CA2251854A1 - Method of preventing gastrointestinal upset - Google Patents

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 of the Invention The present invention relates to a method of preven~ing symptoms of gasllu--~lestin~l distress, such as hcd~ , sour stomach, acid indi~ostion and upset stomach, by the a~minictTation of antacid compositions prior to a meal provoking these sy~ ollls.

BACKGROUND OF THE INVENTION

The human stomach secretes a number of substances, collectively called gastric juice, that are necess~ry 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 plolein digestion, and stimulates the flow of bile andpancreatic juice. Gastric acid secretion is re~ ted by both neural and humoral mech~ni~m~. Factors that affect gastric secretion include the sight 2 o 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 CA 022~18~4 1998-10-14 barrier of the gastric mucosa is not always adequate. Hea~ ", sour stomach, upset stomach, and acid in~ligestion are well known to be associated with excess gastric acid and irritation of the gastric mucosa.

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

Treatment of these uncomfortable s~ lollls 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 syllll)t~lllatic relief. Many such antacids are now marketed, including Rolaids~), Mylanta~9, 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, antacidsalso inhibit the conversion of pepsinogen to pepsin. Excess pepsin production, which is pH dependent, can damage the gastric mucosal barrier.
2 o By increasing the pH of the stomach, therefore, antacids disrupt two major factors d~m~ging 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 mech~nism, antacids may be c~lol.rolective. For example, ~lminiC~ation 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., CA 022~18~4 1998-10-14 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 cyloplote~ /e property of antacids is distin~lished from the role of antacids in the present invention, where they are used to neutralize excess gastnc stomach acid.

Cwlclllly known methods of antacid use require that an individual wait until l o stomach discomfort appears before treating it with an antacid. While antacids are known to work well, an individual will still experience unpleasant Sy~ ollls 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 ga~L,oil-lestinal 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 gastroil~esl;,~l 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 tocause one or more of the symptoms associated with excess gastric acid secretion, without experiencing the sy~ )toll,s 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 of the present invention are achieved by providing a method of preventing the sylllplollls of gastric distress such as hea~ ll,ulll, 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 sylll~toms associated with excess gastric acid secretion, in order to prevent the syll~ ,llls from occurring.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a method of preventing or re~ cing ga~LIoillle~ al distress caused by consuming acid inducing foods, said method consisting of ingesting an antacid prior to eating a meal cc~
acid-inducing foods. Preferably, the antacid is ingested up to about forty-five mimltes before eating the acid-inducing meal. Most preferably, the antacid is in~este~l about five mimltes before eating the acid-inducing meal.

2 o ln 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 of this invention.

2 5 Suitable antacids include, but are not limited to, those which have been recognized by the Food and Drug Atltnini~tration (FDA), as useful for the - relief of hc~ Ll,~,l, sour stomach, or acid indigestion and upset stomach associated with these sy~ lol,ls. These antacids are listed in 2 l C.F.R. 33 l,which is hereby incorporated by r~lence in its entirety.

-_ .

The FDA recognizes several diLre.~ categories of antacids, including al~."i~ "-cont~ining active ingredients; bicarbonate-co~t~;"i"g active ingredients; bismuth-co,~ active ingredients; calciurn-co,,~ active ingredients; citrate-cont~ining active ingredients; glycine; m~gnesium-co~ g active ingredients; dried milk solids; phosphate-co~ ;..i..g active ingredients, potassium-co,.~ -g active ingredients; sodium-co~ i"i.,g active ingredients; silicates and tartrate-co~ in~ active ingredients.

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

OTC antacid labelling states a recommended dose. Due to di~rences 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 S mEq per dose and m~int~in a pH over 3.5 for l0 ...;.,~es in an in-vitro test. Antacids should be ~dmini.~tered according to the2 o 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 ph~lllacologically effective to achieve the results of the claimed invention.
The antacids usable in this invention can be form~ ted 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 CA 022~18~4 1998-10-14 be dissolved in water. It is not believed that the dosage form of the antacid has any significant effect on its utility in the present method. Factors such aspalatability and convenience should therefore dictate the selection of an a~ o~,liate antacid.

Foodstuffs which provoke acid secretion and which cause the uncomfortable s~ln~)lGlns known as heartburn, sour stomach and upset stomach are well-known to physicians and individuals who usually suffer from these sylllpl()llls.Foods known to produce unpleasant ga~lloilltesl.,lal syllll)lullls include, but are not limite~ to, green peppers, spices, spicy foods, such as p~ppelum and chili, onions, garlic, tomatoes, orange juice and other citrus juices, coffee, tea, and pickled foods.

