U.S. patent application number 12/803982 was filed with the patent office on 2011-05-05 for gastric acid secretion inhibiting composition.
This patent application is currently assigned to Orexo AB. Invention is credited to Anders Pettersson.
Application Number | 20110104264 12/803982 |
Document ID | / |
Family ID | 20283818 |
Filed Date | 2011-05-05 |
United States Patent
Application |
20110104264 |
Kind Code |
A1 |
Pettersson; Anders |
May 5, 2011 |
Gastric acid secretion inhibiting composition
Abstract
A method for the treatment of at least one symptom of
gastro-esophageal reflux disease (GERD) in a human suffering from
GERD administers an oral pharmaceutical dosage form into a
gastro-intestinal tract of a human suffering from GERD. The oral
pharmaceutical dosage form contains an acid susceptible proton pump
inhibitor or salt thereof (PPI), an H2 receptor antagonist or salt
thereof (H2RA), a pharmaceutically acceptable carrier, and
optionally an antacid agent and/or alginate. The PPI is selected
from lansoprazole, omeprazole, pantoprazole, rabeprazole,
pariprazole, leminoprazole, their pharmaceutically acceptable
salts, enantiomers and salts of enantiomers and is in a form that
protects the PPI from degradation in a stomach. The H2RA is
selected from cimetidine, ranitidine, nizatidine and famotidine,
their pharmaceutically acceptable salts, isomers and salts of
isomers. The PPI is administered in combination with the H2RA for
passage into a small
Inventors: |
Pettersson; Anders; (Kode,
SE) |
Assignee: |
Orexo AB
|
Family ID: |
20283818 |
Appl. No.: |
12/803982 |
Filed: |
July 12, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10475254 |
Dec 12, 2003 |
7815940 |
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PCT/SE02/00757 |
Apr 17, 2002 |
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12803982 |
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Current U.S.
Class: |
424/451 ;
424/464; 424/489; 514/338; 514/370 |
Current CPC
Class: |
A61P 1/14 20180101; A61K
9/4808 20130101; A61K 9/5078 20130101; A61K 9/0095 20130101; A61K
31/4439 20130101; A61K 31/4439 20130101; A61K 9/167 20130101; A61K
31/4164 20130101; A61K 31/341 20130101; A61K 2300/00 20130101; A61K
31/426 20130101; A61K 9/5084 20130101; A61K 2300/00 20130101; A61K
31/426 20130101; A61P 31/04 20180101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 9/209 20130101; A61P 1/04 20180101; A61K
31/341 20130101; A61K 31/4164 20130101; A61K 9/2081 20130101 |
Class at
Publication: |
424/451 ;
424/464; 424/489; 514/338; 514/370 |
International
Class: |
A61K 9/48 20060101
A61K009/48; A61K 9/20 20060101 A61K009/20; A61K 9/14 20060101
A61K009/14; A61K 31/435 20060101 A61K031/435; A61K 31/4164 20060101
A61K031/4164; A61K 31/426 20060101 A61K031/426; A61P 1/04 20060101
A61P001/04 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 18, 2001 |
SE |
0101379-6 |
Claims
1. A method for the treatment of at least one symptom of
gastro-esophageal reflux disease (GERD) in a human suffering from
GERD consisting essentially of administering an oral pharmaceutical
dosage form into a gastro-intestinal tract of a human suffering
from GERD, the oral pharmaceutical dosage form consisting
essentially of an acid susceptible proton pump inhibitor or salt
thereof (PPI), an H2 receptor antagonist or salt thereof (H2RA), a
pharmaceutically acceptable carrier, and optionally an antacid
agent and/or alginate, wherein the PPI is selected from
lansoprazole, omeprazole, pantoprazole, rabeprazole, pariprazole,
leminoprazole, their pharmaceutically acceptable salts, enantiomers
and salts of enantiomers and is in a form that protects the PPI
from degradation in a stomach, wherein the H2RA is selected from
cimetidine, ranitidine, nizatidine and famotidine, their
pharmaceutically acceptable salts, isomers and salts of isomers,
and wherein administering the oral pharmaceutical dosage form
orally introduces into the gastro-intestinal tract of the human
suffering from GERD the PPI in combination with the H2RA for
passage into a small intestine for absorption.
2. The method of claim 1, wherein the oral pharmaceutical dosage
form is administered to affect a rise in gastric pH above 3 within
about 2 hours from the administration of the first dose, thereby
treating the human suffering from GERD promptly, and wherein the
administering is repeated, if necessary to treat the human
suffering from GERD over a prolonged period until 6 hours from the
administration of the last dose.
3. The method of claim 1, wherein the at least one symptom of
gastro-esophageal reflux disease is indigestion, heartburn, sour
stomach and/or upper abdominal pain and/or discomfort.
4. The method of claim 1, wherein the method is suitable for on
demand treatment of at least one symptom of gastro-esophageal
reflux disease (GERD) in a human suffering from GERD.
5. The method of claim 1, wherein the PPI is in the amount of from
1 mg to 100 mg and/or the H2RA is in the amount of from 1 mg to 800
mg in combination with the PPI.
6. The method of claim 1, wherein the oral pharmaceutical-dosage
form contains the optional antacid agent, and wherein the optional
antacid agent s one or several of aluminum hydroxide, calcium
carbonate, magnesium carbonate, basic magnesium carbonate,
magnesium hydroxide, magnesium oxide, and sodium hydrogen
carbonate.
7. The method of claim 1, wherein the oral pharmaceutical dosage
form is in the form of two concentric layers optionally separated
by one or more separating layer(s), wherein the inner concentric
layer is the PPI and the outer concentric layer is the H2RA.
8. The method of claim 1, wherein the oral pharmaceutical dosage
form is in the form of a capsule, a divided powder/pellet
formulation or a tablet.
