Note: Descriptions are shown in the official language in which they were submitted.
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HEARTBURN TREATMENT
FIELD OF THE INVENTION
This invention discloses use of an omeprazole-bicarbonate combination for
the treatment of heartburn, and acid indigestion.
to
BACKGROUND OF THE INVENTION
US patent, 5,840,737, Phillips, J. issued Nov 24 1998, describes a
combination of a bicarbonate salt and omeprazole. The claims are directed to
treatment of gastric acid disorders (unspecified) with a single dose of a
15 pharmaceutical composition of omeprazole or lansoprazole together with a
bicarbonate salt (Na or K preferred). The dose is orally administered as an
aqueous
solution or suspension.
The Philips patent focuses on the prophylactic prevention of upper GI
bleeding in critically ill patients. It is particularly directed toward stress
ulcer
2o prophylaxis which has become routine therapy in intensive care units in
most
hospitals. An inherent advantage is the ability to infuse the solution via a
nasogastric
tube directly into the stomach. Data indicates that the omeprazole-bicarbonate
solution/suspension combine the rapid onset of pH neutralization (due to
bicarbonate) with the prolonged duration of effect of the proton pump
inhibitor
25 (PPI). There is an enhancement in time to onset of action of the PPI,
omeprazole.
This is postulated to reflect an effect of the bicarbonate to enhance the
absorption of
omeprazole. Indeed, in the presence of the bicarbonate omeprazole is observed
to
more rapidly become available systemically, and initial absorption of
omeprazole is
observed within 10-12 minutes in the combination as compared to 2-3 hours for
30 omeprazole administered 'as enteric coated pellets.
However, Phillips does not suggest that the administration of a PPI plus a
bicarbonate would be useful as a means to provide rapid onset, and prolonged
duration of effect for relief of heartburn symptoms, nor in avoiding the
reocurrence of
heartburn symptoms.
35 Omeprazole has been formulated in many different embodiments such as in a
mixture of polyethylene glycols as shown in U.S. Pat. No. 5,219,870 to Kim;
U.S.
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Pat No. 5,395,323 to Berglund discloses a device for mixing a pharmaceutical
from a
solid supply into a parenterally acceptable liquid form for parenteral
administration to
a patient.
U.S. Pat. No. 4,786,505 to Lovgren et al., discloses a pharmaceutical
preparation containing omeprazole together with an alkaline reacting compound
or
an alkaline salt of omeprazole optionally together with an alkaline compound
as a
core material in a tablet formulation. The use of the alkaline material, which
can be
chosen from such substances as the sodium salt of carbonic acid, are used to
form a
"micro-pH" around each omeprazole particle to protect the omeprazole which is
to highly sensitive to acid pH.
The ability to provide a patient with a single dose administration of a
preparation which has a rapid onset of acid neutralization would be a highly
desirable
dosage form for the treatment or prevention of heartburn symptoms.
15 SUMMARY OF THE INVENTION
The present invention is directed to a method of treating and/or preventing
heartburn symptoms in a human in need thereof, which method comprises
administering to said human a pharmaceutical composition comprising an
effective
amount of a proton pump inhibitor and an effective acid neutralizing amount of
an
2o alkali metal bicarbonate salt.
The administration preferably consists of a single dosage without requiring
further administration of a second dose of a bicarbonate salt.
DETAILED DESCRIPTION OF THE INVENTION
25 The present invention is directed to single dose administration of a
pharmaceutical composition for relief of heartburn symptoms. The term
"heartburn
symptoms" as used herein includes heartburn related to indigestion, sour
stomach,
upset stomach, episodic and co-incidental heartburn with meals, and heartburn
related
to gastroesophageal reflux of acid stomach contents. These are generally well
3o recognized symptoms which are typically treated with, over-the-counter
(OTC)
medications, such as antacids, and more recently histamine H2 receptor
antagonists at
reduced dosage. The treatments considered herein are the same as those
symptoms
for which various regulatory agencies, such as the FDA, have approved the use
of H2
receptor antagonists without prescription.
35 The present invention's use in the treatment of heartburn is a treatment
which
is safe, effective and useful for self limiting gastrointestinal conditions.
