet formulations is available for the treatment of GERD, with the most common formulations being antacids and alginates. Antacids neutralize stomach acid, providing relief from the discomfort of acid reflux by ensuring that any regurgitated stomach contents are no longer acidic in nature. In the acid environment of the stomach, alginates precipitate to form a viscous gel that essentially floats on top of the stomach contents providing a physical barrier between the oesophagus and the acidic gastric contents.³ Traditional alginate products incorporate only a small amount of antacid in the form of bicarbonate, which on contact with the acidic stomach contents generates carbon dioxide (CO₂) bubbles. The CO₂ then becomes trapped in the alginate gel, helping it float.³

Rennie alginate suspension (Bayer Consumer Care, Bladel, the Netherlands) is a combination product containing both high-dose antacid and alginate components, designed to comprehensively treat the symptoms of heartburn and acid reflux by providing the benefits of both treatment approaches. This dual mode of action should allow rapid and long-lasting relief of heartburn, initially through rapid neutralization of both acid that has already entered the distal oesophagus and of the acidic gastric contents, and then by providing longer term protection from heartburn as a result of the formation of an alginate raft. Because the formation of an alginate raft requires acidic conditions, some concern has been raised that the high antacid levels in this formulation will raise the pH in the stomach to the extent that the alginate will no longer precipitate and a raft will, therefore, not form. Here, we describe a series of studies, which characterize the benefits of Rennie alginate suspension, through the determination of the antacid capacity and raft-forming properties of this product.

Materials and methods

Comparative in vitro evaluation of the antacid capacity of Rennie alginate suspension and Gaviscon suspension

The in vitro acid-neutralizing capacity (ANC) of a single dose (10 mL) of Rennie alginate suspension (per 10 mL: calcium carbonate 1200 mg, magnesium carbonate 140 mg and sodium alginate 300 mg) was compared with that of a single dose (10 mL) of Gaviscon Liquid suspension (Reckitt Benckiser, Slough, UK) (per 10 mL: sodium alginate 500 mg, sodium bicarbonate 267 mg, calcium carbonate 160 mg) using a method adapted from Van Dop and Overvliet⁴ and Rosset and Rice.⁵ A Mettler DL70ES titrator (Mettler Toledo Inc., Colombus, OH, USA) was used to evaluate the quantity of acid, expressed in mmol (mmol H⁺), required to titrate a single dose of either product to pH 2.5. The choice of pH 2.5 was chosen arbitrarily as an in vitro evaluation point and was a compromise between representative values of pH 3.5,⁶ 3.0^{5, 7} and 2.0.⁴

Rennie alginate is manufactured by Bayer Consumer Care and marketed under various brand names (Belgium: Rennie Algin Liquid; the Netherlands: Rennie Refluxine; Turkey: Rennie Duo; UK: Rennie Liquid Relief). Gaviscon Liquid suspension is manufactured and marketed by Reckitt Benckiser, GSK Consumer Healthcare or Novartis Italy, depending on the country.

A 300 mL beaker containing 50 mL of 0.1 m HCl was incubated at 37 ± 1 °C in a water bath and a magnetic stirrer in the beaker was set to produce a constant stirring rate of 200 ± 20 rpm. A single dose of 10 mL alginate suspension was then added to the beaker, at which point titration with 0.2 mmol HCl/min was initiated. Changes in the pH of the solution in response to the addition of HCl were recorded using a standardized combination pH electrode until the pH of the solution decreased to 2.5.

In vitro evaluation of the acid dependency of raft formation from Rennie alginate suspension or Gaviscon suspension

In order to determine whether the ANC of Rennie alginate suspension impacts upon the raft-forming properties of this product, the quantity of acid (expressed in mmol H⁺) required to produce a floating gel from a single dose of either Rennie alginate suspension (composition as above) or Gaviscon suspension (composition as above) was determined. Solutions of pH 1.0–1.7 were made up by adding 20, 40, 60, 80 or 100 mL of 0.1 m HCl to 150 mL glass beakers and adding purified water (where required) to a final volume of 100 mL. A single 10 mL dose of each product was then added to each of these 100 mL solutions. Fifteen minutes after adding either Rennie alginate or Gaviscon suspension, the gel formed was collected, placed on filter paper (No. 4) for a further 15 min and then weighed. The weight of gel formed by each of the two products at each pH was recorded.