9. The method of claim 1, wherein the oral pharmaceutical dosage
form is in the form of a core and a layer surrounding the core,
wherein the core is the PPI and the layer is the H2RA.
10. The method of claim 1, wherein the oral pharmaceutical dosage
form contains the antacid agent or the alginate.
Description
RELATED APPLICATIONS
[0001] This application is a divisional application of co-pending
patent application Ser. No. 10/475,254, filed Dec. 12, 2003 and
entitled "Gastric Acid Secretion Inhibiting Composition," which is
a .sctn.371 national phase conversion of PCT/SE02/00757, filed Apr.
17, 2002, which claims priority benefit based on Swedish
Application No. 0101379.6, filed Apr. 18, 2001, all of which are
hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a gastric acid secretion
inhibiting composition, to a method for its manufacture and to its
use in treating conditions which are related to the secretion of
gastric acid.
BACKGROUND OF THE INVENTION
[0003] Dyspepsia (acid dyspepsia) is a common disorder. Heartburn
is a symptom of dyspepsia. It is estimated that 44% of Americans
have heartburn at least once monthly but that only about 25% of
them are seeing the doctor because of their dyspepsia problem.
Symptoms associated with dyspepsia are for instance upper abdominal
pain/discomfort and heartburn, indigestion, "sour" stomach, and
gastro-esophageal reflux.
[0004] Dyspepsia is a multi-factorial disease and may be associated
with organic pathology such as duodenal ulcer, gastric ulcer,
esophagitis, Barrett's esophagus or gastro-duodenal inflammation
(e.g., Helicobacter pylori infection). Dyspepsia also includes
conditions where no organic pathology can be found, e.g., non-ulcer
dyspepsia (NUD) or functional dyspepsia.
[0005] Dyspepsia can be controlled by administration of medicines
that reduce the pH in the stomach. Therapeutic agents effective in
the treatment of dyspepsia include gastric acid suppressing agents,
such as histamine H2 receptor antagonists (in the following called
H2 receptor antagonists), acid susceptible proton pump inhibitors,
antacids/alginates, anticholinergics and prokinetic agents. They
can be distinguished by their mechanism of action, safety profile,
and pharmacokinetics. The stomach pathogen Helicobacter pylori has
been associated with dyspepsia, gastro-duodenal ulcer disease and
stomach cancer. The treatment of H. pylori infection usually
comprises the administration of a combination of acid secretion
suppressing agents and one or two antibiotic agents.
[0006] The therapeutic effect on dyspepsia related discomfort and
organic lesions when inhibiting acid production by administration
of acid secretion-inhibiting drugs is related to the degree of acid
inhibition as well as to the onset and duration of action of the
particular drug. The majority of patients who have symptomatic acid
reflux disease have a normal esophageal mucosa or only a mild
degree of esophagitis. Treatment to relieve symptoms as they occur
may be the best way to manage these patients, to whom the speed of
symptom relief is of primary importance.
[0007] Antacid agents, that is, acid neutralizing agents, and
alginates are the first therapeutic choice in the treatment of mild
heartburn. They have a extremely short duration of action but are
seen as inexpensive and safe. Antacid agents work locally through a
neutralization of gastric acid. Alginates provide some mechanical
protection against reflux of gastric acid into the esophagus. The
main advantages of antacid agents and alginates are, that they
provide fast relief of symptoms. The main disadvantage of antacid
agents and alginates is the extremely short duration of action and
dosing has to be repeated frequently to keep the patients free of
symptoms, further that antacids often do not provide symptom
resolution, i.e. complete relief of symptoms.
[0008] Several classes of compounds are known which affect the
secretion of gastric acid. Among them proton pump inhibitors, such
as the substituted benzimidazoles omeprazole, lansoprazole,
rabeprazole, pantoprazole, and H2 receptor antagonists, such as
cimetidine, ranitidine, famotidine, are the most prominent ones. H2
receptor antagonists and acid susceptible proton pump inhibitors
are widely prescribed for reducing gastric acid secretion
systemically. After days' treatment, acid susceptible proton pump
inhibitors have in clinical studies been proven to be very
effective in providing symptom resolution in patients with
dyspepsia associated with gastric ulcers, duodenal ulcers, reflux
esophagitis and gastroesophageal reflux without esophagitis. Acid
susceptible proton pump inhibitors and H2 receptor antagonists,
respectively, have also proven to be effective in curing H. pylori
infection in combination with one or two antibiotics (Gschwandtler
M et al., Aliment Pharmacol Ther 1999, 13(8):1063-9). It is
established that omeprazole is superior to H2 receptor antagonists
regarding healing of gastro-duodenal and esophageal lesions as well
as providing dyspeptic symptom resolution in these conditions
(Eriksson S., European Journal of Gastroenterology & Hepatology
1995, 7:465).
[0009] Various combinations of antacid and/or mucosa protecting
agents with agents that reduce acid secretion have been disclosed
to be useful in treating dyspepsia.
[0010] WO 95/017080 describes a composition for use in the
treatment of for instance heartburn comprising an H2 receptor
antagonist, such as famotidine, and an alginate and optionally
simethicone (an activated polysiloxane).
[0011] EP 338861 A describes a solid pharmaceutical preparation
consisting of an antacid and excipients which is proposed to be
used in combination with an acid susceptible proton pump inhibitor
or any other substance inhibiting gastric acid secretion. There is
no suggestion to combine these substances in a fixed unit dosage
form.
[0012] U.S. Pat. No. 5,244,670 A describes an ingestible
pharmaceutical composition comprising a substance selected from the
group consisting of antacid agents, acid secretion prevention
agents, bismuth-containing agents and their mixtures, and
3-(1-menthoxy)-propane-1,2-diol which is present to provide a
cooling sensation to the throat.
[0013] WO 97/25066 discloses a pharmaceutical formulation
comprising a combination of an acid susceptible proton pump
inhibitor or an H2 receptor antagonist and one or more antacid
agents or alginates.
