WO1997040843A2

WO1997040843A2 - Method of preventing gastrointestinal upset

Info

Publication number: WO1997040843A2
Application number: PCT/US1997/006594
Authority: WO
Inventors: Carl Shellenberger; Anthony B. J. Eoga; Robert William Schumacher
Original assignee: Warner-Lambert Company
Priority date: 1996-05-02
Filing date: 1997-04-29
Publication date: 1997-11-06
Also published as: CA2251854A1; AU3566697A; WO1997040843A3

Abstract

A method of preventing or reducing gastrointestinal distress caused by excess acid production resulting from eating acid-inducing foods is disclosed. The method comprises ingesting an antiacid prior to eating a meal containing acid-inducing foods. The antiacid compound can be calcium carbonate or an aluminium-containing material such as dihydroxy aluminium sodium carbonate or aluminium hydroxide, the latter compound possibly being in admixture with calcium carbonate.

Description

METHOD OF PREVENTING GASTROINTESTINAL UPSET

Field ofthe Invention

The present invention relates to a method of preventing symptoms of gastrointestinal distress, such as heartburn, sour stomach, acid indigestion and upset stomach, by the administration of antacid compositions prior to a meal provoking these symptoms.

BACKGROUND OF THE INVENTION

The human stomach secretes a number of substances, collectively called gastric juice, that are necessary for digestion. Gastric juice includes mucus, pepsinogen (the precursor of the digestive enzyme, Pepsin), and gastric acid in the form of hydrochloric acid. Gastric acid has a number of functions. It kills ingested bacteria, helps hydrolyze ingested protein, provides the correct pH in order for pepsin to start protein digestion, and stimulates the flow of bile and pancreatic juice. Gastric acid secretion is regulated by both neural and humoral mechanisms. Factors that affect gastric secretion include the sight and smell of food; the presence of food in the mouth; and blood sugar levels.

Gastric mucosal cells protect the stomach lining from damage that could be caused by gastric acid. However, as millions of people know, the protective barrier ofthe gastric mucosa is not always adequate. Heartburn, sour stomach, upset stomach, and acid indigestion are well known to be associated with excess gastric acid and irritation ofthe gastric mucosa.

For the vast majority of people these symptoms are associated with the consumption of certain foods. Tomatoes, spicy foods, pickled foods, peppers, citrus, and spoiled foods for example, are known to cause symptoms of "acid indigestionX

Treatment of these uncomfortable symptoms is also well known. After consuming a meal that provokes these symptoms, an individual can take a commercially available over-the-counter ("OTC") antacid for symptomatic relief. Many such antacids are now marketed, including Rolaids®, Mylanta®, Maalox® and Tums®. These antacids neutralize gastric acid. At usual doses, they can significantly raise gastric pH.

In addition to raising gastric pH, thereby reducing gastric irritation, antacids also inhibit the conversion of pepsinogen to pepsin. Excess pepsin production, which is pH dependent, can damage the gastric mucosal barrier. By increasing the pH ofthe stomach, therefore, antacids disrupt two major factors damaging the gastric mucosa. A more detailed discussion of stomach physiology and the action of antacids may be found in Handbook of Nonprescription Drugs, 10th Ed., Antacid Products, Chapter 11 (1993).

Studies suggest that by some still unknown mechanism, antacids may be cytoprotective. For example, administration of antacids prior to ingesting alcohol or aspirin, substances known to erode the gastromucosal barrier, has been shown to reduce gastric irritation. See, for example, Hollander et al., Scand. J. Gastroenterol., 21 (Suppl. 125) 151-153, 1986; Domschke et al., Scand. J. Gastroenterol., 21 (Suppl. 125) 144-149, 1986; Hollander et al., Gastroenterology 86: 1114, 1984; Tarnawski et al., Gastroenterology 86: 1276, 1984; Hagel et al., Hepato-gastroenterol. 29:271-274, 1982; Szelenyi et al., Eur. J. Pharmacol. 88:403-406, 1983; Szelenyi et al., Gastroenterology 88:5 Part 2, 1604, 1985. This cytoprotective property of antacids is distinguished from the role of antacids in the present invention, where they are used to neutralize excess gastric stomach acid.

Currently known methods of antacid use require that an individual wait until stomach discomfort appears before treating it with an antacid. While antacids are known to work well, an individual will still experience unpleasant symptoms before obtaining relief. Rather than experience any stomach upset, many people simply avoid or limit their intake of certain foods which they enjoy, for fear of experiencing discomfort.

It is therefore an object of this invention to provide a method of preventing gastrointestinal distress, including heartburn, sour stomach, acid indigestion and upset stomach by ingesting an antacid before eating an acid-inducing meal. In this invention, a method of preventing gastrointestinal distress means relieving symptoms of gastrointestinal distress which could be reliably provoked by a particular meal.

