U.S. patent application number 13/621423 was filed with the patent office on 2013-01-17 for gastric acid secretion inhibiting composition.
This patent application is currently assigned to OREXO AB. The applicant listed for this patent is YVONNE HAKANSSON, CHRISTER NYSTROM, ANDERS PETTERSSON. Invention is credited to YVONNE HAKANSSON, CHRISTER NYSTROM, ANDERS PETTERSSON.
Application Number | 20130017263 13/621423 |
Document ID | / |
Family ID | 20289290 |
Filed Date | 2013-01-17 |
United States Patent
Application |
20130017263 |
Kind Code |
A1 |
PETTERSSON; ANDERS ; et
al. |
January 17, 2013 |
GASTRIC ACID SECRETION INHIBITING COMPOSITION
Abstract
An oral pharmaceutical dosage form comprises pharmacologically
effective amounts of an acid-susceptible proton pump inhibitor and
an H2 receptor antagonist in combination with at least on
pharmacologically acceptable excipient which causes a delayed
release and/or an extended release of the proton pump inhibitor.
The H2 receptor antagonist is included in the dosage form in such a
way that it is rapidly released after administration. This dosage
form is suitable for the treatment of conditions associated with an
excessive secretion of gastric acid and provides a suitable
combination of a rapid onset and a long-lasting duration of the
effect. The invention also relates to a method for manufacturing
such a dosage form and to a method for the treatment of conditions
associated with the secretion of gastric acid.
Inventors: |
PETTERSSON; ANDERS; (Lilla
EDT, SE) ; NYSTROM; CHRISTER; (UPPSALA, SE) ;
HAKANSSON; YVONNE; (UPPSALA, SE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PETTERSSON; ANDERS
NYSTROM; CHRISTER
HAKANSSON; YVONNE |
Lilla EDT
UPPSALA
UPPSALA |
|
SE
SE
SE |
|
|
Assignee: |
OREXO AB
UPPSALA
SE
|
Family ID: |
20289290 |
Appl. No.: |
13/621423 |
Filed: |
September 17, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13355935 |
Jan 23, 2012 |
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13621423 |
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12660056 |
Feb 19, 2010 |
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13355935 |
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11544750 |
Oct 10, 2006 |
7771747 |
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12660056 |
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10531598 |
Nov 25, 2005 |
7785626 |
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PCT/SE2003/001598 |
Oct 15, 2003 |
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11544750 |
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Current U.S.
Class: |
424/484 ;
424/400; 424/490; 424/686; 424/687; 424/690; 424/692; 424/715;
427/2.14; 514/338 |
Current CPC
Class: |
A61P 31/04 20180101;
A61K 31/426 20130101; A61K 9/1676 20130101; A61K 9/5078 20130101;
A61P 1/14 20180101; A61K 45/06 20130101; A61K 2300/00 20130101;
A61K 9/209 20130101; A61K 31/4439 20130101; A61P 1/04 20180101;
A61K 31/341 20130101; A61K 31/4164 20130101; A61K 31/426 20130101;
A61K 2300/00 20130101; A61K 31/4164 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 31/341 20130101; A61K 9/5084
20130101; A61K 9/4808 20130101; A61K 9/2081 20130101; A61K 9/167
20130101; A61K 9/0095 20130101; A61K 31/4439 20130101; A61K 9/5073
20130101; A61P 43/00 20180101 |
Class at
Publication: |
424/484 ;
514/338; 424/400; 424/490; 424/686; 424/687; 424/690; 424/692;
424/715; 427/2.14 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 9/14 20060101 A61K009/14; A61P 1/04 20060101
A61P001/04; B05D 7/00 20060101 B05D007/00; A61K 33/10 20060101
A61K033/10; A61K 33/08 20060101 A61K033/08; A61K 33/00 20060101
A61K033/00; A61K 31/4439 20060101 A61K031/4439; A61P 31/04 20060101
A61P031/04 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 16, 2002 |
SE |
0203065-8 |
Claims
1. 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
at least one pharmaceutically acceptable excipient(s) which results
in a delayed release and/or extended release of the
acid-susceptible proton pump inhibitor or the salt thereof, and
said H2 receptor antagonist or the salt thereof is included in such
a way that it is rapidly released from said dosage form.
2. The dosage form of claim 1, wherein the acid-susceptible proton
pump inhibitor is selected from lansoprazole, omeprazole,
pantoprazole, rabeprazole, pariprazole, leminoprazole, their
pharmaceutically acceptable salts, enantiomers and salts of
enantiomers.
3. The dosage form of claim 1, comprising from 1 mg to 100 mg of
the acid-susceptible proton pump inhibitor or a salt thereof per
single dose.
4. The dosage form of claim 1, wherein the H2 receptor antagonist
is selected from cimetidine, ranitidine, nizatidine and famotidine,
their pharmaceutically acceptable salts, isomers and salts of
isomers.
5. The dosage form of claim 4, comprising from 1 mg to 800 mg of H2
receptor antagonist or salt thereof.
6. The dosage form of claim 1, wherein the excipient(s) exerts the
release controlling activity in the form of a membrane applied onto
a core comprising the acid-susceptible proton pump inhibitor or a
salt thereof, or in the form of a matrix system where the
acid-susceptible proton pump inhibitor or a salt thereof is
incorporated into the excipient(s).
7. The dosage form of claim 1, wherein the H2 receptor antagonist
or a salt thereof forms an outer layer applied onto a core
comprising the acid-susceptible proton pump inhibitor or a salt
thereof and excipients, wherein the core forms a matrix or membrane
system, capable of delayed and/or extended release of the
acid-susceptible proton pump inhibitor or a salt thereof.
8. The dosage form of claim 1, wherein the excipient(s) used to
form the membrane or matrix are inert or lipid.
9. The dosage form of claim 8, wherein the inert excipient(s) are
non-polymeric- or polymeric materials such as calcium phosphate,
ethyl cellulose, methacrylate copolymer, polyamide, polyethylene,
polyvinyl alcohol or polyvinyl acetate.
10. The dosage form of claim 8, wherein the lipid excipient(s) are
non-polymeric- or polymeric materials such as carnauba wax, cetyl
alcohol, hydrogenated vegetable oils, microcrystalline waxes, mono-
and triglycerides, polyethylene glycol or polyethylene glycol
monostearate.
11. The dosage form of claim 9, wherein additional hydrophilic
excipient(s) are used, such as alginates, carbopol, gelatin,
hydroxypropyl cellulose, hydroxypropyl metylcellulose or
metylcellulose.
