Note: Descriptions are shown in the official language in which they were submitted.
CA 02566655 2012-08-14
PHARMACEUTICAL FORMULATIONS USEFUL FOR INHIBITING ACID
SECRETION AND METHODS FOR MAKING AND USING THEM
FIELD OF THE INVENTION
The present invention relates to pharmaceutical formulations in solid oral
dosage form
comprising at least one acid-labile proton pump inhibiting agent and at least
one antacid,
which have improved bioavailability, chemical stability, physical stability,
dissolution
profiles, disintegration times, safety, as well as other improved
pharmacokinetic,
pharmacodynamic, chemical and/or physical properties. Also described herein
are
pharmaceutical formulations comprising at least one proton pump inhibiting
agent and about
mEq to about 11 mEq of antacid, which have similar bioavailability, chemical
stability,
physical stability, dissolution profiles, disintegration times, safety, as
well as other improved
pharmacokinetic, pharmacodynamic, chemical and/or physical properties to
similar
combinations comprising greater than 11 mEq of antacid.
The present invention is directed to methods, kits, combinations, and
compositions for
treating, preventing or reducing the risk of developing a gastrointestinal
disorder or disease,
or the symptoms associated with, or related to, a gastrointestinal disorder or
disease in a
subject in need thereof.
BACKGROUND OF THE INVENTION
Upon ingestion, most acid-labile pharmaceutical compounds must be protected
from
contact with acidic stomach secretions to maintain their pharmaceutical
activity. To
accomplish this, compositions with enteric-coatings have been designed to
dissolve at a
neutral pH to ensure that the drug is released in the proximal region of the
small intestine
(duodenum), rather than the acidic environment of the stomach. However, due to
the pH-
dependent attributes of these enteric-coated compositions and the uncertainty
of gastric
retention time, in-vivo performance as well as both inter- and intra;-7abject
variability are all
major set backs of using enteric-coated systems for the controlled release of
a drug.
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In addition, Phillips et al. has described non-enteric coated pharmaceutical
compositions. These compositions, which allow for the immediate release of the
pharmaceutically active ingredient into the stomach, involve the
administration of one or
more antacids with an acid labile pharmaceutical agent, such as a proton pump
inhibitor. The
antacid is thought to prevent substantial degradation of the acid labile
pharmaceutical agent
in the acidic environment of the stomach by raising the pH. See, e.g., U.S.
Patent Nos.
5,840,737 and 6,489,346.
A class of acid-labile pharmaceutical compounds that are administered as
enteric-
coated dosage forms are proton pump inhibiting agents. Exemplary proton pump
inhibitors
include, omeprazole (Prilosec ), lansoprazole (Prevacid ), esomeprazole
(Nexium),
rabeprazole (Aciphex ), pantoprazole (Protonix ), pariprazole, tenatoprazole,
and
leminoprazole. The drugs of this class suppress gastrointestinal acid
secretion by the specific
inhibition of the H+/K+-ATPase enzyme system (proton pump) at the secretory
surface of the
gastrointestinal parietal cell. Most proton pump inhibitors are susceptible to
acid degradation
and, as such, are rapidly destroyed as pH falls to an acidic level. Therefore,
if the enteric-
coating of these formulated products is disrupted (e.g., trituration to
compound a liquid, or
chewing the capsule or tablet) or the antacid fails to sufficiently neutralize
the gastrointestinal
pH, the drug will be exposed to degradation by the gastrointestinal acid in
the stomach.
Omeprazole is one example of a proton pump inhibitor which is a substituted
bicyclic
aryl-imidazole, 5-methoxy-2-[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl]
sulfinyl]-1H-
benzimidazole, that inhibits gastrointestinal acid secretion. U.S. Patent No.
4,786,505 to
Lovgren et al. teaches that a pharmaceutical oral solid dosage form of
omeprazole must be
protected from contact with acidic gastrointestinal juice by an enteric-
coating to maintain its
pharmaceutical activity and describes an enteric-coated omeprazole preparation
containing
one or more subcoats between the core material and the enteric-coating.