It is a further object of this invention to enable people to eat a meal known to cause one or more ofthe symptoms associated with excess gastric acid secretion, without experiencing the symptoms of gastric irritation. It is also an object of this invention to allow individuals to eat foods they once enjoyed without experiencing gastric irritation. SUMMARY OF THE INVENTION

The objectives ofthe present invention are achieved by providing a method of preventing the symptoms of gastric distress such as heartburn, sour stomach, acid indigestion and upset stomach which are associated with excess gastric acid secretion. This method comprises ingesting a dose of an antacid before eating a meal known to produce symptoms associated with excess gastric acid secretion, in order to prevent the symptoms from occurring.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a method of preventing or reducing gastrointestinal distress caused by consuming acid inducing foods, said method consisting of ingesting an antacid prior to eating a meal containing acid-inducing foods. Preferably, the antacid is ingested up to about forty-five minutes before eating the acid-inducing meal. Most preferably, the antacid is ingested about five minutes before eating the acid-inducing meal.

In accordance with this invention, an antacid is defined as a basic compound that reacts with gastric acid to form a salt and water. Antacids therefore neutralize gastric acid. Any non-toxic compound satisfying this definition may be used in the method ofthis invention.

Suitable antacids include, but are not limited to, those which have been recognized by the Food and Drug Administration (FDA), as useful for the relief of heartburn, sour stomach, or acid indigestion and upset stomach associated with these symptoms. These antacids are listed in 21 C.F.R. § 331, which is hereby incorporated by reference in its entirety. The FDA recognizes several different categories of antacids, including aluminum-containing active ingredients; bicarbonate-containing active ingredients; bismuth-containing active ingredients; calcium-containing active ingredients; citrate-containing active ingredients; glycine; magnesium- containing active ingredients; dried milk solids; phosphate-containing active ingredients; potassium-containing active ingredients; sodium-containing active ingredients; silicates and tartrate-containing active ingredients.

In the present invention, any antacid may be used. Those recognized as useful by the FDA are preferred. Calcium carbonate and magnesium hydroxide are more preferred. Calcium carbonate is most preferred.

OTC antacid labelling states a recommended dose. Due to differences in specific antacids and formulations, antacids can vary significantly in their ability to neutralize acid. The FDA evaluates antacids in terms of their acid neutralizing capacity ("ANC"). According to the FDA, an effective antacid must neutralize at least 5 mEq per dose and maintain a pH over 3.5 for 10 minutes in an in-vitro test. Antacids should be administered according to the mEq ANC, not by number of tablets or volume of liquid. In the present invention, dosage amounts and frequency will vary depending on the antacid. One of ordinary skill in the art would be able to select a dosage amount and frequency that would be pharmacologically effective to achieve the results of the claimed invention.

The antacids usable in this invention can be formulated in a number of ways. Liquid suspensions and tablets are the most commonly used and available formulations for antacids. Other suitable formulations include lozenges, chewing gums with antacid coating, and effervescent tablets and powders to be dissolved in water. It is not believed that the dosage form ofthe antacid has any significant effect on its utility in the present method. Factors such as palatability and convenience should therefore dictate the selection of an appropriate antacid.

Foodstuffs which provoke acid secretion and which cause the uncomfortable symptoms known as heartburn, sour stomach and upset stomach are well- known to physicians and individuals who usually suffer from these symptoms. Foods known to produce unpleasant gastrointestinal symptoms include, but are not limited to, green peppers, spices, spicy foods, such as pepperoni and chili, onions, garlic, tomatoes, orange juice and other citrus juices, coffee, tea, and pickled foods.

The usefulness of taking an antacid immediately before eating to relieve symptoms of gastric distress which could be reliably provoked by a particular meal, i.e. to prevent the gastric distress resulting from an acid-inducing meal, was demonstrated in a series of clinical studies.

Study I

The study was conducted in a randomized, double-blind, crossover design and was an adaption ofthe FDA's symptom-producing meal protocol guidelines.

Male and female subjects, 18-65 years of age, in good general health, with a documented history of gastric intolerance to one or more ofthe following were entered into the study: coffee, tea, green peppers, onions, pickled foods, spices, orange juice. These foods were incorporated into a salad-type meal, with appropriate beverage and administered to the subjects to confirm the documented intolerance.

Women who were pregnant, nursing or recently missed a menses were excluded. Other exclusionary criteria were a history of ulcers, esophagitis, cardiovascular, respiratory, renal, endocrine, or metabolic disease; use of steroids, NSAID's, or tetracyclines; use of antacids within 24-hours of a test session; and consumption of a meal within 5 hours of a test session.