12. The dosage form of claim 6, wherein an enteric coating layer is
applied onto the membrane or matrix system and, optionally, a layer
separating the enteric coating from the membrane or matrix
system.
13. The dosage form of claim 6, wherein an alkaline-reacting
substance is admixed together with the acid-susceptible proton pump
inhibitor or the salt thereof.
14. The dosage form of claim 1, wherein said pharmacologically
effective amounts are amounts capable to raise gastric pH to above
4 within two hours after administration and to keep it above 4 for
at least 4 hours.
15. The dosage form of claim 14, wherein said amounts are capable
to keep gastric pH above 4 for at least 8 hours.
16. The dosage form of claim 14, wherein said pharmacologically
effective amounts are amounts capable to raise gastric pH to above
3 within 2 hours from administration and to keep it above 3 for at
least 4 hours.
17. The dosage form of claim 16, wherein said amounts are amounts
capable to keep gastric pH above 3 for at least 8 hours.
18. The dosage form of claim 1, comprising from 100 mg to 1000 mg
of antacid agent and/or alginate.
19. The dosage form of claim 18, wherein the antacid agent
comprises one or several of aluminum hydroxide, calcium carbonate,
magnesium carbonate, basic magnesium carbonate, magnesium
hydroxide, magnesium oxide, sodium hydrogen carbonate.
20. The dosage form of claim 1, wherein the acid-susceptible proton
pump inhibitor or a salt thereof and excipients, together forming a
membrane or matrix system, are present in the form of a
multiple-unit system consisting of a plurality of small units,
consisting of pellets, granules or beads.
21. The dosage form of claim 20, wherein the small units in the
multiple-unit system also contain an outer layer of a H2 receptor
antagonist or a salt thereof.
22. The dosage form of claim 20, wherein the small units are
dispersed in a H2 receptor antagonist or a salt thereof, optionally
admixed with pharmaceutically acceptable excipients, such as
disintegrant(s).
23. The dosage form of claim 1, comprising two halves, one of which
comprising an acid-susceptible proton pump inhibitor or a salt
thereof in admixture with excipients capable of forming a matrix or
membrane system and the other half comprising an H2 receptor
antagonist or a salt thereof, optionally admixed with
pharmaceutically acceptable excipients, such as
disintegrant(s).
24. A capsule according to claim 1.
25. A divided powder/pellet formulation according to claim 1.
26. A tablet according to claim 1.
27. The tablet of claim 26, being divisible.
28. The tablet of claim 26, being dispersible in water.
29. The tablet of claim 28, comprising a disintegrant.
30. A method for the manufacture of 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 at least one
pharmaceutically acceptable excipient which results in a delayed
release and/or extended release of the acid-susceptible proton pump
inhibitor or the salt thereof, and said H2 receptor antagonist or
the salt thereof is included in such a way that it is rapidly
released from said dosage form, said method comprising forming a
first layer comprising said acid-susceptible proton pump inhibitor
or salt thereof, and forming a coating thereon of said at least one
excipient, and forming a second layer comprising said H2 receptor
antagonist or salt thereof surrounding said first layer and said
coating, and subsequently formulating the combined product of said
first layer, said coating and said second layer into an oral
pharmaceutical dosage form.
31. A method according to claim 30, wherein said acid-susceptible
proton pump inhibitor is enclosed in said least one excipient, said
excipient forming a lipid or water-insoluble matrix.
32. A method according to claim 30, wherein said first layer is
formed to pellets, which are subsequently coated with said at least
one excipient and are subsequently mixed with a carrier comprising
said H2 receptor antagonist or salt thereof.
33. A method according to claim 32, wherein said carrier comprises
a pharmacological disintegrant.
34. A method according to claim 30, wherein said combined product
is formulated into a tablet.
35. A method according to claim 30, wherein said combined product
is formulated into a capsule capable of disintegrating in
gastro-intestinal fluids.
36. A method according to claim 30, wherein said oral
pharmaceutical dosage form is provided with an enteric coating.
37. A method according to claim 30, wherein said acid-susceptible
proton pump inhibitor is selected from the group consisting of
lansoprazole, omeprazole, pantoprazole, rabeprazole, pariprazole,
lemiprazole and their pharmaceutically acceptable salts,
enantiomers and salts of enantiomers.
38. A method according to claim 30, wherein said H2 receptor
antagonist is selected from the group consisting of cimetidine,
ranitidine, nizatidine, famotidine and their pharmaceutically
acceptable salts, isomers and salts of isomers.
39. Use of an oral pharmaceutical dosage form according to claim 1,
for the manufacture of a medicament for the treatment of conditions
associated with the secretion of gastric acid.
40. Use of an oral pharmaceutical dosage form according to claim 1
in association with one or more antibiotic agents for the
eradication of Helicobacter pylori.
41. A method of treating a condition associated with the secretion
of gastric acid, wherein an oral pharmaceutical dosage form
according to claim 19 is administered in a therapeutically
effective amount to an individual human or animal afflicted with
said condition.
42. A method for treating an infection by Helicobacter pylori,
wherein an oral pharmaceutical dosage form according to claim 1 in
association with one or more antibiotic agents effective against H.
pylori is administered in a therapeutically effective amount to an
individual or human afflicted with said infection.
43. A method according to claim 41, wherein said oral
pharmaceutical dosage form is administered concomitantly as two
separate oral dosage forms, one comprising a pharmacologically
effective amount of said acid-susceptible proton pump inhibitor or
salt thereof, and the other comprising a pharmacologically
effective amount of said H2 receptor antagonist or salt
thereof.
44. A method according to claim 41, comprising a dose regimen
capable of maintaining gastric pH above 4 for at least 95% of a
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.
45. A method according to claim 44, wherein said time period is at
least one week.
46. A method according to claim 44, wherein said time period is at
least two weeks.
47. A method according to claim 44, wherein said time period is at
least four weeks.
48. A method according to claim 41, comprising a dose regimen
capable of maintaining gastric pH above 3 for at least 95% of a
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 at least four weeks.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of co-pending patent
application Ser. No. 13/355,935 filed 23 Jan. 2012, which is a
continuation of patent application Ser. No. 12/660,056 filed 29
Feb. 2010, which is a continuation of application Ser. No.
11/544,750 filed 10 Oct. 2006, which is a continuation of
application Ser. No. 10/531,598 filed 25 Nov. 2005, which is a 371
of PCT/SE2003/001598 filed 15 Oct. 2003.