This experiment was conducted under blinded conditions in order to prevent bias and the Rennie alginate and Gaviscon suspensions also looked similar.

In vivo antacid activity of Rennie alginate suspension compared with placebo

This was a double-blind, placebo-controlled, randomized crossover study, the primary objective of which was to compare the antacid activity of Rennie alginate suspension (composition as above) with that of placebo (Rennie alginate excipients without sodium bicarbonate) using continuous intragastric pH monitoring in 12 healthy, fasting volunteers. Secondary objectives were to determine tolerance and acceptability. The study protocol was approved by the local ethics committee and the trial was conducted in accordance with the principles of the Declaration of Helsinki and its amendments.

Randomization was conducted by computer-generated random numbers, treatment allocation was blinded and both the Rennie and the placebo treatments looked identical.

Subjects were men or women between 18 and 40 years of age, whose cigarette consumption was <6 per day and who were able to abstain from smoking throughout the study. Subjects who had past or present symptoms of an oesophageal, gastrointestinal or bowel habit disorder, who had undergone gastrointestinal tract surgery other than appendectomy, who were taking drugs (other than oral contraceptives) <2 weeks before the start of the study, who consumed more than three cups of tea, coffee or cola, or who regularly consumed alcohol were excluded from the study. All patients provided written informed consent. Subjects were recruited by and at the Unité de Recherches Thérapeutiques (Hôpital Lariboisière, Paris). All volunteers participated in the study after providing written informed consent and provided they met the selection criteria based on a detailed clinical examination.

After an overnight fast, subjects attended the study centre at 08:15 hours on each of two mornings not <3 days apart. Intragastric basal pH was recorded from 08:30 hours for 30 min, following which a 10 mL sachet of Rennie alginate suspension (ANC 31 mmol H⁺ by titration to pH 2.5) or 10 mL placebo suspension (ANC 0 mmol H⁺ by titration to pH 2.5) were administered at 09:00 hours according to randomized order. Intragastric pH was then monitored for a further 3 h after dosing. Tolerance and acceptability of the study medications were also recorded.

Changes in gastric pH were measured using a combined glass electrode (miniature pH-glass electrode Ag/AgCl Type 440-M3 Ingold; Urdorf, Switzerland), and were recorded using a portable pH meter (GPD & pH monitor Proxima, ABS, Saint-Dié, France) according to a standard procedure. The specific characteristics of the electrode were determined before the start of and after the study by two-point calibration with buffer solutions at pH 1 and 7 (Merck Eurolab, Paris, France). With the volunteer seated, the probe was introduced transnasally and pushed down to the gastro-oesophageal junction, i.e. the site at which a sharp drop in pH from 6 to 4 arises. The probe was then placed 10 cm below the gastro-oesophageal junction and fixed to the cheek with a piece of adhesive tape. After use, the probe was immersed in an aqueous solution of glutaraldehyde 2% for 30 min.

Baseline pH in each individual was calculated as the median of 100 values taken in the 15 min prior to administration of the test product. The pH recordings were then used to determine the onset of antacid action (lag-time to reach pH 3), peak gastric pH, time to reach peak gastric pH and the duration of pH spent above baseline. Acceptability of treatment taste was also evaluated in response to the question ‘What do you think of the taste of the product’ using a visual analogue scale (VAS) of 0–100 mm, where 0 = very unacceptable and 100 =very acceptable.

Results were analysed in accordance with the randomized, crossover trial study design, using anova for repeated measures (crossover study), including two factors (treatment and period) and their interaction. The taste and acceptability of the medications for the two groups were compared using a Wilcoxon test. Statistical significance was defined as P ≤ 0.05.

Results

In vitro evaluation of antacid capacity

As anticipated from the differences in formulation and as presented in Table 1, Rennie alginate suspension was found to have a high ANC using titration to pH 2.5 compared with that of Gaviscon suspension (31 vs. 8.1 mmol H⁺, respectively). In line with this finding, the maximum pH achieved following Rennie alginate administration was higher and the duration of antacid activity longer than those seen with Gaviscon suspension (Table 1; Figure 1).