This
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treatment is in contrast to the use of a proton pump inhibitor and an alkali
metal
bicarbonate salt for medically diagnosable gastrointestinal diseases, such as
active
duodenal ulcers, gastric ulcers, gastroesophageal reflux disease (GERD),
severe
erosive esophagitis, poorly responsive systematic GERD, and pathological
hypersecretory conditions such as Zollinger Ellison syndrome. The dosage
administration is basically a once only treatment, and is not necessarily used
for
multiple daily dosing over a period of many days, weeks or long term duration,
although it is recognized that it could be used as such.
Suitable proton pump inhibitors (PPI) useful in the present invention include
to those antisecretory compounds belonging to the class of compounds generally
referred to
as substituted benzimidazoles. Omeprazole is a substituted benzimidazole, 5-
methoxy-2-
[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulflnyl]-1H-benzimidazole. Also
suitable
for use herein are the individual enantiomers, of omeprazole, such as the (S)
isomer, or a
suitable salt form, such as the calcium or magnesium salts, or a combination
of both such
15 as the (S) magnesium salt of omeprazole. Other substituted benzimidazoles
suitable for
use herein include, but are not limited to lansoprazole, 2-[[[3-Methyl-4-
(2,2,2-
trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole; pantoprazole,
5-
(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1 H-
benzimidazole,
and rabeprazole 2[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]
methyl]sulfinyl]-1H-
2o benzimidazole.
This class of compounds (the proton pump inhibitors) inhibit gastric acid
secretion and do not exhibit anti-cholinergic or histamine H2 antagonist
properties.
Drugs of this class suppress gastric acid secretion by the specific inhibition
of the H< + >
/K< + > ATPase enzyme system at the secretory surface of the gastric parietal
cell.
25 Current use of proton pump inhibitors, particularly intravenous or oral
liquid
dosage forms is primarily directed towards medically diagnosable treatment of
ulcers,
or other medical determined mucosal bleeding of the gastrointestinal tract.
Combinations of various H2-antagonists, antacids and sucralfate are other
currently
used treatment options as prophylaxis for such damage.
3o These uses are however, not directed to the prevention or the treatment of
heartburn symptoms.
Several buffered omeprazole solutions have been disclosed in publications,
Andersson et al., Clinical Pharmacokinetics 24(1):71-8 (1993); Landahl et al.
Clinical
Pharmacokinetics 23 (6); 469-76 (1992); Andersson et al., Br. J. Clin.
Pharmacol.,
35 29(5):557-63 (1990); Regardh et al., Ther. Drug Monit. 12(2):163-72 (1990);
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Andersson et al., Eur. J. Clin. Pharmacol., 39(2):195-7 (1990); and Pilbrant
et al.,
Gastroenterol Suppl., 108:113-20 (1985).
All of the buffered omeprazole solutions described in these publications were
administered orally and were given to healthy subjects who were able to ingest
the
oral dose. In all of these studies, omeprazole was suspended in a solution
including
sodium bicarbonate, as a pH buffer, in order to protect the acid sensitive
omeprazole
during administration. In all of these studies, the repeated administration of
sodium
bicarbonate both prior to, during, and following omeprazole administration
were
required in order to prevent acid degradation of the omeprazole given via the
oral
1o route of administration.
The bicarbonate was not given for its acid neutralizing capacity as an
antacid,
but for its use in preventing the degradation of the PPI. As a result, the
ingestion of
the large amounts of sodium bicarbonate and large volumes of water were
required in
contrast to the present invention. In these above-cited studies, as much as 48
15 millimoles of sodium bicarbonate in 300 ml of water were ingested in
association with
a a single dose of omeprazole for oral administration.
The present invention does not require the ingestion of excessive volumes of
bicarbonate with water. Furthermore, the enhancement in onset of the PPI's
action
allows use of a minimal dose to achieve rapid and long-lasting relief of
heartburn
2o symptoms. The use of the combination of the PPI and bicarbonate permits
using the
PPI at dosages which are often suboptimal for standard Rx therapeutic
applications
(e.g., healing of duodenal or gastric ulcers, healing esophageal erosions,
etc.). In the
case of omeprazole, a dosage of about 10 to about 20 mg is desired.
Another aspect of the present invention is a dosage form of the omeprazole
25 and bicarbonate which can be utilized to quickly make an omeprazole
solution/suspension which is supplied in a solid form, such as in a powder
form of a
sachet, or as readily dispersible tablet or capsule. Alternatively the solid
dosage form
of omeprazole and bicarbonate, such as in a compressed tablet or capsule for
oral
ingestion may also be suitable, or even desired for use by the patient for the
treatment
30 of their heartburn symptoms.