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] During the latest decades, much progression has been made in
the suppression of acid secretion, an integral part of the
treatment of dyspeptic disorders such as gastro-oesophageal reflux
disease (GORD), duodenal and gastric ulcers and non-ulcer
dyspepsia. Although the pathophysiology of these disorders is not
identical, the inhibition of gastric acid secretion is pivotal to
healing organic lesions, alleviating symptoms of discomfort and
improving the quality of life. Moreover, acid-related damage may
underlie the progression to cancers and other late complications of
these conditions. Inhibition of acid secretion is also a
cornerstone in the treatment regimens aiming for eradication of
Helicobacter pylori infection.
[0004] 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.
[0005] 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.
[0006] Dyspepsia can be controlled by administration of medicines
that raise 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.
[0007] 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 oesophagitis. 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.
[0008] 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 their 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. Moreover, these
agents are not at all useful in the treatment of acid induced
organic lesions, GORD or Helicobacter pylori infection.
[0009] Several classes of compounds are known which affect the
secretion of gastric acid. Among them, acid susceptible proton pump
inhibitors, such as the substituted benzimidazoles omeprazole,
lanzoprazole, rabeprazole and pantoprazole and histamine H2
receptor antagonists, such as cimetidine, ranitidine and famotidine
are the most prominent ones. H2 receptor and acid susceptible
proton pump inhibitors are widely prescribed for reducing gastric
acid secretion systemically.
[0010] The design of acid suppression therapy requires a detailed
understanding of the mechanisms behind the secretion of hydrogen
ions, namely the parietal cell and hydrogen-potassium adenosine
triphosphate (H+, K+-ATPase) so that these mechanisms can be
effectively targeted with pharmacological intervention. Three key
factors have been identified in order to achieve an effective
pharmacological treatment of acid related disorders (Dig Dis Sci
1995 vol 40: 24S-49S. Optimizing acid suppression for treatment of
acid-related diseases.):
[0011] 1) Time to onset of action, i.e. the inhibition of acid
secretion should occur as rapidly as possible.
[0012] 2) Degree of acid inhibition, i.e. the intragastric pH
should be kept well above 4.
[0013] 3) Duration of action, i.e. the inhibition of acid secretion
should remain virtually complete during 24 hours on the first dose
and remain complete during the course of treatment.
[0014] All of these factors must be considered when deciding how to
optimize said suppressive therapy. However, several aspects of the
parietal cell physiology and the pharmacology/biochemistry of
existing pharmaceuticals have to date prevented the achievement of
this goal.
[0015] Central to the acid secretory mechanism are the parietal
cells of the stomach. These cells secrete hydtogen ions into the
gastric lumen under the control of neurocrine, paracrine and
endocrine pathways. One of the major paracrine factors is histamine
released by the enterochromaffine-like (ECL) cells. The histamine
released from the ECL cells stimulates parietal cells to acid
secretion via histamin-2(H2) receptors located on the cell surface.
Engagement of these receptors results in cyclic
adenosine-3,5-monophosphate (cAMP) elevation and cAMP binding to
the regulatory subunit. A variety of proteins will be
phosphorylated, all of which will be relevant to activation of
secretion. The molecular dissection of this intracellular pathway
is far from complete, however, the action of cAMP includes
translocation of H+, K+-ATPase into the secretory canaliculus and
activation of the KCL transporters, i.e. put the parietal cell into
a secretory state.
[0016] The first attempts of decreasing acid secretion targeted the
paracrine pathway, namely the histamine H2 receptor
activation-induced stimulation of acid secretion. Accordingly, the
first class of acid inhibitors was the H2 receptor antagonists (H2
blockers), including compounds such as cimetidine, ranitidine,
famotidine and nizatidine. Their mode of action is to antagonize
the effects of histamine, i.e. to inhibit the recruitment of proton
pumps to the secretory canaliculus and reduce the activity of KCL
transport. This will put the parietal cells into a non-secretory
state and thereby reduce the output of hydrogen ions (Dig Dis Sci
1995, vol 40:3 S-23S. Pharmacological aspects of acid
secretion).
[0017] However, phenomena of acid rebound and tolerance are major
drawbacks to the use of these drugs in treating acid related
diseases. There is an approximately 50% loss in acid reduction
capacity during repeated dosing, which severely restricts the use
of this class of drug in the treatment of, for example, GORD
(Aliment Pharmacol Ther 1990, vol 4: 29-46. Tolerance during 29
days of conventional dosing with cimetidine, nizatidine, famotidine
or ranitidine). Moreover, these agents are not at all useful in the
treatment of Helicobacter pylori infection, a treatment dependent
on an effective and sustained reduction of acid secretion.
[0018] Current treatment of acid related disorders is focused on a
more direct target, the H+, K+-ATPase ("proton pump") of the active
parietal cell. These cells constitute the final acid sources--the
acid secretory canaliculus and the acid pump itself. Therefore,
drugs designed to inhibit acid secretion at this level show a
greater efficacy and specificity. Because proton pump inhibitors
(PPIs) act at a step downstream of the parietal cell stimulus,
tolerance does not occur with the use of these compounds, in
contrast to the H2 receptor antagonists. Moreover, these drugs hit
the final target to which all other pathways converge, the H+,
K+APPase in the acid space or canaliculus of the stimulated
parietal cell.
[0019] Individual PPIs are similar with respect to their general
structure, which consists of a substituted pyridylmethylsulfinyl
benzimidazole. PKa values for these compounds vary from 4.0 to 5.0.
All PPIs share the same pharmacological mechanism that is
essentially the same: their pKa restricts accumulation of the
compound to acid spaces, such as that in the parietal cell. PPI
accumulation in the canaliculus of the parietal cell is followed by
an acid-dependent activation step whereby the PPI is converted to
sulphenic acid or sulphenamides. Formation of these reactive
intermediates allows for binding to cysteine residues within the
exposed luminal surface of the H+, K+-ATPase. The enzyme is
functionally inactivated via the production of covalent disulphide
bonds. The inhibition of H+, K+-ATPase by PPIs thus results in a
relatively stable inhibition of the enzyme, as de novo synthesis of
the enzyme is required to reverse the inhibition. These mechanisms
of action is described in Dig Dis Sci 1995, vol 40:3 S-23S.
Pharmacological aspects of acid secretion.
[0020] One of the fundamental characteristics of the PPIs is that
they are only functional in active parietal cells, i.e. the cells
have to be in a secretory state. The reason for this is three-fold.