An antacid and a peppermint free placebo were evaluated. The antacid contained 334 mg of dihydroxy aluminum sodium carbonate as the active ingredient. This corresponds to 9.3 mEq antacid per tablet. Half of the subjects received a two tablet dose ofthe test products 5 minutes before consuming the symptom-provoking meal and the other half immediately after the meal, before symptom occurrence.

The test meal was administered three times, at weekly intervals. With meal one (referred to above) no medication was given, with meal two, half the subjects received the antacid and the other half placebo and at meal three the subjects were crossed over to the other medication (i.e., subjects who previously received the antacid now received placebo and vice versa).

Three symptoms, heartburn, acid indigestion, and sour stomach were evaluated for time to onset and severity (on a 0 = none, 1 = mild, 2 = moderate, 3 = severe basis). Subjects were considered symptom free if none occurred for one hour following the meal.

Thirty females (mean age 39.5 years) and 14 males (mean age 38.9 years) completed the study. The type of food intolerance exhibited by the subjects is presented in Table 1. While there were not enough subjects with intolerance to a given food to make analysis within a given food group meaningful, the percent of symptom free subjects is presented.

All subjects had their food intolerance confirmed by exhibiting symptoms after the first (baseline) test meal. These symptom scores are compared to those for the antacid and placebo, taken before or after a meal, in Table 2. Symptoms were significantly less severe following both antacid and placebo regardless of order of administration (p O.0004).

Student's T-test was used to compare the onset time of symptoms for the antacid and placebo versus baseline. The total number of onset times recorded were 132; of these 55 (41.7%) were of less than 10 minutes duration, 53 (40.2%) were between 10 minutes and 1 hour and 24 (18.2%) were longer than 1 hour. These times were converted to ranks and all subsequent analysis were made using the ranked times. These results are summarized in Table 3. Both the antacid and the placebo provided a significantly longer symptom free period than no treatment (baseline) (p = 0.0001).

Analysis of variance was used to evaluate the effects of treatment (antacid vs. placebo) and order of administration (before vs. after test meal), for heartburn (Table 4), acid indigestion (Table 5), sour stomach (Table 6) and onset of symptoms (Table 7).

Severity of heartburn was significantly less with the antacid than with placebo

(p = 0.037) as was the severity of acid indigestion (p = 0.007). The difference in severity of sour stomach between the antacid (0.423) and placebo (0.764) approached significance (p = 0.057). The time for symptoms to occur with the antacid was significantly greater than with placebo (p = 0.007). Although there were no differences due to the order of administration the differences that did exist between the antacid and placebo were, for the most part, greater when the products were given before the test meal.

These data show that an antacid containing 334 mg of dihydroxy aluminum sodium carbonate effectively prevents gastric symptoms when taken before a meal containing foods that ordinarily cause these symptoms.

TABLE 2

TABLE 3

TABLE 5

Means of Severity of Symptom* for Indigestion

Placebo Antacid Order Effect Prob.

After Meal 0.905 0.496 0.700

Before Meal 1.020 0.520 0.770 .781

Treatment Effect 0.962 0.508

Prob. .007

*) = none, 1 = mild, 2 = moderate, 3 = severe

TABLE 6

Means of Severity of Symptom for Sour Stomach

Placebo Antacid Order Effect Prob.

After Meal 0.820 0.411 0.616

Before Meal 0.709 0.436 0.572 .873

Treatment Effect 0.764 0.428

Prob. .057

*) = none, 1 = mild, 2 = moderate, 3 = severe

TABLE 7

Study II

In yet another study, using the same methodology used in the previously discussed clinical protocol, a sodium free antacid, the regular antacid of Study I and a peppermint placebo were evaluated. The sodium free antacid contained 317 mg calcium carbonate and 64 mg of magnesium hydroxide as the active ingredients. This corresponds to about 8.5 mEq per antacid tablet. As before the regular antacid of Study I contained 334 mg dihydroxy aluminum sodium carbonate, corresponding to 9.3 mEq per antacid tablet. The subjects received a two tablet dose ofthe test products five minutes before consuming the symptom provoking meal.

Thirty-one females (mean age 39.3 years) and 13 males (mean age 40.9 years) completed the study. The type of food intolerance exhibited by the subjects is presented in Table 8. While there were not enough subjects with intolerance to a given food to make analysis within a given food group meaningful, the percent of symptom free subjects is presented. All subjects had their food intolerance confirmed by exhibiting symptoms after the first test meal.

The percent of patients who were symptom free in each treatment group is presented in Table 9; the antacid and sodium free antacid each being compared to its respective crossover placebo. Both the antacid and the sodium free antacid provided greater than 90% protection from symptom occurrence.

Separate analyses of variance were used to compare the antacid to placebo (Table 10) and sodium free antacid to placebo (Table 11). These analyses were done with respect to mean symptom severity, including global (total) symptoms. Mean onset time was calculated by the same procedure used in Study I.