Proton pump inhibitors are typically prescribed for short-term treatment of
active
duodenal ulcers, gastrointestinal ulcers, gastro esophageal reflux disease
(GERD), severe
erosive esophagitis, poorly responsive symptomatic GERD, and pathological
hypersecretory
conditions such as Zollinger Ellison syndrome. These above-listed conditions
commonly
arise in healthy or critically ill patients of all ages, and may be
accompanied by significant
upper gastrointestinal bleeding.
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It is believed that omeprazole, lansoprazole and other proton pump inhibiting
agents
reduce gastrointestinal acid production by inhibiting H+/K+-ATPase of the
parietal cell the
final common pathway for gastrointestinal acid secretion. See, e.g., Fellenius
et al.,
Substituted Benzimidazoles Inhibit Gastrointestinal Acid Secretion by Blocking
H+/K+-
ATPase, Nature, 290: 159-161 (1981); Wallmark et al., The Relationship Between
Gastrointestinal Acid Secretion and Gastrointestinal H+/K+-ATPase Activity, J.
Biol. Chem.,
260: 13681-13684 (1985); and Fryklund et al., Function and Structure of
Parietal Cells After
H+/K+-ATPase Blockade, Am. J. Physiol., 254 (1988).
Proton pump inhibitors have the ability to act as weak bases that reach
parietal cells
from the blood and diffuse into the secretory canaliculi. There, the drugs
become protonated
and thereby trapped. The protonated compound can then rearrange to form a
sulfenamide,
which can covalently interact with sulfhydryl groups at critical sites in the
extra cellular
(luminal) domain of the membrane-spanning H+/K+-ATPase. See, e.g., Hardman et
al.,
Goodman & Gilman's The Pharmacological Basis of Therapeutics, 907 (9th ed.
1996). As
such, proton pump inhibitors are prodrugs that must be activated to be
effective. The
specificity of the effects of proton pump inhibiting agents is also dependent
upon: (a) the
selective distribution of H+/K+-ATPase; (b) the requirement for acidic
conditions to catalyze
generation of the reactive inhibitor; and (c) the trapping of the protonated
drug and the
cationic sulfenamide within the acidic canaliculi and adjacent to the target
enzyme. See, e.g.,
Hardman et al.
SUMMARY OF THE INVENTION
The present invention is directed to pharmaceutical formulations in a solid
oral dosage
form comprising (a) at least one acid-labile proton pump inhibitor, and (b) at
least one antacid
sufficient to increase gastric pH to a pH that prevents acid degradation of at
least some of the
proton pump inhibitor in the gastric fluid, wherein upon oral administration
to a patient, a
therapeutically effective amount of the proton pump inhibitor is delivered and
Tmaõ of the
proton pump inhibitor is obtained within about 75 minutes after
administration. In alternative
embodiments, Tmax of the proton pump inhibitor is obtained within about 60
minutes, or
within about 45 minutes, or within about 30 minutes after administration. In
some
embodiments, the solid oral dosage form is a capsule. In other embodiments,
the solid oral
dosage form is a caplet.
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In one embodiment, pharmaceutical formulations in a solid oral dosage form
comprising (a) at least one acid-labile proton pump inhibitor; (b) a
sufficient amount of
sodium bicarbonate to increase gastric fluid pH to a pH that prevents acid
degradation of at
least some of the proton pump inhibitor in the gastric fluid; and (c) less
than about 3% of
disintegrant, wherein upon oral administration to a patient a therapeutically
effective amount
of the proton pump inhibitor is delivered and T,,a,, of the proton pump
inhibitor is obtained
within about 75 minutes after administration are described. In other
embodiments, the
pharmaceutical formulations comprise less than about 2% or less than about 1 %
of
disintegrant. In alternative embodiments, Tõa, of the proton pump inhibitor is
obtained
within about 60 minutes, or within about 45 minutes, or within about 30
minutes after
administration. In some embodiments, the solid oral dosage form is a capsule.
In other
embodiments, the solid oral dosage form is a caplet.