Firstly, in most parietal cells, the acid space (canaliculus) has a
pH of about 1.0. At this pH, the pKa values of PPIs allow them to
accumulate in the parietal cell 1000- to 10,000-fold. However, at
higher pH, for example 3, this accumulation decreases by two orders
of magnitude, i.e. to 10- to 100-fold. Thus, the weak base
characteristics of the PPIs allow them to accumulate only when acid
is being formed by the parietal cell. This becomes important when
administering PPIs during conditions when the parietal cell is put
into a non-secretory state. Secondly, the conversion of PPI to
sulphenic acid or sulphenamide is an acid-dependent process.
Thirdly, the H+, K+-ATPase has to be activated, i.e. the enzyme has
to be inserted into the membrane of the secretory canaliculus,
where its cysteine residues can be reached by the sulphenamides
(Pharmacotherapy 1997 vol 17:22-37. Proton pump inhibitors and acid
related diseases; Drugs 1998 vol 56:307-335. Proton pump
inhibitors: pharmacology and rationale for use in gastrointestinal
disorders; Ann NY Acad Sci 1997 vol 834:65-76 Structural aspects of
the gastric H+, K+-ATPase; Annu Rev Pharmacol Toxicol 1995 vol
35:277-305. The pharmacology of the gastric acid pump).
[0021] These characteristics of the pharmacology/biochemistry of
the PPIs will profoundly affect the pharmacodynamics of this class
of compounds. On one hand, these drugs require an active enzyme for
inhibition and some pumps are not active while the drug is present
in the blood. On the other hand, the PPIs exhibit a relatively
short plasma half-life of 60 minutes, and new pumps are synthesized
at a rate of 25% per 24 hours.
[0022] These facts point to the therapeutic dilemma of PPIs at
present. As the compounds are accumulated and converted in the
acidic space of the parietal cell, only those pumps which are
secreting acid will be inhibited. Since the cell has a reserve of
inactive pumps and is in the process of synthesizing new pumps,
many pumps destined to be active within the next 24 hours will not
be inhibited by the first dose. However, the following day, when
PPI is given again, new pumps have been recruited and can be
inhibited, and the pumps inhibited 24 hours previously have not
been replenished entirely. Therefore, the response to PPIs is
cumulative, reaching a steady state and therapeutic acid inhibition
first after at least three consecutive days of treatment.
[0023] Thus, the current concept regarding PPIs mechanisms of
action is the need for active pumps to mediate their effects. In
the resting state, parietal cells produce no acid and the pumps are
inactive. The inhibition of acid production by PPIs occurs when
these pumps are in the active state, via accumulation in the
parietal cell, such that subsequent activation of the drug results
in an inhibition of the pump (Eur J of Gastroentereol Hepatol 2001
vol 13:S35-S41. Improving on PPI-based therapy of GORD)
[0024] In summary, neither class of anti-secretory drugs available
today attain the goal for acid control stated above, i.e. of a
rapid onset of action, potent inhibition of acid secretion and a
sustained duration of action during the course of treatment. This
goal is of the utmost importance for the clinical outcome of
treatment, as the therapeutic effect is related to the onset,
degree and duration of action, i.e. how quickly, how much and for
how long the pH is raised in the stomach.
[0025] Various combinations of antacid and/or mucosa-protecting
agents with agents that reduce acid secretion have been disclosed
to be useful in treating dyspepsia.
[0026] 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).
[0027] 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.
[0028] 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.
[0029] 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.
[0030] 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. Thus, none of the solid pharmaceutical preparations
for per-oral administration reported to date, satisfies the basic
requirements; rapid onset of acid secretion inhibition, potent
reduction of acid secretion and a sustained inhibition of acid
secretion.
[0031] Furthermore, the use of proton pump inhibitors has a serious
shortcoming regarding chemical stability:
[0032] The substances are extremely acid-labile, which has made
special formulations necessary. Normally, the substances are
protected in vivo by the application of a gastric acid-resistant
coating (enteric coating) over the active substance. As such
coatings in themselves are acidic (release hydrogen ions), it has
been found that it is also necessary to provide some sort of
protection in vitro, i.e. when the product is stored.
[0033] This protection in vitro may be arranged such as is
described in U.S. Pat. No. 6,183,776 B1 (Depui et al.), where an
alkaline-reacting substance is added together with the proton pump
inhibitor, and a supplementary protective coating (sub-coat) is
applied just under the gastric acid-resistant coating.
[0034] Another approach is disclosed in WO 00/78284 (U.S. Pat. No.
5,225,202), where the gastric acid-resistant coating is neutralized
such that it shows no acid reaction during storage. After
swallowing, the hydrogen ions present in the stomach will acidify
the coating and thus recreate the acid-protecting properties of the
coating in situ.
[0035] It has now been found that both the problem regarding rapid
and long lasting relief of symptoms as well as the chemical
instability problem of acid susceptible proton pump inhibitors may
be solved by the present invention.
OBJECTS OF THE INVENTION
[0036] 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.
[0037] 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.
[0038] 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
[0039] The present invention relates to a solid pharmaceutical
dosage form for oral administration, which is characterized in that
it comprises a H2 receptor antagonist formulated for a rapid
release and a PPI which is formulated for an extended release. In
the present dosage form, the rapidly released H2 receptor
antagonist will be rapidly absorbed and inhibit acid secretion by
the mechanisms described above. The PPI formulated for delayed
and/or extended release will maintain a maximal acid suppression
already after the first dose and maintain a maximal acid
suppression during the course of treatment.
[0040] 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, proton pump inhibitors such as 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.
[0041] In gastric mucosa, the acid-susceptible proton pump is
situated in the apical membrane and in the tubovesicles bordering
the secretory canaliculus 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 of treatment.
[0042] 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.
[0043] The present invention is based on the unexpected finding
that an almost complete inhibition of acid secretion is achieved by
the first dose of an acid susceptible proton pump inhibitor
administered as an extended release formulation. Furthermore, as
only activated proton pumps secreting acid during the time PPI is
present in the plasma is expected to be inhibited, it was
surprisingly found that a sustained inhibition of acid secretion
could be achieved while the parietal cells is put into a
non-secretory state by means of the rapidly released H2 receptor
antagonist.
[0044] Thus, according to the invention, there 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 excipients resulting in delayed and/or
extended release of the proton pump inhibitor. 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.
[0045] 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.