An advantage of either the solution/suspension formulation or the solid
dosage formulation are that both provide a means for the rapid onset and
prolonged
duration of effect for relief of heartburn symptoms and avoid the recurrence
of these
heartburn symptoms.
35 The pharmaceutical composition of the present invention may be prepared in
accordance with Phillips, J., US Patent No. 5,840,737 whose disclosure is
incorporated
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herein by reference in its entirety. The composition may also be prepared by
mixing
omeprazole or other substituted benzimidazoles and derivatives thereof, with a
solution
including a bicarbonate salt of a Group IA metal. Preferably, omeprazole
powder or
granules, which may be enteric coated or not, are mixed with a sodium
bicarbonate
solution to achieve a desired final omeprazole concentration. The
concentration of
omeprazole in the solution/suspension can range from approximately 0.25 mg/ml
to
approximately 6.0 mg/ml. The preferred concentration for the omeprazole in the
solution/suspension ranges from approximately 0.5 mg/ml to approximately 2
mg/ml.
The pharmaceutically acceptable alkali metal salt of a bicarbonate is
preferably a
to Group IA metal salt, such as potassium or sodium. The concentration of the
bicarbonate
salt in the composition generally ranges from approximately 5.0 percent to
approximately
60.0 percent. Preferably, the concentration of the bicarbonate salt ranges
from
approximately 7.5 percent to approximately 10.0 percent. In one embodiment of
the
present invention, sodium bicarbonate is the preferred salt and is present in
a
concentration of approximately 8.4 percent. A sufficient acid neutralizing
capacity
(ANC) amount is necessary and that will range from about 5 to about 40 ANC
values,
preferably from about 18 to 40 ANC values. It should be noted that the FDA
considers
an ANC value of 5 to be the minimum amount useful as an antacid. In the case
of
sodium or potassium bicarbonate preferred range is 18 to 40mEq, for calcium
2o bicarbonate it is from about 36 to 80 mEq.
The amount of sodium bicarbonate used in the solution/suspension of the
present
invention is approximately 1 meq (or mmole) sodium bicarbonate per 1-2 mg
omeprazole, with a range of approximately 0.75 meq (mmole) to 2.0 meq (mmole)
per 1-
2 mg of omeprazole, preferably 0.5 to I.SmEq/1-2 mg of omeprazole.
In an another aspect of the present invention, enterically-coated omeprazole
granules may be used and admixed with the sodium or potassium bicarbonate
(NaHC03)
solution which dissolves the enteric coating and forms an omeprazole
solution/suspension
for use in accordance with the present invention. Alternatively a solid dosage
formulation of the enteric coated granules with the bicarbonate may be made
and placed
3o into capsules, or using the many techniques now known in the art,
formulated into a
compressed tablet.
Alternatively, micronized granules of a PPI, such as omeprazole may be used in
place of conventional granules or powder. The process known as micronization
is
utilized in order to produce a particle having a smaller diameter.
Micronization is the
process by which solid drug particles are reduced in size. Since the
dissolution rate is
directly proportional to the surface area of the solid, and reducing the
particle size
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increases the surface area, reducing the particle size increases the
dissolution rate.
Although micronization results in increased surface area causing particle
aggregation,
which can negate the benefit of micronization and is an expensive
manufacturing step, it
does have the significant benefit of increasing the dissolution rate of
relatively water
insoluble drugs, such as oineprazole.
The formulation may contain suitable flavoring agents for use herein
including, but not limited to, wintergreen, orange, grapefruit, chocolate, and
cherry-
raspberry. The amount of flavouring present in the formulation may be from
about
0.1 % to about 5.0% by weight of the composition.
1o The solid formulations may optionally contain suitable disintegrants such
as, but
not limited to, sodium starch glycolate [Explotab~], crosslinked
polyvinylpyrrolidone,
corn starch, acacia , Croscarmellose of sodium [Ac-di-sol~], sodium
carboxymethylcellulose, veegum, or alginates. The amount of disintegrant
present may
be from about 1% to about 10.0% by weight of the composition.
The formulation may also include additional diluents or fillers which are
preferably swellable agents, and may include, but are not limited to, various
grades of
microcrystalline cellulose, such as Avicel PH101, Avicel PH102, & Avicel
PH200; corn
starch; or Starch 1500. The amount of diluent or filler present in the
formulation may be
from about 1% to about 90.0% by weight of the composition.