Stable pharmaceutical formulations in a solid oral dosage form comprising (a)
at least
one acid-labile proton pump inhibitor, and (b) at least one antacid in an
amount sufficient to
increase gastric fluid pH to a pH that prevents acid degradation of at least
some of 'the proton
pump inhibitor in the gastric fluid, wherein the pharmaceutical formulation
does not comprise
a binder; and wherein upon oral administration to a patient: a therapeutically
effective
amount of the proton pump inhibitor is delivered and Tmax of the proton pump
inhibitor is
obtained within about 75 minutes after administration are also provided
herein. In some
embodiments, the antacid is present in an amount of greater than about 5 mEqs.
In other
embodiments, the antacid is present in an amount of about 5 mEq to about 30
mEq, or about
mEq to about 20 mEq, or about 8 mEq to about 15 mEq, or about 10 mEq to about
15 mEq.
In still other embodiments, the antacid is present in an amount of about 5
mEq, or about 6
mEq, or about 7 mEq, or about 8 mEq, or about 9 mEq, or about 10 mEq, or about
11 mEq,
or about 12 mEq, or about 13 mEq, or about 14 mEq, or about 15 mEq, or about
16 mEq, or
about 17 mEq, or about 18 mEq, or about 19 mEq, or about 20 mEq, or about 22.5
mEq, or
about 25 mEq, or about 27 mEq, or about 30 mEq, or about 35 mEq. In some
embodiments,
the solid oral dosage form is a capsule. In other embodiments, the solid oral
dosage form is a
caplet.
Stable pharmaceutical formulations in a solid oral dosage form comprising (a)
at least
one acid-labile proton pump inhibitor, (b) at least about 5 mEq of antacid,
wherein the
antacid is a combination of at least two different antacids, and (c) between
about 3% to about
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11 % of a disintegrant, wherein upon oral administration to a patient a
therapeutically
effective amount of the proton pump inhibitor is delivered and Tmax of the
proton pump
inhibitor is obtained within about 75 minutes, are also provided herein. In
some
embodiments the pharmaceutical formulation comprises about 4% to about 8%
disintegrant.
In other embodiments, the pharmaceutical formulation comprises about 5% to
about 7%
disintegrant. In alternative embodiments, Tmax of the proton pump inhibitor is
obtained
within about 60 minutes, or within about 45 minutes, or within about 30
minutes after
administration. In some embodiments, the solid oral dosage form is a capsule.
In other
embodiments, the solid oral dosage form is a caplet.
Also provided herein are stable pharmaceutical formulations in a single
capsule
dosage form comprising (a) at least one acid-labile proton pump inhibitor, (b)
about 5 to
about 15 mEq of sodium bicarbonate, and (c) less than about 3% of a
disintegrant, wherein
upon oral administration to a patient a therapeutically effective amount of
the proton pump
inhibitor is delivered and Tmax of the proton pump inhibitor is obtained
within about 75
minutes. In some embodiments, the pharmaceutical formulation comprises about 8-
mEq to
about 15 mEq of sodium bicarbonate. In other embodiments, the pharmaceutical
formulation
comprises about 10 mEq to about 15 mEq of sodium bicarbonate. In yet other
embodiments,
the pharmaceutical formulation comprises about 13 mEq of sodium bicarbonate.
In still other
embodiments, Tmax of the proton pump inhibitor is obtained within about 60
minutes, or
within about 45 minutes, or within about 30 minutes after administration.
Stable pharmaceutical formulations in a solid oral dosage form comprising (a)
omeprazole or a salt, hydrate, ester, amide, enantiomer, isomer, tautomer,
polymorph, or
prodrug thereof, (b) at least about 5 mEq of sodium bicarbonate, and (c) less
than about 3%
of a disintegrant, wherein the pharmaceutical formulation does not comprise a
binder; and
wherein upon oral administration to a patient a therapeutically effective
amount of the proton
pump inhibitor is delivered and Tmax of the proton pump inhibitor is obtained
within about 75
minutes after administration are also provided herein. In some embodiments,
the
pharmaceutical formulation comprises between about 5 mEq to about 20 mEq, or
between
about 5 mEq to about 15 mEq, or between about 10 mEq to about 15 mEq of sodium
bicarbonate. In other embodiments, the pharmaceutical formulation comprises
less than
about 2% sodium bicarbonate. In yet other embodiments, Tmax of the proton pump
inhibitor
is obtained within about 60 minutes, or within about 45 minutes, or within
about 30 minutes
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after administration. In some embodiments, the solid oral dosage form is a
capsule. In other
embodiments, the solid oral dosage form is a caplet.