[0046] To overcome the previously mentioned problems associated
with the proton pump inhibitors, the invention comprises three
parts:
[0047] 1) By formulating the proton pump inhibitor into a
composition which releases active substance with a delayed effect
(delayed release) and/or with a prolonged effect (extended
release), a composition is obtained which acts completely opposite
to what has been desired up to now regarding a rapid onset of the
effect. However, a new type of protection for these acid-labile
pharmaceutical substances is provided.
[0048] This type of release-controlled composition is well-known to
those skilled in the art and has a number of different
designations.
[0049] In the present specification, the expression "extended
release" is used as a synonym to "prolonged release" and "sustained
release". Irrespective of which expression is used, the common
function is that the release of the active substance is retarded
and extended over a longer time. This is normally obtained by
either providing a core of active substance with a coating or
membrane of suitable auxiliary agents which control the release, or
by incorporating the active substance in a matrix of suitable
auxiliary agents.
[0050] The expression "delayed release" is used in the present
specification to describe compositions which do not release active
substance immediately. The start of the release is thus displaced
to the small intestine or large intestine. This type of composition
is normally obtained by providing a core of active substance with a
coating or membrane which is changed during the transport in the
gastro-intestinal tract by the changes in pH encountered by the
composition, or by a change in the coating as a function of the
time when the composition is in contact with body fluids. The
present type of composition is not to be confused with gastric
acid-resistant compositions ("non-enteric release), which are only
intended to protect the composition from hydrogen ions or,
alternatively, to protect the patient from a deleterious effect of
the medical compound on the stomach.
[0051] The expressions "controlled release" and "modified release"
may also be used to describe this part of the invention, but they
constitute more collective designations which do not specifically
describe the present type of release mechanisms.
[0052] All these types of designations, principles for formulation
and suitable auxiliary agents are well-known to those skilled in
the art, and reference is here made to the manual "Pharmaceutics.
The Science of Dosage Form Design", 1st edition; Ed. M. E. Aulton,
Churchill Livingstone, Edinburgh 1988, which is hereby incorporated
by reference. Reference is especially made to pages 289-305.
[0053] It is clear that the basic composition hereby provided may
be combined with further additions of auxiliary agents. Thus, for
example, the proton pump inhibitor may be blended with an alkaline
reacting substance to neutralize the small amount of hydrogen ions
which may pass through the membrane or matrix structures during the
passage through the stomach. This measure is not strictly
necessary, but leads to a more perfect composition. In the same
manner, a gastric acid-resistant coating may be provided on the
exterior side of the membrane or matrix part of the composition. In
a further embodiment, these two formulation measures may be used at
the same time.
[0054] 2) The problem of a too slow onset of the increase in pH is
not obviously solved by further retarding or time-expanding the
release. However, it has now turned out that it is possible to
administer an H2 receptor antagonist having a rapid onset of effect
(obtained through a rapid release), without compromise the onset of
action of the subsequently released acid susceptible proton pump
inhibitor. This was unexpected since an important feature of PPIs
is the need for active pumps to mediate their effects. During
influence of an H2 receptor antagonist, the parietal cells are put
into a resting state. In the resting state, parietal cells produce
no acid and the pumps are inactive. The inhibition of acid
production by PPIs occurs only when these pumps are in the active
state, via accumulation in the parietal cells, such that subsequent
activation of the drug results in an inhibition of the pump. Thus,
the present invention provides a novel pharmacological composition
utilizing the rapid inhibition of acid secretion from a histamine 2
receptor antagonist without offsetting the effect of the
concomitantly administered PPI.
[0055] 3) From the current knowledge of PPI mode of action and the
biochemistry of H+, K+-ATPase, it is not obvious how to achieve
maximal inhibition of acid secretion with the first dose of a PPI
(wide supra).
[0056] However, it has now turned out that expanding the time
during which PPI is released results in an unexpected efficient
first dose inhibition of acid secretion. By extend the time for PPI
present in the blood, newly synthesized pumps will be continuously
inactivated. This was unexpected, as following the initial
inhibition of the pump, the pH in the secretory space would rise
and the drug will depronate and diffuse back out of the
canaliculus. Furthermore, the second clearly essential step in the
PPIs action, the acid-catalysed conversion into the active
sulphenamide, would not take place.
[0057] The combination described here may be obtained in two ways.
Firstly, a separate dose having a delayed/extended release of the
proton pump inhibitor may be administered concurrently with a
separate dose of the H2 receptor antagonist. Alternatively, these
two substances having different release profiles may be combined
into the same preparation. A number of examples will illustrate how
this is suitably arranged.
[0058] Thus, the present invention provides a sustained acid
suppression already after the first dose.
[0059] This cannot be attained by the products proposed by the
prior art:
[0060] H2 blockers are only active during the first 6-8 hours.
[0061] H2 blockers+antacids give a rapid onset, but are only active
for 6-8 hours
[0062] PPIs give no action at all after the first dose.
[0063] PPIs+antacids are active for about one hour through the
antacid effect.
[0064] PPI enantiomer will not reach its full potential after the
first dose.
[0065] PPI slow release alone will give an effect first after 5-6
hours
[0066] Thus, the present invention provides an important
improvement over the formulations of the prior art. This improved
effect is considered to be due to the unexpected
clinical/physiological effect attained through he unique
preparation of the invention, i.e. the delayed/extended effect of
the PPI in combination with the rapid release of the H2
blocker.
[0067] Some patent publications are known which disclose
combinations of a proton pump inhibitor and compositions for
delayed release, and reference may here be made to U.S. Pat. No.
6,132,768, U.S. Pat. No. 6,274,173 B1 and DE 199 25 710 A1. These
references are directed to increasing the stability of proton pump
inhibitors against degradation and discoloration caused by hydrogen
ions. However, they do not teach anything about any combination of
a proton pump inhibitor and an H2 receptor antagonist and the
unexpected advantages attained thereby.
[0068] Furthermore, a gastric acid secretion inhibiting composition
is known from the international patent application PCT/SE02/00757.
This composition comprises a combination of an acid-susceptible
proton pump inhibitor and an H2 receptor antagonist, but no mention
is made of the excipient system of the present invention and its
unexpected advantages.
[0069] According to the invention, there 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 8 hours, more preferred for at least 16 hours.
[0070] 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 inhibit or block the secretion of gastric acid
by binding to histamine type 2 receptors 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 the 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.
[0071] 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.
[0072] 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. The acid-susceptible proton pump inhibitor or salt thereof
is separated from the H2 receptor antagonist by he formulation
principle, where only the proton pump inhibitor is coated by the
membrane or incorporated in a matrix for the purpose of delayed
and/or extended release.