[0014] Neither acid susceptible proton pump inhibitors nor H2
receptor antagonists, alone or in combination with antacids and/or
alginates, provide fully satisfactory quick and lasting relief to
patients, to whom the speed of symptom relief is of primary
importance but who also desire to be free of symptoms for a longer
period of time.
OBJECTS OF THE INVENTION
[0015] It is an object of the invention to provide a medicine which
provides quick and lasting relief to a patient suffering from
conditions related to gastric acid secretion.
[0016] It is another object of the invention to provide a method
for treating a patient suffering from conditions related to gastric
acid secretion which provides quick and lasting relief.
[0017] Further objects of the invention will be evident from the
following short description of the invention, a preferred
embodiment thereof, and the appended claims.
SUMMARY OF THE INVENTION
[0018] The present invention is based on the insight that acid
susceptible proton pump inhibitors and H2 receptor antagonists
possess mutually supplementing properties in respect of inhibiting
acid secretion and that they can be used for designing a
pharmaceutical composition which provides quick and lasting relief
to a patient suffering from conditions related to gastric acid
secretion.
[0019] Acid susceptible proton pump inhibitors are acid activated
prodrugs that covalently inhibit the gastric H+,K+-ATPase, the
proton-transporting enzyme involved in the production of
hydrochloric acid in the stomach. The action of gastric
H+,K+-ATPase represents the final step in the sequence of events
resulting in secretion of hydrochloric acid by the parietal cell.
Thus inhibition of this enzyme is the most effective and specific
means of controlling acid secretion regardless of the nature of the
stimulus to secretion. As would be expected with such a mechanism
of action, omeprazole has been shown to inhibit both basal and
stimulated acid secretion. Omeprazole is a weak base which
accumulates in the acidic milieu of the secretory membrane of the
parietal cell where it undergoes rearrangement in acid to its
active sulphenamide form which subsequently reacts with sulfhydryl
groups of the acid pump.
[0020] In gastric mucosa, the acid susceptible proton pump is
situated in the apical membrane and in the tubovesicles bordering
the secretory canaliculi of the parietal cell. Thus, after a single
dose, omeprazole rapidly accumulates in the acidic compartment of
the secretory membrane where its active sulphenamide form
irreversible binds to the H+,K+-ATPase. The H+,K+-ATPase situated
in the tubovesicles will however not be exposed for activated
omeprazole. A major portion of synthesized H+,K+-ATPase will thus
escape blockade after a single omeprazole dose. This may explain
why the maximal acid inhibitory effect of omeprazole is reached
only after about five days treatment.
[0021] H2 receptor antagonists competitively inhibit the action of
histamine on all H2 receptors, mainly on the surface of the
parietal cells. At therapeutic doses these agents are capable not
only of decreasing both basal and nocturnal acid secretion, but
also secretion stimulated by food, histamine, insulin and
pentagastrin. A single dose of an H2 receptor antagonist results in
maximal acid inhibitory effect already within 2 hours after intake.
Furthermore, the acid inhibitory effect obtained with high doses of
an H2 receptor antagonist is built up rapidly but has a tendency to
fade substantially during the following 2-7 days, while the acid
inhibitory effect of omeprazole gradually is built up during the
same period of time.
[0022] According to the invention, by combining an H2-receptor
antagonist with an acid susceptible proton pump inhibitor, it is
possible to obtain rapid onset of action as well as good long-term
efficacy.
[0023] Thus, according to the invention, is provided an oral
pharmaceutical dosage form comprising pharmacologically effective
amounts of an acid susceptible proton pump inhibitor or a salt
thereof, and an H2 receptor antagonist or a salt thereof, and a
pharmaceutically acceptable carrier. The terms "proton pump
inhibitor" and "H2 receptor antagonist" include their isomers, such
as enantiomers of proton pump inhibitors, as well as
pharmaceutically acceptable salts of such isomers.
[0024] The invention is especially suitable for "on demand"
treatment of gastro-esophageal reflux complaints e.g. heartburn,
where potent acid reduction is needed for a shorter period of time
and where a rapid onset of action is most important and a maximal
acid reduction is to prefer. The maximal acid inhibitory effect
would be able to be maintained during a 7 days period by the
elimination of the "fade-off" phenomenon seen after H2-blocker
given alone. This will be important in order to reduce the time for
the treatment of stomach ulcers, acid related lesions in the
esophagus and Helicobacter pylori eradication.
[0025] According to the invention is provided an oral dosage form
comprising an H2 receptor antagonist in an amount effective to
reduce the acidity in the stomach after administration and an acid
susceptible proton pump inhibitor in an amount effective to sustain
the low acidity effected by the H2 receptor antagonist over an
extended period of time. It is preferred for the pharmacologically
effective amounts to be amounts capable of raising gastric pH to
above 3 within 2 hours from administration and to keep it above 3
for at least 4 hours, preferably for at least 8 hours. It is more
preferred for said pharmacologically effective amounts to be
amounts capable of raising gastric pH to above 4 within two hours
after administration and to keep it above 4 for at least 4 hours,
more preferred for at least 8 hours.
[0026] According to a first preferred aspect of the invention the
H2 receptor antagonist is provided in an amount which is capable of
providing at least 80% of maximal reduction, more preferred at
least 95% of maximal reduction, of the acidity in the stomach
within about two hours. "Maximal reduction" is the reduction of
acidity which can be maximally obtained by administering an H2
receptor antagonist alone in therapeutically accepted amounts, that
is, in amounts in which such drugs are administered in the art. The
term "H2 receptor antagonist(s)" as used herein includes all agents
that substantially inhibitor block the secretion of gastric acid by
binding to a histamine receptor in the stomach. At therapeutic
doses such H2 receptor antagonists are capable not only of
decreasing basal and nocturnal acid secretion, but also secretion
stimulated by food, histamine, insulin and pentagastrin. Exemplary
H2 receptor antagonists according to the invention are cimetidine,
ranitidine, nizatidine and famotidine which are normally used in
form of their pharmacologically acceptable salts, in particular
hydrochlorides. The dosage form of the invention preferably
comprises from 1 mg to 800 mg of H2 receptor antagonist or salt
thereof, more preferred from 5 mg to 400 mg.