Also provided herein are stable pharmaceutical formulations in single capsule
dosage
form comprising (a) at least one acid-labile proton pump inhibitor, and (b)
about 5 to about
30 mEq of antacid wherein the antacid is selected from magnesium hydroxide,
magnesium
oxide, sodium carbonate, sodium bicarbonate, and calcium carbonate, wherein
upon oral
administration to a patient: a therapeutically effective amount of the proton
pump inhibitor is
delivered; and Tmax of the proton pump inhibitor is obtained within about 75
minutes. In
other embodiments, Tmax of the proton pump inhibitor is obtained within about
60 minutes, or
within about 45 minutes, or within about 30 minutes after administration.
Also provided herein are pharmaceutical compositions in solid oral dosage
forms
wherein the wt-% of disintegrant is at least as great as the wt-% of binder.
In some
embodiments, the pharmaceutical formulation is substantially free of a binder.
In other
embodiments, the solid oral dosage form is a tablet (such as a caplet) and the
binder is present
in an amount of less than about 20 wt%, or less than about 10 wt-%, or less
than about 5 wt-
%. In other embodiments, the solid oral dosage form is a capsule and the
binder is present in
an amount of about 0 wt-% to about 5 wt-%.
The present invention provides a pharmaceutical composition comprising a
proton
pump inhibiting agent and about 5 mEq to about 11 mEq of antacid for oral
administration
and ingestion by a subject.
Pharmaceutical formulations are included that comprise (a) at least one acid-
labile
proton pump inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid,
wherein
upon oral administration to a subject, the oral bioavailability of the proton
pump inhibitor is
at least 25% and the maximum serum concentration of the proton pump inhibitor
is obtained
within about 75 minutes after administration. In other embodiments, the
maximum serum
concentration is obtained within about 60 minutes, or within about 50 minutes,
or within
about 40 minutes, or within about 30 minutes, or within about 20 minutes after
administration
of the pharmaceutical formulation. In still other embodiments, the oral
bioavailability of the
proton pump inhibitor is about 25% to about 60%, or about 30% to about 50%, or
at least
about 30%, or at least about 35%, or at least about 40%.
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Pharmaceutical formulations that comprise (a) at least one acid-labile proton
pump
inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid, wherein the
pharmaceutical formulation is bioequivalent to a pharmaceutical formulation
comprising (a)
at least one acid-labile proton pump inhibitor, and (b) greater than 11 mEq of
antacid. In
some embodiments, the area under the serum concentration time curve for the
proton pump
inhibitor is within about 15% of the area under the serum concentration time
curve for the
proton pump inhibitor when an administered with greater than 11 mEq of
antacid. In other
embodiments, the area under the serum concentration time curve for the proton
pump
inhibitor is within about 10% of the area under the serum concentration time
curve for the
proton pump inhibitor when an administered with greater than 11 mEq of
antacid. In still
other embodiments, the area under the serum concentration time curve for the
proton pump
inhibitor is within about 5% of the area under the serum concentration time
curve for the
proton pump inhibitor when administered with greater than 11 mEq of antacid.
Pharmaceutical formulations that comprise (a) at least one acid-labile proton
pump
inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid, wherein the
pharmaceutical formulation is bioequivalent to a pharmaceutical formulation
comprising (a)
at least one acid-labile proton pump inhibitor, and (b) greater than 15 mEq of
antacid. In
some embodiments, the area under the serum concentration time curve for the
proton pump
inhibitor is within about 15%, or within about 10%, or within about 5%
of the area
under the serum concentration time curve for the proton pump inhibitor when an
administered with greater than 15 mEq of antacid.