[0073] According to a third preferred aspect of the invention the
H2 receptor antagonist formulated for rapid release and the
acid-susceptible proton pump inhibitor formulated for delayed
and/or extended release 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.
[0074] The oral dosage form of the invention thus comprises an
acid-susceptible proton pump inhibitor formulated for delayed
and/or extended release, an H2 receptor antagonist formulated for
rapid release 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 and
sodium hydrogen carbonate.
[0075] 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. In this new invention,
this is largely solved by the use of excipients for delayed and/or
extended release which offers protection, without the known
disadvantage of enteric coating layers (i.e. liberation of hydrogen
ions, that will increase the degradation rate of the proton pump
inhibitors). 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.
[0076] 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
firstly, in adding the membrane--or matrix system to the part of
the formulation that contains the proton pump inhibitor and
secondly, 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.
[0077] According to the invention, there is provided an oral,
multiple-unit tableted dosage form comprising an acid-susceptible
proton pump inhibitor in individually delayed/extended release
coated units optionally coated with an enteric coating layer 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 coated units. Furthermore, the multiple unit
tableted dosage form provides a good stability to the active
substances during long-term storage.
[0078] According to the invention, there is also provided a
multiple-unit tableted dosage form, which is divisible and easy to
handle. Such a multiple-unit tableted dosage form comprises
delayed/extended release coated pellets of an acid-susceptible
proton pump inhibitor optionally coated with an enteric coating
layer compacted with a powdery H2 receptor antagonist. This dosage
form may also contain effervescent components for making it
disintegrate rapidly when put into water. The pH of the aqueous
phase must then be made slightly acidic to prevent dissolution of
any present enteric layer. This dosage form 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.
[0079] According to the invention, there is also provided a tablet
preparation comprising an acid-susceptible proton pump inhibitor in
admixture with tablet excipients forming a tablet core which is
coated with excipients for delayed and/or extended release, and a
separate layer surrounding the tablet core. The surrounding layer
comprises an H2 receptor antagonist in admixture with a
pharmaceutical excipient. Optionally a separating layer is applied
on the tablet core before the core is covered with the coating. A
further option is than to also apply, on top of the other coats, an
enteric coating layer. 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 coated 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 coated core, comprising
the acid-susceptible proton pump inhibitor may also advantageously
be coated with an enteric layer by following, for instance,
procedures disclosed in WO 00/78284, which is incorporated herein
by reference.
[0080] According to the invention, the acid-susceptible proton pump
inhibitor in the form of coated 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.
[0081] 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 a coating layer for delayed and/or extended
release and optionally also an enteric coating layer. 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.
[0082] The inner layer comprises the acid-susceptible proton pump
inhibitor or a salt thereof and the outer layer comprises the H2
receptor antagonist or a salt thereof. According to a preferred
aspect the outer 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.
[0083] Further, the proton pump-containing part of the formulations
have above been described to exert their delayed and/or extended
release effect by applying coatings to a core material of the
proton pump inhibitor. However, another approach is instead to
exchange the coating layer(s), i.e. the membrane system to a matrix
system. The excipients are then chosen to form a lipid or water
insoluble matrix. The function of the matrix is then to exert an
extended release of the proton pump inhibitor.
[0084] According to the invention, there is also disclosed a method
for the manufacture of an oral tableted dosage form comprising
amounts of an acid-susceptible proton pump inhibitor or a salt
thereof and an H2 receptor antagonist or a 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, a
coating of excipients for delayed and/or extended release and
optionally an enteric coating surrounding said first layer, and a
second layer comprising said H2 receptor antagonist or salt thereof
surrounding said first layer and said coating. Also disclosed is a
method for the manufacture of an oral dosage form comprising
amounts of an acid-susceptible proton pump inhibitor or a salt
thereof and an H2 receptor antagonist or a 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 the above mentioned coatings, and mixing said
pellets with a carrier comprising said H2 receptor antagonist or
salt thereof; the carrier optionally comprising a disintegrant. The
aforementioned methods of the invention further comprise a final
tablet forming step, optionally followed by a film-covering
step.
[0085] 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 coated proton pump inhibitor pellets
and a H2 receptor antagonist in powdery or granular form.
[0086] Regarding the methods for the manufacture, the proton
pump-containing part of the formulations have above been described
to exert their delayed and/or extended release effect by applying
coatings to a core material of the proton pump inhibitor. However,
another approach is instead to exchange the coating layer(s), i.e.
the membrane system to a matrix system. The excipients are then
chosen to form a lipid or water insoluble matrix. The function of
the matrix is then to exert an extended release of the proton pump
inhibitor.
[0087] 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 gastric- and
duodenal-ulcers and 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.
[0088] 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.
[0089] According to the invention, there 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 a salt thereof,
formulated for delayed and/or extended release, the other
comprising a pharmacologically effective amount of an H2 receptor
antagonist or a salt thereof, formulated for rapid release.
[0090] Furthermore, according to the invention, there 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 a salt thereof, the other
comprising a pharmacologically effective amount of an H2 receptor
antagonist or a salt thereof, in association with the
administration of one or more antibiotic agent(s) effective against
H. pylori.
[0091] 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 regimen 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.