2o The dosage form may also optionally contain suitable lubricants or wetting
agents, such as but not limited to, magnesium stearate, stearic acid and its
pharmaceutically acceptable alkali metal salts, calcium stearate, sodium
stearate,
Cab-O-Sil, Syloid, sodium lauryl sulfate, sodium chloride, magnesium lauryl
sulfate or
talc. Preferably, a suitable lubricant is magnesium stearate or stearic acid.
Preferably,
a suitable wetting agent is a surfactant, such as sodium lauryl sulfate. The
amount of
lubricant present in the formulation may be from about 0.1% to about 10.0% by
weight
of the composition, wherease the amount of wetting agent may be from about 0.1
-
20% by weight.
The formulation may also include additional binding agents, such as
3o polyvinylpyrrolidone, (PVP), or Povidone 29K/32. The amount of binding
agent present
in the formulation may be from about 0.1% to about 30.0% by weight of the
composition.
The formulation may also include coloring agents, or pigments, such as FD&C or
D&C approved lakes and dyes, iron oxide and titanium dioxide. The amount of
pigment
present may be from about 0.1 % to about 5.0% by weight of the composition.
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Additional other conventional pharmaceutical diluents or excipients may also
be included, as needed, in the admixture. Suitable excipients which may be
employed
include, for example, fillers, binders, lubricants, binders, compression aids,
and
wetting agents. To further assist patient compliance, the formulation may also
contain sweeteners such as various natural sugars, aspartame, sodium cyclamate
and
sodium saccharinate; in addition to the flavorants. The amount of sweetner
present
may be from about 0.1% to about 20.0% by weight of the composition.
The formulations may also be manufactured in a concentrated form, such as an
effervescent tablet, for oral administration upon admixture with water.
Suitable
1o effervescent formulations for use herein are well known in the art.
The following data illustrates the utility of the pharmaceutical composition
of
the present invention.
Comparison of onset of acid inhibition between omeprazole alone and the
omeprazole - bicarbonate combination.
Khoury, et al. studied onset of acid inhibition following a single
postprandial
administration of omeprazole 10 or 20 mg in healthy volunteers. Khoury, et
al., Am.
.l. Gastroenterol. 93: 1619, ( 1998). The effect of omeprazole was compared
with
2o ranitidine, 75 and 150 mg. Gastric acid was measured via an intragastric pH
probe.
The design was a randomized crossover in 24 subjects. A standardized breakfast
was
consumed, drug was administered once intragastric pH returned to pH < 2.0, and
intragastric pH recorded for 6 hr. Omeprazole, at both 10 and 20 mg failed to
elevate intragastric pH to values >_ 3.0 during the 6 hour postprandial
recording
period. In contrast, ranitidine 75 mg and 150 mg elevated intragastric pH >
3.0
within 178 and 145.5 min of dosing, respectively, and sustained pH > 3.0 for 2
and 3
hours of the recording period. Hence in this study, a single postprandial dose
of 10
or 20 mg omeprazole had no effect on intragastric acidity for 6 hours
following
administration in healthy individuals.
Similarly, Decktor, et al. compared effects of single administrations of
omeprazole 10 or 20 mg, famotidine 10 mg and placebo on meal-stimulated
gastric
acid secretion. Decktor, et al., Am. J. Gastroenterol. 92: 1588, (1997). In a
blinded,
placebo-controlled cross-over study, each of 12 subjects randomly received the
treatments one hour prior to intragastric infusion of a liquid peptone meal
(600 ml
8% peptone, pH 4.0) designed to maximally stimulate acid output. Intragastric
pH
was maintained at pH 4.0 by continuous infusion of NaOH. Compared to placebo,
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onset of significant acid antisecretory activity was observed 45 min, 75 min
and 90
min following meal infusion for famotidine, omeprazole 20 mg and omeprazole 10
mg respectively. Over a 5 hr recording period. 10 mg famotidine reduced the
amount
of titrant required to maintain pH at 4.0 by 81 %, while reductions of 56% and
27%
were obtained with 20 mg and 10 mg omeprazole respectively. Famotidine 10 mg
had a significantly faster onset of action and significantly greater
antisecretory effect
than omeprazole
The Phillips U.S. patent No. 5,840,737 in contrast, reports that single
administration of bicarbonate + omeprazole elevates intragastric pH in
critically ill
to patients from 3.0 ~ 0.7 to 7.0 ~ 0.6 within 2 hours after dosing. The dose
was 20
mEq ANC provided by bicarbonate and a 40 mg omeprazole dose. Neutralization
was then maintained by single daily administration of omeprazole (10 mEq ANC +
20
mg omeprazole) over the course of the study.