Pharmaceutical formulations that comprise (a) at least one acid-labile proton
pump
inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid, wherein the
pharmaceutical formulation is bioequivalent to a pharmaceutical formulation
comprising (a)
at least one acid-labile proton pump inhibitor, and (b) greater than 20 mEq of
antacid. In
some embodiments, the area under the serum concentration time curve for the
proton pump
inhibitor is within about 15%, or within about 10%, or within about 5%
of the area
under the serum concentration time curve for the proton pump inhibitor when an
administered with greater than 20 mEq of antacid.
Pharmaceutical formulations comprising (a) at least one acid-labile proton
pump
inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid wherein the
pharmaceutical formulation is bioequivalent to a proton pump inhibitor
product. In some
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embodiments, the pharmaceutical formulation is bioequivalent to Priolosec ,
Nexium ,
Prevacid , Protonic , and Aciphex . In other embodiments, the maximum
concentration of
the proton pump inhibitor for the pharmaceutical formulation is within about
80% and about
120% of the maximum concentration (Cmax) for the proton pump inhibitor
product. In some
embodiments, the maximum concentration of the proton pump inhibitor for the
pharmaceutical formulation is within about 80% and about 120% of the maximum
concentration (Cmax) for the proton pump inhibitor product when the
pharmaceutical
formulation and proton pump inhibitor product are administered to the same
patient.
Pharmaceutical formulations comprising (a) at least one acid-labile proton
pump
inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid are provided
herein,
wherein upon oral administration to a subject, the pharmaceutical composition
has an area
under the serum concentration time curve (AUC) for the proton pump inhibitor
that is
equivalent to an area under the serum concentration time curve (AUC) for the
proton pump
inhibitor when an enteric form of the proton pump inhibitor is delivered
without antacid. In
some embodiments, the area under the serum concentration time curve for the
proton pump
inhibitor is within about 20% of the area under the serum concentration time
curve for the
proton pump inhibitor when an enteric form of the proton pump inhibitor is
delivered without
antacid. In still other embodiments, the area under the serum concentration
time curve for the
proton pump inhibitor is within about 15%, or within about 10%, or with
about 5% of
the area under the serum concentration time curve for the proton pump
inhibitor when an
enteric form of the proton pump inhibitor is delivered without antacid.
Pharmaceutical formulations comprising (a) at least one acid-labile proton
pump
inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid are provided
herein,
wherein a therapeutic dose of the proton pump inhibitor is delivered as a
single capsule, tablet,
or caplet.
A pharmaceutical formulations comprising (a) at least one acid-labile proton
pump
inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid, wherein
upon oral
administration to a patient: a therapeutically effective amount of the proton
pump inhibitor is
delivered; the antacid increases the gastric pH to at least about 3.5 for no
more than about 30
minutes measured by a simulated stomach model such as Fuchs kinetic in-vitro
pH model;
and the maximum concentration of the proton pump inhibitor is obtained within
about 75
minutes are also provided herein. In some embodiments, the antacid increases
the gastric pH
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to at least about 3.5 for less than about 30 minutes, or less than about 25
minutes, or less than
about 20 minutes, or less than about 15 minutes, or less than about 10
minutes. In other
embodiments, the maximum concentration of the proton pump inhibitor is
obtained within
about 60 minutes.
Pharmaceutical formulations comprising (a) at least one acid-labile proton
pump
inhibitor, and (b) between about 5 mEq to about 11 mEq of antacid are provided
herein,
wherein the formulation comprises about 5 mgs to about 200 mgs of the proton
pump
inhibitor. In other embodiments, the pharmaceutical formulation comprises
about 10 mgs, or
about 20 mgs, or about 30 mgs, or about 40 mgs, or about 50 mgs, or about 60
mgs, or about
80 mgs, or about 120 mgs of the proton pump inhibitor. In yet other
embodiments, the
pharmaceutical formulation comprises about 5 mEq, or about 6 mEq, or about 7
mEq, or
about 8 mEq, or about 9 mEq, or about 10 mEq, or about 11 mEq of antacid.