[0027] According to a second preferred aspect of the invention the
acid susceptible proton inhibitor is provided in an amount which is
capable of maintaining the low acidity effected by the histamine H2
antagonist over at least 6 hours. Acid susceptible proton pump
inhibitors are rapidly taking market share from H2 receptor
antagonists. The term "acid susceptible proton pump inhibitor(s)",
as used herein, comprises benzimidazole derivatives having
substantial H+,K+-ATPase inhibiting activity, in particular
omeprazole, pantoprazole, lanzoprazole, rabeprazole, pariprazole,
leminoprazole and their pharmaceutically acceptable salts and
enantiomers and salts of enantiomers, but include also the other
compounds disclosed on pages 7-11 of WO 97/25066 which are hereby
incorporated by reference as well as those disclosed in EP 005 129
A1, EP 174 726 A1, EP 166 287 A1, GB 2 163 747, WO 90/06925,
WO91/19711, WO91/19712, WO94/27988, WO95/01977. Omeprazole is known
to offer significant gain over H2 receptor antagonists in terms of
symptom resolution, healing and prevention of relapse.
[0028] Thus the dosage form of the invention comprises preferably
from 1 mg to 100 mg, more preferred from 5 mg to 50 mg, per single
dose of an acid susceptible proton pump inhibitor or a salt
thereof. Preferably the acid susceptible proton pump inhibitor or
salt thereof is separated from the H2 receptor antagonist by an
enteric coating.
[0029] According to a fourth preferred aspect of the invention the
H2 receptor antagonist and the acid susceptible proton pump
inhibitor need not to be comprised by the same pharmaceutical
composition but may be administered separately but within a narrow
time interval, such as a time interval of one hour, in particular a
time interval of 30 min, most preferred a time interval of 10 min.
Thus is disclosed a corresponding dose regimen for separate but
joint administration of an acid susceptible proton pump inhibitor
and an H2 receptor antagonist to treat a condition related to
gastric acid secretion.
[0030] The oral dosage form of the invention thus comprises an acid
susceptible proton pump inhibitor, an H2 receptor antagonist and a
pharmaceutical carrier and, optionally, a gastric acid suppressing
agent and/or an alginate. Preferably, the dosage form, of the
invention comprises from 100 mg to 1000 mg of antacid agent and/or
alginate. The antacid agent of the invention comprises one or
several of aluminum hydroxide, calcium carbonate, magnesium
carbonate, basic magnesium carbonate, magnesium hydroxide,
magnesium oxide, sodium hydrogen carbonate.
[0031] According to a fifth preferred aspect of the invention the
bioavailability of the acid susceptible proton pump inhibitor is
improved for the first three consecutive doses of a dose regimen or
composition of the invention in the treatment of dyspepsia, in
particular the first five consecutive doses, since less proton pump
inhibitor will be degraded during passage of the drug through the
stomach.
[0032] Due to the fact that acid susceptible proton pump inhibitors
are generally sensitive to acid (acid susceptible proton pump
inhibitors) they need to be administered in a form which protects
them from degradation in the stomach to make them pass into the
small intestine where they are absorbed. H2 receptor antagonists,
on the other hand, can be administered without such protection.
According to a further preferred aspect of the invention,
compositions can be adapted to suit the purpose of the present
invention are among those disclosed in WO 97/25066.
[0033] The oral dosage forms of WO 97/25066 comprise an acid
susceptible proton pump inhibitor in an amount similar or identical
to that used in the composition of the present invention, and one
or several antacid agents and/or alginate(s). The adaptation of the
compositions of WO 97/25066 essentially consists in substituting a
pharmacologically effective amount of an H2 receptor antagonist for
a portion of or the entire amount of the antacid agent(s) and/or
alginate.
[0034] According to the invention is provided an oral, multiple
unit tableted dosage form comprising an acid susceptible proton
pump inhibitor in individually enteric coating layered units in
combination with an H2 receptor antagonist in the form of a powder
or granules compressed into a tablet. The enteric coating layer(s)
covering the individual units of the acid susceptible proton pump
inhibitor has properties such that the compression of the units
into a tablet does not significantly affect the acid resistance of
the individually enteric coating layered units. Furthermore, the
multiple unit tableted dosage form provides a good stability to the
active substances during long-term storage.
[0035] According to the invention is also provided a multiple unit
tableted dosage form, which is divisible and easy to handle. Such a
multiple unit tableted dosage form comprises enteric coating
layered pellets of an acid susceptible proton pump inhibitor
compacted with a pulverous H2-antagonist. This dosage form may also
contain effervescent components for making it rapidly disintegrate
when put into water; the pH of the aqueous phase thereby must be
made slightly acidic to prevent dissolution of the enteric layer.
This dosage for can be given to patients with swallowing disorders
and in pediatrics. Such a suspension of dispersed units/pellets of
appropriate size can be used for oral administration and also for
feeding through a naso-gastric tube.
[0036] According to the invention is also provided a tablet
preparation comprising an acid susceptible proton pump inhibitor in
admixture with tablet excipients forming a tablet core which is
enterically coated, and a separate layer surrounding the tablet
core. The surrounding layer comprises an H2 receptor antagonist in
admixture with a pharmaceutical carrier. Optionally a separating
layer is applied on the tablet core before the core is enteric
coating layered. Alternatively, the prepared tablet is sectioned in
separate layers, each one comprising different active substances.
One of the layers, preferably the innermost layer (core), comprises
the acid susceptible proton pump inhibitor in the form of enteric
coating layered pellets in admixture with pharmaceutical excipients
and the other layer(s) comprise(s) the histamine H2-antagonist(s),
respectively in admixture with pharmaceutical excipient(s).