Table 1.  Acid neutralizing properties of Rennie alginate suspension 10 mL and Gaviscon suspension 10 mL when added to 50 mL 0.1 m HCl and titrated to pH 2.5

Measure	Rennie alginate suspension	Gaviscon suspension
* At a titration rate of 0.2 mmol HCl per min.
Acid-neutralizing capacity (mmol H^+/10 mL dose)	31	8.1
Maximum pH achieved	6.4	4.6
Time to end point of pH 2.5 (min)*	130	16
Duration of pH >3 (min)*	115	13

Figure 1. Duration of antacid activity (pH > 2.5) and acid-neutralizing capacity for Rennie alginate suspension 10 mL and Gaviscon suspension 10 mL when added to 50 mL 0.1 M HCl and titrated to pH 2.5 at a rate of 0.2 mmol HCl/min.

In vitro evaluation of the acid dependency of raft formation

At each pH evaluated, Rennie alginate suspension and Gaviscon suspension produced comparable floating gels (Table 2; Figure 2), although there was a trend to obtain heavier floating gels with Rennie alginate suspension. For both Rennie alginate suspension and Gaviscon suspension, raft formation (as determined by weight of gel produced) increased with increasing acid concentration, with both drugs requiring similar minimum levels of acid (6–10 mmol H⁺) to produce a floating gel (Table 2).

Table 2.  Floating gel formation from Rennie alginate suspension 10 mL or Gaviscon suspension 10 mL as a function of acid content (mmol H⁺)

Volume of 0.1 m HCl per 100 mL	mmol H^+	pH	Rennie alginate gel weight (g)	Gaviscon gel weight (g)
20	2	1.7	1.6	0.55
40	4	1.4	5.4	4.5
60	6	1.2	11.7	7.9
80	8	1.1	19.0	14.8
100	10	1.0	19.5	17.9

Figure 2. Weight of the alginate raft produced by 10 mL Rennie alginate suspension or Gaviscon suspension as a function of acid content: an in vitro comparison.

In vivo antacid activity of Rennie alginate suspension compared with placebo

Twelve subjects (five men and seven women) took part in the study. Their mean age was 24.4 years (range: 20–30) and their mean weight was 63.9 kg (range: 54–82). They were non-smokers (n = 6) or smoked 1–5 cigarettes per day (n = 6).

Basal pH was similar in the two groups and in the two periods. The mean values (±s.d.) resulting from the median values of pH were 1.6 (0.31) prior to administration of Rennie alginate suspension, and 1.6 (0.26) prior to administration of placebo. anova showed no significant group or period effects (P = 0.83 and P = 0.94, respectively). Following administration of Rennie alginate suspension, rapid and effective in vivo acid neutralization was apparent, with an onset of action of <5 min, and a duration of action (time at which pH was greater than baseline) of almost 90 min (Table 3). As anticipated, the impact of placebo on acid levels was minimal, with the difference between placebo and Rennie alginate suspension being statistically significant for all parameters reported (P < 0.01; Table 3). On the other hand, there were no significant differences between the two periods, and no significant interaction between period and treatment for any of the parameters. No adverse events were reported during the study.

Table 3.  Antacid activity of Rennie alginate suspension compared with placebo after single oral dosing in 12 healthy volunteers: results of intragastric pH monitoring

Measure	Rennie alginate	Placebo	P-value
Values are expressed as mean (s.d.). ND, not determined.
Onset of action (lag-time to reach pH 3; min)	4.1 (2.8)	ND	ND
Peak gastric pH	7.3 (1.0)	3.5 (1.7)	<0.01
Time to reach peak pH (min)	9.2 (4.8)	65.4 (50.7)	<0.01
Duration at which pH >baseline (min)	87 (61)	20 (15)	<0.01

In terms of acceptability of treatment, Rennie alginate suspension was judged to taste slightly better than placebo (score of 75 ± 18 mm vs. 72 ± 21 mm, respectively), although differences between treatments and between periods were not significant (P = 0.23 and P = 0.09, respectively).