Compositions are provided such that an initial serum concentration of the
proton
pump inhibitor is greater than about 100 ng/ml at any time within about 30
minutes after
administering the formulation. Initial serum concentration of the proton pump
inhibitor can
be greater than about 100 ng/ml at any time within about 15 minutes. Initial
serum
concentration of the proton pump inhibitor can be greater than about 200 ng/ml
at any time
within about 1 hour after administration, greater than about 300 ng/ml at any
time within
about 45 minutes after administration.
Compositions are provided such that a serum concentration of greater than
about 100
ng/ml can be maintained from at least about 30 minutes to about 1 hour after
administration
of the composition. Compositions are provided such that a serum concentration
of proton
pump inhibitor greater than about 100 ng/ml can be maintained from at least
about 15
minutes to about 30 minutes after administration. Compositions are provided
such that a
serum concentration of greater than about 100 ng/ml can be maintained from at
least about 30
minutes to about 45 minutes after administration. Compositions are provided
such that a
serum concentration of greater than about 250 ng/ml can be maintained from at
least about 30
minutes to about 1 hour after administration. Compositions are provided such
that a serum
concentration of greater than about 250 ng/ml can be maintained from at least
about 30
minutes to about 45 minutes after administration. Compositions are provided
such that a
serum concentration of greater than about 250 ng/ml can be maintained from at
least about 15
minutes to about 30 minutes after administration.
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Compositions of the invention can be administered in an amount to maintain a
serum
concentration of the proton pump inhibitor greater than about 150 ng/ml from
about 15
minutes to about 1 hour after administration. Compositions of the invention
can be
administered in an amount to maintain a serum concentration of the proton pump
inhibitor
greater than about 150 ng/ml from about 15 minutes to about 1.5 hours after
administration.
Compositions of the invention can be administered in an amount to maintain a
serum
concentration of the proton pump inhibitor greater than about 100 ng/ml from
about 15
minutes to about 1.5 hours after administration. Compositions of the invention
can be
administered in an amount to maintain a serum concentration of the proton pump
inhibitor
greater than about 150 ng/ml from about 15 minutes to about 30 minutes after
administration.
Compositions of the invention can be administered in an amount to achieve an
initial
serum concentration of the proton pump inhibitor greater than about 150 ng/ml
at any time
from about 5 minutes to about 30 minutes after administration. Compositions of
the
invention can be administered in an amount to achieve an initial serum
concentration of the
proton pump inhibitor greater than about 150 ng/ml at any time within about 30
minutes after
administration.
Compositions are provided wherein, upon oral administration to the subject,
the
composition provides a pharmacokinetic profile such that at least about 50% of
total area
under serum concentration time curve (AUC) for the proton pump inhibitor
occurs within
about 2 hours after administration of a single dose of the composition to the
subject.
Compositions are provided wherein, upon oral administration to the subject,
the area under
the serum concentration time curve (AUC) for the proton pump inhibitor in the
first 2 hours is
at least about 60% of the total area. Compositions are provided wherein the
area under the
serum concentration time curve (AUC) for the proton pump inhibitor in the
first 2 hours is at
least about 70% of the total area.
Compositions are provided wherein at least about 50% of total area under the
serum
concentration time curve (AUC) for the proton pump inhibitor occurs within
about 1.75 hours
after administration of a single dose of the composition to the subject.
Compositions are
provided wherein at least about 50% of total area under the serum
concentration time curve
(AUC) for the proton pump inhibitor occurs within about 1.5 hours after
administration of a
single dose of the composition to the subject. Compositions are provided
wherein at least
about 50% of total area under the serum concentration time curve (AUC) for the
proton pump
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inhibitor occurs within about 1 hour after administration of a single dose of
the composition
to the subject.
Compositions and methods are provided wherein, upon oral administration to the
subject, the composition provides a pharmacokinetic profile such that the
proton pump
inhibitor reaches a maximum serum concentration within about 75 minutes after
administration of a single dose of the pharmaceutical formulation. In yet
other embodiments
the maximum serum concentration is reached within about 60 minutes after
administration, or
within about 45 minutes after administration of the pharmaceutical
formulation. In still other
embodiments, the maximum serum concentration is reached within about 30
minutes after
administration of the pharmaceutical formulation.