The usefillness of taking an antacid immediately before eating to relieve sylll~lollls 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 of the FDA's symptom-producing meal protocol gui-lelines.

Male and female subjects, 18-65 years of age, in good general health, with a documented history of gastric intolerance to one or more of the following - were entered into the study: coffee, tea, green peppers, onions, pickled foods, spices, orange juice. These foods were incol~olaled intû a salad-type meal, with a~ ol,liate beverage and ~lmini~tered 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, esonh~gitic cardiovascular, les~,lato~y, renal, endocrine, or metabolic ~i.ce~e; 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 al~lmin-~m sodium carbonate as the active ingredient. This corresponds to 9.3 mEq antacid per tablet. Half of the subjects received a two tablet dose of the test products 5 minllte~ before consuming the symplon~-provoking meal and the other half immediately after the meal, before sy~ tom occurrence.

The test meal was ~-lministered 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 omer half placebo and at meal three the 2 o subjects were crossed over to the other medication (i.e., subjects who previously received the antacid now received placebo and vice versa).

Three S~ Jtollls, heallbulll, acid indigestion, and sour stomach were ev~ te~ for time to onset and severity (on a 0 = none, 1 = mild, 2 = moderate, 3 = severe basis). Subjects were considered S~/lllptOIll 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. Wllile there were not enough subjects with intolerance to a given food to make analysis within a given food group me~ningful, the percent of s~ln~lolll free subjects is presented.

All subjects had their food intolerance confirmed by exhibiting sylll~lollls after the first (baseline) test meal. These symptom scores are col"pared to those for the antacid and placebo, taken before or after a meal, in Table 2.
Sylllptollls were significantly less severe following both antacid and placebo regardless of order of ~lmini~tration (p ~0.0004).

Student's T-test was used to COllll)~l e the onset time of symptoms for the antacid and placebo versus baseline. The total number of onset times recorded were 132; of these SS (41.7%) were of less than 10 ~ es duration, 53 (40.2%) were between }0 I..i..--~es 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 s-lmm~rized in Table 3.
Both the antacid and the placebo provided a signi1ic~ntly longer syn~ o~ ee period than no tre~nent (baseline) (p = 0.0001).

2 o Analysis of variance was used to evaluate the effects of treatment (antacid vs.
placebo) and order of ~lministTation (before vs. after test meal), for he~~
(Table 4), acid indigestion (Table 5), sour stomach (Table 6) and onset of sy~ ol~s (Table 7).

2 5 Severity of he~ ~bulll was significantly less with the antacid than with placebo (p = 0.037) as was the severity of acid indigestion (p = 0.007). The dirr~ nce - in severity of sour stomach between the antacid (0.423) and placebo (0.764) approached significance (p = 0.057). The time for syl-l~tou~s to occur with the antacid was significantly greater than with placebo (p = 0.007).

Although there were no differences due to the order of ~lmini~tration the di~lcnces 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 co.~ .g 334 mg of dihydroxy ~1l....;~,l....
sodium carbonate effectively prevents gastric sy-uplo-.-s when taken before a meal CG-~I~;ll;llg foods that ordinarily cause these symptoms.

TABLE I
Foodlntolerance Frequency %S~ loll, Free Females Males All Antacid Placebo Green Pepper 18 8 26 48.7 29.5 Spices 5 3 8 79.2 37.5 Orange Juice 4 3 7 57.1 33.3 Pickled Foods 3 0 3 22.2 22.2 Baseline Comparisons of Mean Severity*
of S~ ,lom Scores Syrnpto Order Comparison Prob.
Antacid vs. Baseline Hea~ l Before Meal 0.545 2.818 .0001 After Meal 1.000 2.273 .0001 Indigestion Before Meal 0.682 2.500 .0001.00 After Meal 0.636 2.000 01 Sour Stomach Before Meal 0.545 1.909 .0001 After Meal 0.455 1.773 .0001 Placebo vs. Baseline Prob.
Heartburn Before Meal 1.227 2.818 .0001 After Meal 1.136 2.273 .0001 Indigestion Before Meal 1.818 2.500 .0001 After Meal 1.045 2.000 .0002 Sour Stomach Before Meal 0.818 1.909 .0001 After Meal 0.864 1.773 .0004 *) = none, 1 = mild, 2 = moderate, 3 = severe Baseline Comparisons of Ranked Onset Time of S~ )toll,s Order Comparison Prob.
Antacid vs. Baseline Before Meal 106.6 38.1 .0001 After Meal 88.4 21.2 .0001 Placebo vs. Baseline Before Meal 82.7 38.1 .0001 After Meal 78.2 21.2 .0001 Means of Severity of Sy~ olll*
for Heartbum Order Placebo Antacid Effect Prob.
After Meal 0.816 0.679 0.747 Before Meal 1.114 0.432 0.773 .930 Treatment 0.965 0.556 Effect Prob. .037 *) = none, 1 = mild, 2 = moderate, 3 = severe 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 Means of Severity of Sylllplo 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 Means of Ranked Time for Onset of Sy.llplollls Placebo Antacid Order Effect Prob.
After Meal 56.2 66. l 6 l . l Before Meal 36.9 58.6 47.8 .454 Tre~nent Effect 46.6 62.3 Prob. 007 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 StudyI and a peppermint placebo were evaluated. The sodium free antacid contained 3 l7 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 al~ ... sodium carbonate, corresponding to 9.3 mEq per antacid tablet.
The subjects received a two tablet dose of the test products five ...;.~ es before consuming the syl,lplolll provoking meal.