Optionally the two layers are separated by a separating layer to
prevent tacking between the two layers. The core comprising the
acid susceptible proton pump inhibitor may also be advantageously
coated directly with an enteric layer by following, for instance,
procedures disclosed in WO 00/78284 which is incorporated herein by
reference.
[0037] According to the invention the acid susceptible proton pump
inhibitor in the form of enteric coating layered pellets may be
mixed with histamine H2-antagonist(s) and optionally pharmaceutical
excipient(s) to be administered in a sachet intended for oral
administration after dispersion in a slightly acidic aqueous
solution.
[0038] It is thus preferred for the dosage form of the invention to
comprise the acid susceptible proton pump inhibitor or a salt
thereof protected by an enteric coating layer and, optionally, a
layer separating it from the enteric coating. Preferably the dosage
form of the invention comprises two concentric layers optionally
separated by one or more separating layer(s), one layer comprising
said acid susceptible proton pump inhibitor or salt thereof, the
other layer comprising said H2 receptor antagonist or salt thereof.
The inner layer comprises the acid susceptible proton pump
inhibitor or salt thereof and the outer layer comprises the H2
receptor antagonist or salt thereof. According to the invention it
is also possible for the outer layer to comprise the acid
susceptible proton pump inhibitor or salt thereof and fort the
inner layer to comprise the H2 receptor antagonist or salt thereof.
According to a preferred aspect the inner layer comprises a
disintegrant. The oral dosage form of the invention may take
different shapes, such as a tablet, a capsule, a divided
powder/pellet formulation, and the like.
[0039] According to the invention is also disclosed a method for
the manufacture of an oral tableted dosage form comprising amounts
of an acid susceptible proton pump inhibitor or salt thereof and an
H2 receptor antagonist or salt thereof pharmacologically effective
in treating a condition related to dyspepsia, the method comprising
forming a first layer comprising said acid susceptible proton pump
inhibitor or salt thereof, an enteric coat surrounding said first
layer, and a second layer comprising said H2 receptor antagonist or
salt thereof surrounding said first layer and said enteric coat.
Also disclosed is a method for the manufacture of an oral dosage
form comprising amounts of an acid susceptible proton pump
inhibitor or salt thereof and an H2 receptor antagonist or salt
thereof pharmacologically effective in treating a condition related
to dyspepsia, the method comprising forming pellets comprising said
acid susceptible proton pump inhibitor or salt thereof, covering
said pellets with enteric coat, and mixing said pellets covered
with said enteric coat with a carrier comprising said H2 receptor
antagonist or salt thereof; the carrier may comprise a
disintegrant. The aforementioned methods of the invention further
comprise a final tablet forming step, possibly followed by a
film-covering step.
[0040] Another method for the manufacture of the oral dosage form
of the invention comprises filling a capsule capable of
disintegrating in gastrointestinal fluids to release its contents
with the mixture comprising enteric proton pump inhibitor pellets
and a H2 receptor antagonist in powderous or granular form.
[0041] A further method for the manufacture of the oral dosage form
of the invention comprises forming a layer comprising an acid
susceptible proton pump inhibitor or salt thereof and an H2
receptor antagonist or salt thereof, and covering said layer with
an enteric coat.
[0042] A still further method for the manufacture of the oral
dosage form of the invention comprises forming a mixture comprising
an acid susceptible proton pump inhibitor or salt thereof and an H2
receptor antagonist or salt thereof, filling the mixture in a
capsule capable of disintegrating in gastrointestinal fluids to
release its contents, and covering the capsule with an enteric
coat.
[0043] The use of the pharmaceutical dosage form of the invention
is however not restricted to provide quick and lasting relief to a
patient suffering from conditions related to gastric acid
secretion. The rapid onset of inhibition of gastric acid secretion
combined with the maintenance of inhibition as long as desired (by
repeated administration of a composition comprising an acid
susceptible proton pump inhibitor, preferably by repeated
administration of the composition of the invention) can be expected
to have a positive effect on the healing of esophagitis for which
the maintenance of intra-gastric pH above 4 for a maximal duration
is acknowledged (Huang J. Q and Hunt R H, pH, healing rate and
symptom relief in patients with GERD, Yale J Biol Med 1999,
72:181-94). The composition of the invention thus is also preferred
for maintaining gastric pH above 4 for extended periods of time,
such as 4 hours and more.
[0044] According to the invention the aforementioned mixture
comprising an acid susceptible proton pump inhibitor or salt
thereof and an H2 receptor antagonist or salt thereof can be used
for the manufacture of a medicament for the treatment of a disorder
associated with gastric acid secretion.
[0045] The dosage form of the invention can also be used, in
association with one or more antibiotic agent(s), for the
eradication of Helicobacter pylori.
[0046] According to the invention is also disclosed a method of
treating disorders associated with gastric acid secretion, the
method comprising the administration of the dosage form of the
invention or the concomitant administration of two separate oral
dosage forms, one comprising a pharmacologically effective amount
of an acid susceptible proton pump inhibitor or salt thereof, the
other comprising a pharmacologically effective amount of an H2
receptor antagonist or salt thereof.
[0047] Furthermore, according to the invention is disclosed a
method of treating an infection by Helicobacter pylori, comprising
the administration of the dosage form of the invention or the
concomitant administration of two separate oral dosage forms, one
comprising a pharmacologically effective amount of an acid
susceptible proton inhibitor or salt thereof, the other comprising
a pharmacologically effective amount of an H2 receptor antagonist
or salt thereof, in association with the administration of one or
more antibiotic agent(s) effective against H. pylori.