Severity of heartburn (p = O.001) and acid indigestion (p= <0.001) were significantly less with the antacid than with placebo. While the difference in severity of sour stomach between the antacid (0.192) and placebo (0.500) was not significant (p = 0.195), the sum total global evaluation of symptoms was significantly prevented by the antacid over placebo (p = 0.001). The time for symptoms to occur with the antacid was significantly greater than with placebo (p = <0.001).

The sodium free antacid was significantly better than placebo in all measurements of efficacy.

A t-test severity of the antacid and the sodium free antacid revealed no significant differences in any of the parameters measured. The mean severity of symptom scores and ranked onset times for placebo (peppermint) was compared to those ofthe placebo (peppermint free) from Study I. The antacid results were used as the covariate. There were no significant differences noted between the placebo treatments (Table 12).

While sodium free antacid effectively prevents gastric symptoms when taken before a meal containing foods that ordinarily cause these symptoms, the peppermint oil in the antacid products has no efficacy in this regard.

TABLE 8

TABLE 9

TABLE 10

TABLE 11

Symptom Severity*

Sodium Free Placebo P Antacid

Heartburn 0.045 1.182 O.001

Acid Indigestion 0.091 0.818 O.001

Sour Stomach 0.045 0.545 0.021

Global 0.182 2.545 <0.001

Onset 127.0 52.32 <0.001

*) = none, 1 = mild, 2 = moderate, 3 = severe

TABLE 12

Corrected Symptom Scores*

Peppermint Free Peppermint P Placebo Placebo

Heartburn 1.143 1.305 0.485

Acid Indigestion 1.045 1.410 0.111

Sour Stomach 0.828 0.526 0.168

CORRECTED ONSET 57.00 45.45 0.297 TIME

^♦Antacid as Cc ivariate

Study III

In another clinical study, using the same methodology utilized in the two previously described studies, the formulation of a sodium free cherry flavored antacid was evaluated. The cherry antacid contained 553.5mg of calcium carbonate as the active ingredient, which corresponds to 11.1 mEq per tablet. The results of this study showed that symptoms were effectively prevented in 65.9% of the subjects taking the cherry antacid. The efficacy was highly significant (p O.001 ) when compared to placebo (13.6%).

When symptoms did occur, the cherry antacid significantly decreased severity of heartburn (p <0.001), acid indigestion (p O.001) and sour stomach (p <0.05) and time to onset was significantly greater with the cherry antacid over that of placebo (p O.001).

It is concluded that the cherry antacid effectively prevents gastric symptoms when taken before a meal containing foods that ordinarily cause these symptoms.

In vivo studies of antacid products have demonstrated that the pH of nasogastrically aspirated gastric fluid from healthy, fasted adults is elevated to a mean pH of 6.2 as quickly as two minutes after administration of an antacid. Such an elevated pH within two minutes after antacid administration indicates the onset of antacid action (i.e. a pH above 3.0) was less than two minutes. The length of time after administration of the antacid that the pH was 3.0 or higher has also been measured and evaluated. The mean length of time the pH remained above 3.0 reported in one study was seventeen minutes. Duration of pH values of 3.0 or more for as long as 40 minutes have been reported in individual cases.

In Studies I, II and III the antacid was administered five minutes before the start of the meal. However, based on the studies showing the rapid onset of antacid action, the longevity of antacid effects in the empty stomach (up to 40 minutes in some cases), together with the known slowing of stomach emptying due to the presence of foods, in the present invention the antacids may be aό^ninistered up to 45 minutes before a meal and as late as at the start of a meal and still provide a prevention or a reduction in symptoms.

Claims

WHAT WE CLAIM IS:

1. A method of preventing gastrointestinal distress known to be caused by excess gastric acid production resulting from acid-inducing foods, said method comprising of ingesting an antacid prior to eating a meal containing acid-inducing foods.

2. The method according to claim 1 wherein the antacid is ingested up to forty-five minutes before the meal.

3 The method according to claim 1 wherein the antacid is ingested about five minutes before the meal.

4. The method according to claim 1 wherein the antacid is ingested at the start of a meal.

5. The method according to claim 1 wherein the antacid is an aluminum- containing compound.

6. The method according to claim 1 wherein the antacid is dihydroxy aluminum sodium carbonate.

7. The method according to claim 1 wherein the antacid is calcium carbonate.

8. The method according to claim 1 wherein the antacid is a combination of calcium carbonate and magnesium hydroxide.

9. The method according to claim 1 wherein the antacid is flavored.

10. The method according to claim 1 wherein the gastrointestinal distress is one or more symptoms selected from the group consisting of heartburn, sour stomach, acid indigestion and upset stomach.