Thirty-one females (mean age 39.3 years) and }3 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 m~ninefill, 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 sylllplolll free in each treatment group is presetlte~ 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 sy~ )lom occurrence.

Se~)al~le 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 sylllplo,ll severity, including global (total) sylll~tonls. Mean onset time was calculated by the same procedure used in Study I.

Severity of heartburn (p = <0.001) and acid indigestion (p= <0.001) were significantly less with the antacid than with placebo. While the liLrelence 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 sy~ lollls to occur with the antacid was significantly greater than with placebo (p = <0.001).

2 5 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 dirrerences in any of the parameters measured.

WO 97/40843 rCT/US97/06594 The mean severity of S~lllptOIll scores and ranked onset times for placebo (peppermint) was compared to those of the 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 cont~ining foods that ordinarily cause these Sy~ tollls, the peppermint oil in the antacid products has no efficacy in this regard.

Frequency % Symptom Free ~ood Intolerance Females Males All Sodium Regular Placebo Free Antacid Antacid Coffee 2 - 2 100 100 0 Green Pepper 2 1 3 100 - 0 Spices 22 10 32 75 93 10 Orange Juice 2 1 3 100 67 0 Pickled Foods 3 1 4 --- 100 0 Percent of Subjects Symptom Free Antacid X Placebo Sodium Free X Placebo Antacid Heartburn 90.9113.64 95.45 27.27 Acid Indigestion 95.4518.18 95.45 36.36 Sour Stomach 90.9163.64 95.45 63.64 Symptom Severity*
Antacid Placebo P
Hca,Ll~ 0.136 1.227 C0.001 Acid Indigestion 0.091 1.273 <0.001 Sour Stomach 0.182 0.500 0.195 Global 0.409 3.000 C0.001 Onset 125.5 6.55 <0.001 *) = none, 1 = mild, 2 = moderate, 3 = severe Sylllplol,l Severity*
Sodium Free Placebo P
Antacid Heartburn 0.045 1.182 <0.001 Acid Indigestion 0.091 0.818 <0.001 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 Corrected S~l"~lolll Scores*
PeppermintFree Peppermint P
Placebo Placebo He~Ll~ 1.143 1.305 0.485 Acid TnliigPstion 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 Covariate Study III

In another clinical study, using the same methodology llt~ e~ 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 <0.001) when co~ red to placebo (13.6%).

When S~lllptOlllS did occur, the cherry antacid significantly decreased severityof he~lbulll (p <0.001), acid indigestion (p <0.001) and sour stomach (p <0.05) and time to onset was significantly greater with the cherry antacid over 1 o that of placebo (p <0.001).

It is concluded that the cherry antacid effectively prevents gastric sy,ll~toms when taken before a meal conlai"illg 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 ~lministration of an antacid.
Such an elevated pH within two min~ltes after antacid ~dministration in-iiC~tes the onset of antacid action (i.e. a pH above 3.0) was less than two mim~tes. The length of time after a~ministration 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 mimltes.
Duration of pH values of 3.0 or more for as long as 40 min~ltes have been reported in individual cases.

- In Studies I, II and III the antacid was a(lmini~tPred five minutes before the start of the meal. However, based on ~e studies showing the rapid onset of antacid action, the longevity of antacid effects in the empty stomach (up to 40 mimltes 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 ~flministered up to 45 mim~tes before a meal and as late as at the start of a meal and still provide a prevention or a reduction in sy",plol"s.

Claims (10)

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.