[0092] 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 DRAWINGS
[0093] FIGS. 1-4 of the drawings are schematic cross sections
illustrating:
[0094] FIG. 1 is a multiple unit tableted dosage form comprising an
acid-susceptible proton pump inhibitor in the form of delayed
and/or extended release coated pellets in admixture with an
H2-receptor antagonist dispersed in a pharmaceutical carrier;
[0095] FIG. 2 is a tableted dosage form consisting of two halves,
one of which comprises delayed and/or extended release
coating-covered pellets of an acid-susceptible proton pump
inhibitor in admixture with excipients whereas the other comprises
an H2 receptor antagonist in admixture with excipients;
[0096] FIG. 3 a multiple-layered tableted dosage form comprising an
acid-susceptible proton pump inhibitor in a core surrounded by a
delayed and/or extended release coating layer and a layer
containing an H2 receptor antagonist dispersed in a pharmaceutical
carrier surrounding the core;
[0097] FIG. 4 is a capsule dosage form containing an
acid-susceptible proton pump inhibitor in delayed and/or extended
release coating-covered pellets in admixture with an H2 receptor
antagonist and pharmaceutical excipients;
DESCRIPTION OF PREFERRED EMBODIMENTS
[0098] Multiple-Unit Tableted Dosage Form:
[0099] 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 1. The pellets 2 contain an acid-susceptible
proton pump inhibitor in form of the racemate, an alkaline salt or
one of its enantiomers. The individual units 2 (small beads,
granules or pellets) containing the acid-susceptible proton pump
inhibitor and optionally containing alkaline substances, are coated
with a layer(s) possessing delayed release and/or extended release
and optionally an additional enteric coating layer. The coated
units, 2 are then 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 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 yet
another embodiment of the invention, also the H2 receptor
antagonist is coated onto the "individual units". Then the H2
receptor antagonist must be positioned in a pheripheral position in
relation to the coating layers for delayed and/or extended release
and enteric release, in order to be rapidly released in the
gastro-intestinal tract. In compressing the mixture into tablets,
care must be taken not to significantly affect the acid resistance
of the coated pellets. In regard of the core material for coating
layered pellets comprising an acid-susceptible proton pump
inhibitor reference is made to WO 97/25066, page 13, second to last
paragraph, to page 15, end of second paragraph, which are hereby
incorporated by reference. In regard of the coating layer(s)
excerting the delayed and/or extended release reference is made to
U.S. Pat. No. 6,274,173, which are hereby incorporated as
reference. Reference is also made to "Pharmaceutics. The Science of
Dosage Form Design.", 1st edition; Ed. M. E. Aulton, Churchill
Livingstone, Edinburgh 1988. Reference is then especially made to
pages 289-305. In regard of the enteric coating layer(s) reference
is made to WO 97/25066, page 15, second to last paragraph, to page
18, end of second paragraph, which are hereby incorporated by
reference. The acid-susceptible proton pump inhibitor pellets
covered with layers for delayed and/or extended release and
optionally an 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). As mentioned above, in another embodiment of the
invention the H2 receptor antagonist can be coated onto the small
units, 2, rather than mixed with excipients to form the tablet
body, 1. Irrespective of how the H2 receptor antagonist is
incorporated it should possess a rapid release.
[0100] Multi-Unit Tablets:
[0101] The coated layered 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 film-forming agent(s) to obtain
a smooth surface. Such a coating layer may further comprise
additives such as anti-tacking agents, colorants and pigments or
other additives.
[0102] The fraction of coated pellets preferably constitutes less
than 60% by weight of the total tablet weight. The preferred
multiple-unit table formulation thus consists of delayed and/or
extended release coated layered pellets optionally coated with an
enteric coating layer, 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 optional 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 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 delayed
release coating layer, will then start to release the acid
susceptible proton pump inhibitor after a certain time period in
the gastrointestinal tract or at a certain pH, reached at some
position in the intestine or colon. The extended release coating
layer will extend the release of the proton pump inhibitor in order
to result in drug absorption during several hours. The delayed
and/or extended release coated 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 other layers.
[0103] Process for Making Multi-Unit Tablets:
[0104] The process for the manufacture of this 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 covered
with the delayed and/or extended release layer(s) and then
optionally covered with the enteric coating layer(s). The coating
is carried out as described above and in the accompanying examples.
The preparation of the H2 receptor antagonist mixture is also
described in the examples. Optionally the H2 receptor antagonist
can be coated onto the already existing layers comprising delayed
and/or extended release layer(s) and enteric coating layer.
[0105] The coated 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 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 coated pellets 4 may be
intimately mixed with excipients 5 and pre-compressed whereafter
the H2 receptor antagonist preparation 7 is added and the entire
tablet mass 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 the form of a powder may be mixed with tablet
excipients and compressed into a tablet 8 which is optionally
covered with a separating layer and thereafter covered with delayed
and/or extended release coating 9. Optionally, an enteric coating
layer is applied. The thus produced tablet core is subsequently
press-coated with the H2 receptor antagonist preparation 10.
Finally the table may be covered with a tablet coat 11 to obtain a
smooth surface.
[0106] It is also possible to fill the acid-susceptible proton pump
inhibitor in form of coated layered pellets in a sachet together
with H2 receptor antagonist and optionally mixed with
excipients.
[0107] FIG. 4 illustrates a hard gelatin capsule 16 filled with the
uncompressed core material 14, 15 of the embodiment of FIG. 1.
[0108] In the examples given (FIGS. 1, 2, 3 and 4) the terms
coating, coating layer or layer have been used. These terms are
exchangeable and also identical to the term membrane. Irrespective
of the nomenclature they have in common that they correspond to
more or less continuous phases of excipient materials applied by
e.g. spraying onto a core material. Due to the nature of the
processing these membranes are relatively thin with regard to
thickness.
[0109] Suitable excipient materials for forming coatings layers (or
membranes) for delayed and/or extended release are non-polymeric-
or polymeric materials such as calcium phosphate, ethyl cellulose,
methacrylate copolymer, polyamide, polyethylene, polyvinyl alcohol
or polyvinyl acetate.
[0110] Further, the proton pump-containing part of the formulations
(2 in FIG. 1, 4 in FIG. 2, 8 in FIGS. 3 and 15 in FIG. 4) have
above been described to exert their delayed and/or extended release
effect by applying coatings to a core material of the proton pump
inhibitor. However, another approach is instead to exchange the
coating layer(s), i.e. the membrane system to a matrix system. The
excipients are then chosen to form a lipid or water insoluble
matrix. The function of the matrix is then to exert an extended
release of the proton pump inhibitor. Suitable matrix forming
excipients are non-polymeric- or polymeric materials such as
calcium phosphate, ethyl cellulose, methacrylate copolymer,
polyamide, polyethylene or polyvinyl acetate, carnauba wax, cetyl
alcohol, hydrogenated vegetable oils, microcrystalline waxes, mono-
and triglycerides, polyethylene glycol or polyethylene glycol
monostearate and most preferably carnauba wax, cetyl alcohol,
hydrogenated vegetable oils, microcrystalline waxes, mono- and
triglycerides, polyethylene glycol or polyethylene glycol
monostearate. In order to obtain an optimal release rate,
hydrophilic, pore-forming excipients can be optionally added.
Suitable hydrophilic, pore forming materials are alginates,
carbopol, gelatin, hydroxypropyl cellulose, hydroxypropyl
metylcellulose or metylcellulose.
[0111] 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 present invention by firstly, adding the
membrane- or matrix system to the part of the formulation that
contains the proton pump inhibitor and secondly, 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, ant the
like.
[0112] Use of the Dosage Forms According to the Invention.
[0113] 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 800 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 has been made slightly
acidic by the addition of citric acid.
