Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02251854 1998-10-14
W0 97/40843 PCT/US97106594
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
WO 97/40843 PCT/US97/06594
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
WO 97/40843 PCT/US97/06594
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.
CA 02251854 1998-10-14
W0 97/40843 PCTIUS97/06594
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.
-
_ .
CA 02251854 1998-10-14
W0 97/40843 PCT/US97/06594
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
WO 97/40843 PCTIUS97/06594
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,
CA 02251854 1998-10-14
WO 97/40843 PCT/US97/06594
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
CA 02251854 1998-10-14
WO 97/40843 PCT/US97/06594
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).
CA 02251854 1998-10-14
WO 97/40843 PCT/US97/06S94
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
TOTAL 30 14 44
CA 02251854 1998-10-14
WO 97/40843 PCT/US97/06594
TABLE 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
CA 02251854 1998-10-14
W0 97/40843 PCT/US97/06594
11
TABLE 3
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
TABLE 4
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
CA 02251854 1998-10-14
WO 97/40843 PCT/US97/06594
12
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 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
CA 02251854 1998-10-14
WO 97/40843 PCT/US97/06594
13
TABLE 7
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.
CA 02251854 1998-10-14
WO 97/40843 PCT/US97106594
14
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.
CA 02251854 1998-10-14
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.
CA 02251854 1998-10-14
- W097/40843 PCTJUS97/06594
16
TABLE 8
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
TOTAL 31 13 44
CA 02251854 1998-10-14
W0 97/40843 PCT/US97/06594
17
TABLE 9
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
TABLE 10
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
CA 02251854 1998-10-14
WO 97/40843 PCT/US97/06594
18
TABLE 11
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
TABLE 12
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
CA 02251854 1998-10-14
WO 97/40843 PCT/US97/06594
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
CA 02251854 1998-10-14
W0 97/40843 PCT/US97/06594
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.