[0048] It is preferred for the aforementioned methods of treatment
according to the invention to comprise a dose regimen capable of
maintaining gastric pH above 4 for at least 95% of the time period
starting at 2 hours from the administration of the first dose and
extending until 6 hours from the administration of the last dose,
in particular a regiment wherein the time period is one week or
more, preferably two weeks or more, even more preferred four weeks
or more. Also preferred in this context is a dose regimen capable
of maintaining gastric pH above 3 for at least 95% of the time
period starting at 2 hours from the administration of the first
dose and extending until 6 hours from the administration of the
last dose, in particular for four weeks or more.
[0049] The invention will now be described in greater detail by
reference to a number of preferred but not limiting embodiments
illustrated in a drawing.
BRIEF DESCRIPTION OF THE FIGURES
[0050] FIGS. 1-6 are schematic cross sections illustrating:
[0051] FIG. 1 a multiple unit tableted dosage form comprising an
acid susceptible proton pump inhibitor in the form of enteric
coating layered pellets in admixture with an H2-receptor antagonist
dispersed in a pharmaceutical carrier;
[0052] FIG. 2 a tableted dosage form consisting of two halves, one
of which comprises enteric coating layered pellets of an acid
susceptible proton pump inhibitor in admixture with excipients
whereas the other comprises an H2 receptor antagonist in admixture
with excipients;
[0053] FIG. 3 a multiple-layered tableted dosage form comprising an
acid susceptible proton pump inhibitor in a core surrounded by an
enteric coating layer and a layer containing an H2 receptor
antagonist dispersed in a pharmaceutical carrier surrounding the
core;
[0054] FIG. 4 a tableted dosage form comprising an acid susceptible
proton pump inhibitor, an H2-receptor antagonist and excipients in
admixture, provided with an enteric coating;
[0055] FIG. 5 a capsule dosage form containing an acid susceptible
proton pump inhibitor in enteric coating layered pellets in
admixture with an H2 receptor antagonist and pharmaceutical
excipients;
[0056] FIG. 6 an acid resistant capsule dosage form containing an
acid susceptible proton pump inhibitor, an H2 receptor antagonist
and excipients;
[0057] FIG. 7 is a diagram of the gastric pH trace in a person
after administration of a conventional omeprazole oral dosage
form;
[0058] FIG. 8 is a diagram of the gastric pH trace in the same
person after joint administration of omeprazole and famotidine
according to the invention.
DESCRIPTION OF PREFERRED EMBODIMENTS
[0059] Multiple unit tableted dosage form. The multiple unit
tableted dosage form of the invention illustrated in FIG. 1
consists of a tablet body 1 optionally covered by a film layer 3
and small pellets 2 distributed at random in the tablet body 2. The
pellets 2 contain an acid susceptible proton pump inhibitor in form
of the racemate, an alkaline salt or one of its enantiomers. The
individually enteric coating layered units 2 (small beads, granules
or pellets) containing the acid susceptible proton pump inhibitor
and optionally containing alkaline substances, are mixed with the
H2 receptor antagonist and conventional tablet excipients forming,
in combination, the tablet body 1. The H2 receptor antagonist and
tablet excipients may be dry mixed or wet mixed into granules. The
mixture of enteric coated layered units, H2 receptor antagonist and
excipients are compressed into the multiple unit tableted dosage
forms. By the expression "individual units" is meant small beads,
granules or pellets, in the following referred to as proton pump
inhibitor pellets. In compressing the mixture into tablets, care
must be taken not to significantly affect the acid resistance of
the enteric coated layered pellets. In regard of the core material
for enteric coating layered pellets comprising an acid susceptible
proton pump inhibitor reference is made to WO 97/25066, page 13,
next but last paragraph, to page 15, end of second paragraph, which
are hereby incorporated by reference. In regard of the enteric
coating layer(s) reference is made to WO 97/25066, page 15, next
but last paragraph, to page 18, end of second paragraph, which are
hereby incorporated by reference. The acid susceptible proton pump
inhibitor pellets covered with enteric coating layer(s) may be
further covered with one or more over-coating layers. In regard of
such over-coating layer(s) reference is made to WO 97/25066, page
18, last paragraph, to page 19, end of first paragraph, which are
hereby incorporated by reference. The H2 receptor antagonist is dry
mixed with inactive excipients such as filler, binders,
disintegrants, and other pharmaceutically acceptable additives. The
mixture is wet massed with a granulation liquid. The wet mass is
dried preferably to a loss on drying of less than 3% by weight.
Then the dry mass is milled to a suitable size for granules,
preferably smaller than 1 mm. Suitable inactive excipients are, for
instance, mannitol, corn starch, potato starch, low substituted
hydroxypropyl cellulose, microcrystalline cellulose and crosslinked
polyvinylpyrrolidone. The dry mixture comprising the H2 receptor
antagonist may be mixed with a suitable granulation liquid
comprising, for instance, hydroxypropylcellulose or
polyvinyl-pyrrolidone dissolved in water or alcohol or their
mixtures. Alternatively the H2 receptor antagonist is dry mixed
with pharmaceutically acceptable excipients (see supra).
[0060] Multi unit tablets. The enteric coated layer pellets
comprising an acid susceptible proton pump inhibitor are mixed with
the H2 receptor antagonist granules or with the prepared dry
mixture comprising the H2 receptor antagonist. The mixture is
admixed with lubricant(s) and compressed into a multiple unit
tableted dosage form. Suitable lubricants for the tableting process
are, for instance, sodium stearyl fumarate, magnesium stearate and
talc. The compressed tablets are optionally covered with
filmforming agent(s) to obtain a smooth surface. Such coating layer
may further comprise additives such as anti-tacking agents,
colorants and pigments or other additives.