Discussion

Rennie alginate suspension is a combination product containing a high-dose antacid together with an alginate that is anticipated to provide a rapid symptomatic relief for mild GERD as a result of the dual treatment approach. The addition of alginate to the formulation does not reduce the in vitro ANC of Rennie alginate, which at 31 mmol H⁺ remains high. This can be compared with an ANC of two times 16 mmol H⁺ for two tablets of Rennie (1360 mg calcium carbonate and 160 mg magnesium carbonate) as reported in the literature.⁸

Historically, alginate-containing products have a relatively low ANC (as confirmed by the low ANC of Gaviscon identified in the first study) being just sufficient to produce enough CO₂ to enable the formation of a floating raft. Previous studies have demonstrated that Rennie alginate rafts are formed quickly, are cohesive and have high buoyancy and good strength.⁹ The results of this study indicate that the higher ANC provided by Rennie alginate suspension does not interfere with the formation of a floating gel in vitro– similar weights of gel are produced from Rennie alginate and Gavison suspensions when the products are added to solutions of similar pH. Of note is that there was in fact a trend towards heavier floating gels with Rennie alginate suspension at a given pH. It is likely that this is the result of the high calcium content of the product, with calcium having been shown to increase in vitro raft strength.¹⁰ These promising in vitro findings were further supported by the in vivo study, which demonstrated (as anticipated) that Rennie alginate suspension significantly elevated intragastric pH in humans, providing rapid, potent and sustained antacid activity following one therapeutic dose. The onset of action, peak pH and duration of action reported here for Rennie alginate suspension were similar to those reported following administration of a Rennie suspension which does not contain the alginate component,¹¹ confirming that the addition of alginate to the suspension does not impair antacid activity.

While the in vivo study reported here provides clinical evidence of the antacid activity of Rennie alginate suspension, it does not provide information regarding the formation or duration of action of the alginate raft in vivo. Studies using Gaviscon suspension have demonstrated that the mean duration of action of the alginate raft produced in vivo was approximately 3–4 h.¹² Although confirmation from in vivo studies would be of benefit, the results from the in vitro study of raft formation reported here suggest that the alginate rafts formed from Rennie alginate and Gavison suspensions have similar characteristics and thus a similar duration of action may be anticipated with Rennie alginate suspension. The duration of protection against heartburn provided by Rennie alginate suspension is therefore anticipated to be longer than that provided by the antacid component alone.

Clinical implications of the dual mode of action of Rennie alginate suspension

Using conventional oesophageal pH monitoring, carried out with the pH sensor 5 cm above the lower oesophageal sphincter, it has been suggested that the distal oesophagus can be exposed to a pH <4 for up to 5% of a 24-h monitoring period.¹³ However, studies of lower oesophageal acid exposure in the most distal oesophagus, with a pH sensor placed below the conventional position have suggested that acid reflux is greatly underestimated, with a pH <4 being recorded for 11.7% of the 24-h monitoring period.¹⁴ In addition, it is generally considered that when food is ingested, it neutralizes stomach acid from pH 1 to >2.5 during the first steps of the digestion process. However, Fletcher et al.¹⁵ have shown that, after eating, highly acidic (median pH 1.6) unbuffered gastric juice remains at the gastro-oesophageal junction (known as the ‘acid pocket’). These two findings are important in the context of understanding and managing acid reflux, as they suggest that the combination of both a raft-forming agent and an acid-neutralizing agent, by providing more comprehensive relief and protection from reflux than either agent alone, would be of benefit in the treatment of mild GERD.

Conclusions

The data described here illustrate that the high ANC of Rennie alginate suspension provides rapid, potent and prolonged antacid activity in vivo. It is anticipated that this high antacid content will ensure that the benefits of this product extend to raising the pH of the ‘acid pocket’ that has been shown to be involved in the pathophysiology of postprandial heartburn. Thereafter, the raft-forming properties (similar to those of Gaviscon suspension) are anticipated to provide long-lasting protection against heartburn. This dual mode of action makes Rennie alginate suspension a highly effective treatment option for managing mild symptomatic GERD.

Acknowledgement

The studies on which this publication is based were supported by Bayer Consumer Care.