Lack of Effect of omeprazole in prevention of meal-induced heartburn
Decktor recently reported a single administration of omeprazole 10 or 20 mg
failed to prevent meal-induced heartburn. Decktor, et al., Am. J.
Gastroenterol. 93:
1614, (1998). 385 subjects with a history of food-induced heartburn
participated in a
single-dose, parallel, blinded, randomized, placebo-controlled trial. 60
minutes prior
2o to receiving a standardized heartburn-inducing meal (chili and soft drink),
subjects
received either placebo, 10 mg famotidine (Pepcid AC), omeprazole 10 mg or
omeprazole 20 mg. Subjects rated their heartburn symptom severity on a VAS
scale
beginning immediately prior to the meal, and at 30 min. intervals for 3 '/2 hr
postprandially. Compared to placebo, neither dose of omeprazole significantly
prevented or reduced postprandial heartburn; 54, 52 and 55% of subjects
treated with
placebo, 10 mg omeprazole or 20 mg omeprazole reported moderate-to-severe post-
prandial heartburn symptoms. In contrast, 34% of subjects treated with
famotidine
were heartburn free, and only 27% reported moderate to severe symptoms
(consistent with previously published trials). 64% of subjects reported relief
from 10
3o mg famotidine as good or excellent, compared to 40%, 42% and 47% treated
with
placebo, 10 mg omeprazole and 20 mg omeprazole, respectively (p < 0.03 vs.
famotidine). Neither dose of omeprazole differed significantly from placebo
for any
efficacy parameter. This study showed a clear performance advantage for
famotidine
over omeprazole in prevention of meal-induced heartburn symptoms.
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The present invention is directed to the recognition that a 10 or 20 mg dosage
of omeprazole and a preferred acid neutralizing capacity of a bicarbonate salt
is/will
be sufficient to induce relief of heartburn symptoms without requiring
additional
dosing of the bicarbonate salt.
Study to prove effectiveness of a combination therapy in heartburn relief and
prevention.
A suitable study involves administration of a provocative meal (chili, soft
drink) to individuals who report suffering from meal-induced heartburn, and
whose
to heartburn symptoms can be reproduced by the provocative meal and responds
to
antacid/acid neutralization treatment. Following development of heartburn,
usually
within 30 - 60 min of eating the meal, the combination of omeprazole and
bicarbonate is administered in a randomized, blinded manner (10 - 20 mL
containing
- 20 mEq (ANC) bicarbonate and 10 -20 mg omeprazole). Control treatments
include bicarbonate alone, omeprazole alone, and placebo. Both the combination
and
bicarbonate treatments will provide rapid relief of heartburn symptoms, while
lesser
relief is attained with omeprazole and placebo (no difference between the
latter
treatments in degree of relief). A second heartburn provoking meal is then
consumed
at least 4 hours after the first meal, but no further treatments are
administered. Those
2o subjects who receive omeprazole-containing treatments after the initial
meal
experience a reduction in heartburn symptoms to the second meal. Subjects who
receive antacid alone (bicarbonate) or placebo treatment with the first meal
are
expected to have fi.~lly recurrent symptoms to the later meal. Hence, the
combination
of bicarbonate + omeprazole provides for a rapid onset and a prolonged
duration of
heartburn relief.
All publications, including but not limited to patents and patent
applications,
cited in this specification are herein incorporated by reference as if each
individual
publication were specifically and individually indicated to be incorporated by
3o reference herein as though fizlly set forth.
The above description fizlly discloses the invention including preferred
embodiments thereof. Modifications and improvements of the embodiments
specifically disclosed herein are within the scope of the following claims.
Without
further elaboration, it is believed that one skilled in the are can, using the
preceding
description, utilize the present invention to its fizllest extent. Therefore,
the Examples
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herein are to be construed as merely illustrative and not a limitation of the
scope of
the present invention in any way. The embodiments of the invention in which an
exclusive property or privilege is claimed are defined as follows.
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