[0061] The fraction of enteric coating layered pellets constitutes
preferably less than 60% by weight of the total tablet weight. The
preferred multiple unit table formulation thus consists of enteric
coated layered pellets comprising the acid susceptible proton pump
inhibitor, optionally in admixture with alkaline reacting
compound(s), compressed into tablets with the prepared H2 receptor
antagonist/excipient(s) mixture. The enteric coating layer(s)
make(s) the pellets of the dosage form insoluble in acidic media
but disintegrating/dissolving in near neutral to alkaline media
such as, for instance, the gastric fluid present in the proximal
part of the small intestine where the dissolution and uptake of the
acid susceptible proton pump inhibitor is desired. The enteric
coating layered proton pump inhibitor pellets may also be covered
with an overcoating layer before being formulated into tablets, and
they may also contain one or more separating layer(s) in between
the core material and the enteric coating layer(s).
[0062] Process for making multi-unit tablets. The process for the
manufacture of the dosage form represents a further aspect of the
invention. After formulating the pellets by dry mixing (ordered
mixture), spray coating or layering of the acid susceptible proton
pump inhibitor onto seeds, or by extrusion/spheronization or
granulation, the pellets are first optionally covered with the
separating layer(s) and then with the enteric coating layer(s), or
a separating layer is spontaneously developed in situ between the
core material and the enteric coating layer material. The coating
is carried out as described above and in the accompanying
examples.
[0063] The preparation of the H2 receptor antagonist mixture is
also described in the examples.
[0064] The enteric coating layered pellets, with or without an
overcoat, are mixed with the prepared H2 receptor antagonist
granules or dry powder, tablet excipients and other
pharmaceutically acceptable additives and compressed into tablets.
Alternatively, the enteric coated proton pump inhibitor pellets may
be covered by a second layer containing the H2 receptor antagonist
as described in the following examples. Furthermore, as illustrated
in FIG. 2, the enteric coating layered pellets 4 may be intimately
mixed with excipients 5 and precompressed and further layered with
the H2 receptor antagonist preparation 7 and finally compressed
into a tablet, optionally with film-forming agent(s) 6 to obtain a
smooth surface. As a further alternative illustrated in FIG. 3 the
acid susceptible proton pump inhibitor in form of a powder may be
mixed with tablet excipients and compressed into a tablet 8 which
is optionally layered with a separating layer and thereafter
enteric coating 9 layered. The thus produced tablet core is
presscoated with the H2 receptor antagonist preparation 10. Finally
the table may be covered with a tablet coat 11 to obtain a smooth
surface.
[0065] It is also possible to fill the acid susceptible proton pump
inhibitor in form of enteric coated layered pellets in a sachet
together with H2 receptor antagonist optionally mixed with
excipients.
[0066] FIG. 4 illustrates a tableted dosage form with a core 12
comprising an acid susceptible proton pump inhibitor and an H2
receptor antagonist dispersed in a pharmaceutical carrier, the core
12 being surrounded by an enteric coat 13.
[0067] FIG. 5 illustrates a hard gelatin capsule 16 filled with the
uncompressed core material 14, 15 of the embodiment of FIG. 1.
[0068] FIG. 6 illustrates a hard gelatin capsule 18 comprising an
enteric coat filled with the uncompressed core material 17 of the
embodiment of FIG. 4.
[0069] In general, the methods of WO 97/25066 for making oral
pharmaceutical dosage forms comprising an acid susceptible proton
pump inhibitor and an antacid agent or alginate can be adapted to
suit the purpose of the invention by substituting part or the
entire amount of antacid agent or alginate by a pharmacologically
effective amount of an H2 receptor antagonist, the remainder of the
antacid agent or alginate (if substitution is not 1:1 by weight)
being omitted or substituted by excipients like microcrystalline
cellulose, silica, lactose, mannitol, and the like.
[0070] Use of the Dosage Forms According to the Invention.
[0071] The dosage forms according to the invention are especially
advantageous in the treatment of dyspepsia and other
gastrointestinal disorders related to the production of gastric
acid to provide quick and lasting relief from symptoms. The dosage
forms are administered once or several times a day. The typical
daily dose of the acid susceptible proton pump inhibitor and the H2
receptor antagonist will depend on various factors such as
individual requirements of patients, the mode of administration,
and the particular condition to be treated. In general each dosage
form will comprise from 1 mg to 100 mg of acid susceptible proton
pump inhibitor and from 1 to BOO mg of the H2 receptor antagonist.
Preferably each dosage form will comprise from 5 to 50 mg of the
acid susceptible proton pump inhibitor and from 5 to 200 mg of the
H2 receptor antagonist. The multiple unit tablet preparation is
also suitable for dispersion in water which had been made slightly
acidic by the addition of citric acid.
Example 1
[0072] Multiple unit tableted dosage form comprising magnesium
omeprazole and ranitidine hydrochloride; batch size 400 tablets.
For omeprazole Mg-salt pellet production (core material, separating
layer, enteric coating layer and over-coating layer, see WO
97/25066, p. 22-23 under respective headings), see WO 97/25066,
first two paragraphs, all of which is hereby incorporated by
reference.
Tablets
TABLE-US-00001 [0073] Prepared pellets comprising omeprazole
Mg-salt 31.3 g Microcrystalline cellulose 300.0 g Cimetidine
hydrochloride 40.0 g Potato starch 50.0 g Water 200.0 g PVP
crosslinked 38.0 g Sodium stearyl fumarate 4.6 g
[0074] A small amount of the potato starch is dissolved in purified
hot water to form the granulation liquid. Cimetidine hydrochloride,
the rest of potato starch and microcrystalline cellulose are dry
mixed. The granulation liquid is added to the dry mixture and the
mass is wet mixed. The wet mass is dried in an oven at 50.degree.
C. The prepared granulation is milled through sieve 1 mm in an
oscillating mill equipment. The enteric coating layered pellets
with an over-coating layer, the prepared receptor antagonist
granules, crosslinked polyvinylpyrrolidone and sodium stearyl
fumarate are mixed and compressed into tablets using a tableting
machine equipped with oval punches. The amount of omeprazole in
each tablet is approx. 10 mg and the amount of cimetidine
hydrochloride is approx. 100 mg.