Example 1
[0114] Multiple-unit tableted dosage form comprising magnesium
omeprazole and cimetidine 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. The extended release layer is applied, by a coating
process, in between the separation layer and the enteric coating
layer, in accordance with what is described in patent U.S. Pat. No.
6,274,173, Example 1-4, using ethyl cellulose or polyvinyl acetate
as extended release forming excipients, the information under which
is hereby incorporated as reference.
TABLE-US-00001 Tablets 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
[0115] 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 coated pellets with an over-coating
layer, the prepared H2 receptor antagonist granules, cross-linked
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.
[0116] 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
[0117] 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.
TABLE-US-00002 First tablet layer Cimetidine hydrochloride 200.0 g
Microcrystalline cellulose 250.0 g PVP crosslinked 13.0 g Sodium
stearyl fumarate 3.8 g
TABLE-US-00003 Separating layer Microcrystalline cellulose 80.0
g
TABLE-US-00004 Second tablet layer Coated pellets comprising 78.3 g
omeprazole magnesium salt (same as in EXAMPLE 1) Microcrystalline
cellulose 174.0 g PVP crosslinked 26.0 g Sodium stearyl fumarate
1.4 g
[0118] The constituents of the first tablet layer are dry mixed and
pre-compressed 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
Capsule Dosage Form
[0119] No. 1 hard gelatin capsules (16) (FIG. 5; volume 0.48 ml)
were filled with extended release-coated omeprazole pellets (15)
containing 20 mg omeprazole (as prepared in EXAMPLE 1) and a dry
mixture 14 of commercially available famotidine 20 mg and
closed.
Example 4
Divided Powder/Pellet Formulation
[0120] Extended release pellets containing 15 mg lansoprazole (as
prepared in analogy with EXAMPLE 1) and the famotidine preparation
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
Multiple-Unit Capsule Dosage Form
[0121] The capsule comprises magnesium omeprazole and famotidine
hydrochloride. For extended release coating layer, see U.S. Pat.
No. 6,274,173, Example 1-4, the information under which is hereby
incorporated as reference. 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.
[0122] Magnesium omeprazole is mixed with microcrystalline
cellulose spheres to an ordered mixture. The ordered mixture is
coated with an extended release layer, consisting of polyvinyl
acetate, micronised lactose, propylene glycol and ammonia (25%) in
a fluid bed apparatus. These extended release pellets were the
coated with an enteric coating layer consisting of methacrylic acid
copolymer, mono- and diglycerides, triethyl citrate and polysorbate
in a fluid bed apparatus. The extended release/enteric coated
ordered units is then over-coated with a water suspension
containing famotidine hydrochloride, hydroxypropylmethyl cellulose
and magnesium stearate in a fluid bed apparatus. The extended
release/enteric coated ordered mixture with an over-coating layer
was filled into hard gelatin capsules. The amount of omeprazole is
approx. 10 mg and that of famotidine hydrochloride approx. 20 mg
per capsule.
Example 6
Multiple-Unit Tableted Dosage Form
[0123] The tablet comprises magnesium omeprazole and cimetidine
hydrochloride. Magnesium omeprazole is mixed with mannitol granules
to an ordered mixture which is coated with both an extended release
coating layer and an enteric coating layer as described in EXAMPLE
5. Cimetidine hydrochloride is granulated as described in EXAMPLE
1. The 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 7
[0124] Multiple-unit tableted dosage form for instant release of H2
receptor antagonist and colon extended release of proton pump
inhibitor. The tablet comprises magnesium omeprazole and cimetidine
hydrochloride.
Core material Omeprazole magnesium salt 120 g Sugar sphere seeds
150 g Hydroxypropyl methylcellulose 18 g
Polysorbate 80 2.4 g
[0125] Water purified 562 g Suspension layering was performed in a
fluid bed apparatus. Omeprazole magnesium salt was sprayed onto
sugar sphere seeds from a water suspension containing the dissolved
binder and polysorbate 80. The size of sugar sphere seeds were in
the range of 0.25 to 0.35 mm.
Extended Release Layer
[0126] Core material (acc. to above) 200 g
Eudragit.RTM. RTM 100 g
[0127] Hydroxypropyl cellulose 10 g
Delayed Release Layer
[0128] Pellets covered with extended release layer (acc. to above)
250 g
Eudragit.RTM. FS 30 D 100 g
[0129] The prepared core material was covered with both an extended
release layer and a delayed release layer in a fluid bed apparatus
with commercially available water-based suspensions, Eudragit.RTM.
RTM and Eudragit.RTM. FS 30 D, respectively.
Enteric Coating Layer
[0130] Pellets covered with both a delayed release and extended
release layer (acc. to above) 250 g Methacrylic acid copolymer (30%
suspension) 333.7 g Triethyl citrate 30 g Mono- and diglycerides
(NF) 5 g
Polysorbate 80 0.5 g
[0131] Water purified 196 g The enteric coating layer consisting of
methacrylic acid copolymer, mono- and diglycerides, triethyl
citrate and polysorbate was sprayed onto the pellets covered with
extended/delayed release layers in a fluid bed apparatus. The
enteric coating layered pellets were classified by sieving.
Tablets
[0132] Prepared pellets comprising omeprazole Mg-salt 63.7 g
Cimetidine hydrochloride 65.0 g Calcium carbonate 123.9 g Magnesium
hydroxide 123.9 g Potato starch 52.2 g Water purified 435 g
Microcrystalline cellulose 175 g Polyvidone crosslinked 50.0 g
Sodium stearyl fumarate 6.0 g
[0133] A small amount of the potato starch was dissolved in hot
purified water to form the granulation liquid. Cimetidine
hydrochloride, calcium carbonate, magnesium hydroxide and potato
starch were dry-mixed. The granulation liquid was added to the dry
mixture and the mass was wet-mixed.
[0134] The wet mass was dried in a steamoven at 40 DEG C. The
prepared granulation was milled through sieve 1 mm in an
oscillating mill equipment.
[0135] The multiple coated layered pellets, prepared granules,
polyvidone crosslinked, microcrystalline cellulose and sodium
stearyl fumarate were mixed and compressed into tablets using a
tableting machine equipped with 9.times.20 mm oval punches. The
amount of omeprazole in each tablet was approx. 20 mg and the same
amount was used for cimetidine hydrochloride.
[0136] Tablet hardness was measured to 30N.
[0137] Optionally the obtained tablets were covered with a tablet
coating layer.
* * * * *