[0075] By a slight modification this multiple unit tablet form can
be made to comprise an antacid agent (instead of microcrystalline
cellulose, 300 mg: microcrystalline cellulose, 100 g; calcium
carbonate, 100 mg; magnesium oxide, 100 mg; all other constituents,
except water, in the amounts given above).
Example 2
[0076] Three-layered tableted dosage form. The tablet comprises the
acid susceptible proton pump inhibitor omeprazole, a separating
layer and a core layer comprising cimetidine hydrochloride. Batch
size 1000 tablets.
First Tablet Layer
TABLE-US-00002 [0077] Cimetidine hydrochloride 200.0 g
Microcrystalline cellulose 250.0 g PVP crosslinked 13.0 g Sodium
stearyl fumarate 3.8 g
Separating Layer
TABLE-US-00003 [0078] Microcrystalline cellulose 80.0 g
Second Tablet Layer
TABLE-US-00004 [0079] Enteric coating layered pellets comprising
78.3 g omeprazole magnesium salt (same as in EXAMPLE 1)
Microcrystalline cellulose 174.0 g PVP crosslinked 26.0 g 10 Sodium
stearyl fumarate 1.4 g
[0080] The constituents of the first tablet layer are dry mixed and
precompressed as a first layer in a tableting machine equipped with
oval punches. Microcrystalline cellulose is filled on the top of
the first layer to form a separating layer to the next layer. The
constituents of the second tablet layer are dry mixed and filled on
top of the separating layer. The three layers are compressed into a
three layer tablet which may be coated by a tablet coating layer.
The amount of omeprazole is approx. 10 mg and that of cimetidine
hydrochloride approx. 200 mg per tablet.
Example 3
[0081] Capsule dosage form. No. 1 hard gelatin capsules (16) (FIG.
5; volume 0.48 ml) were filled with enteric coated omeprazole
pellets (15) containing 20 mg omeprazole recovered from
commercially available omeprazole (Losec.RTM.) capsules and a dry
mixture 14 of commercially available famotidine 20 mg for injection
(Pepcidin.RTM.; containing 20 mg famotidine hydrochloride, 8 mg
aspartic acid and 40 mg mannitol), and closed.
Example 4
[0082] Divided powder/pellet formulation. Enteric pellets
containing 15 mg lansoprazole recovered from commercially available
capsules (Lanzo.RTM., enterocapsules) and the famotidine
preparation for injection of EXAMPLE 4 were dry mixed with citric
acid. Single dose portions thereof containing 10 mg each of
lansoprazole and famotidine hydrochloride and 200 mg powderous
citric acid were dry packed in plastic laminate. The composition is
intended to be poured into 20 ml of water, stirred for a short
time, and swallowed.
Example 5
[0083] Multiple unit capsule dosage form. The tabled comprises
magnesium omeprazole and famotidine hydrochloride. For enteric
coating layer and over-coating layer, see WO 97/25066, page 22-23
under respective headings, the information under which is hereby
incorporated by reference.
[0084] Magnesium omeprazole is mixed with microcrystalline
cellulose spheres to an ordered mixture. The ordered mixture is
coated with an enteric coating layer consisting of methacrylic acid
copolymer, mono- and diglycerides, triethyl citrate and polysorbate
in a fluid bed apparatus. The enteric coated ordered mixture is
then over-coated with a water suspension containing famotidine
hydrochloride, hydroxypropylmethyl cellulose and magnesium stearate
in a fluid bed apparatus. The enteric coated ordered mixture with
an over-coating layer was filled in hard gelatin capsules. The
amount of omeprazole is approx. 10 mg and that of famotidine
hydrochloride approx. 20 mg per capsule.
Example 7
[0085] Multiple unit tableted dosage form comprising magnesium
omeprazole and cimetidine hydrochloride. Magnesium omeprazole is
mixed with microcrystalline cellulose spheres to an ordered mixture
which is coated with an enteric coating layer as described in
EXAMPLE 6. Cimetidine hydrochloride is granulated as described in
EXAMPLE 1 . The enteric coated ordered mixture comprising magnesium
omeprazole, the cimetidine granules and excipients are dry mixed
and compressed into tablets. The amount of omeprazole in each
tablet is approx. 10 mg and that of cimetidine is approx. 100
mg.
Example 8
[0086] Inhibition of gastric acid secretion. A healthy subject
(male, 31 years of age, having fasted for 10 hours) was provided
with a double lumen nasogastric tube through one nasal passage and
with a microelectrode for pH registration through the second nasal
passage. A two point calibration of the electrode was performed
before and after each 24 h recording, using standard buffers of pH
7.0 and 1.7. The electrode was placed 10 cm below the lower
esophagal sphincter during the pH recording and the position marked
on the electrode lead to ensure proper positioning during
consecutive recordings. A commercially available omeprazole
(Losec.RTM.) capsule containing 20 mg omeprazole was carefully
opened and the contents (pellets) placed in a plastic syringe which
had been put into communication with one of the lumina of the
nasogastric tube. The syringe was filled with 20 ml tap water and
the pellets injected through the nasogastric tube immediately
thereafter. The syringe was flushed with 20 ml water. The gastric
pH trace recorded by the microelectrode during a period of more
than four hours is illustrated in FIG. 7. In a second experiment 10
the syringe was filled with the same amount of omeprazole
micropellets and famotidine 20 mg for injection (Pepcidin.RTM.;
containing 20 mg famotidine, 8 mg aspartic acid and 40 mg
mannitol), the procedure of injection and measurement being the
same as with omeprazole. The gastric pH trace for the combination
is illustrated in FIG. 8. The experiments demonstrate that a
reduction of pH to about 6 is obtained with the
omeprazole/famotidine within about 2 hours and maintained until the
end of recording (4 hours from injection) whereas with omeprazole
alone no increase in pH can be noted after 4 hours from
injection.
* * * * *