Methods are provided for treating a gastric acid related disorder including,
but not
limited to duodenal ulcer disease, gastric ulcer disease, gastroesophageal
reflux disease,
erosive esophagitis, poorly responsive symptomatic gastroesophageal reflux
disease,
pathological gastrointestinal hypersecretory disease, Zollinger Ellison
syndrome, heartburn,
esophageal disorder, and acid dyspepsia. Method are provided wherein the
proton pump
inhibitor treats an episode of gastric acid related disorder.
In some embodiments, the proton pump inhibitor is a substituted bicyclic aryl-
imidazole. In other embodiments, the proton pump inhibitor is selected from
the group
consisting of omeprazole, hydroxyomeprazole, esomeprazole, tenatoprazole,
lansoprazole,
pantoprazole, rabeprazole, dontoprazole, habeprazole, perprazole,
ransoprazole, pariprazole,
leminoprazole; or a free base, free acid, salt, hydrate, ester, amide,
enantiomer, isomer,
tautomer, polymorph, or prodrug thereof. In still other embodiments, the
proton pump
inhibitor is selected from lansoprazole, tenatoprazole, esomeprazole,
rabeprazole and
pantoprazole, or a free base, free acid, salt, hydrate, ester, amide,
enantiomer, isomer,
tautomer, polymorph, or prodrug thereof.
Pharmaceutical formulations of the present invention comprise, for example,
about 5
mgs to about 200 mgs of a proton pump inhibitor. In various embodiments, the
pharmaceutical formulation may comprise about 10 mgs, or about 15 mgs, or
about 20 mgs,
or about 40 mgs, or about 60 mgs, or about 120 mgs of the proton pump
inhibitor.
In various embodiments of the present invention, the antacid is an alkaline
metal salt
or a Group IA metal selected from a bicarbonate salt of a Group IA metal, a
carbonate salt of
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a Group IA metal. In other embodiments, the antacid can be, but is not limited
to, an amino
acid, an alkali metal salt of an amino acid, aluminum hydroxide, aluminum
hydroxide/magnesium carbonate/calcium carbonate co-precipitate, aluminum
magnesium
hydroxide, aluminum hydroxide/magnesium hydroxide co-precipitate, aluminum
hydroxide/sodium bicarbonate coprecipitate, aluminum glycinate, calcium
acetate, calcium
bicarbonate, calcium borate, calcium carbonate, calcium citrate, calcium
gluconate, calcium
glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate,
calcium phosphate,
calcium succinate, calcium tartrate, dibasic sodium phosphate, dipotassium
hydrogen
phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium
succinate, dry
aluminum hydroxide gel, L-arginine, magnesium acetate, magnesium aluminate,
magnesium
borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate,
magnesium
gluconate, magnesium hydroxide, magnesium lactate, magnesium metasilicate
aluminate,
magnesium oxide, magnesium phthalate, magnesium phosphate, magnesium silicate,
magnesium succinate, magnesium tartrate, potassium acetate, potassium
carbonate, potassium
bicarbonate, potassium borate, potassium citrate, potassium metaphosphate,
potassium
phthalate, potassium phosphate, potassium polyphosphate, potassium
pyrophosphate,
potassium succinate, potassium tartrate, sodium acetate, sodium bicarbonate,
sodium borate,
sodium carbonate, sodium citrate, sodium gluconate, sodium hydrogen phosphate,
sodium
hydroxide, sodium lactate, sodium phthalate, sodium phosphate, sodium
polyphosphate,
sodium pyrophosphate, sodium sesquicarbonate, sodium succinate, sodium
tartrate, sodium
tripolyphosphate, synthetic hydrotalcite, tetrapotassium pyrophosphate,
tetrasodium
pyrophosphate, tripotassium phosphate, trisodium phosphate, trometamol,
Effersoda (a
mixture of sodium bicarbonate and sodium carbonate) and mixtures thereof. In
yet other
embodiments, the antacid can be sodium bicarbonate, sodium carbonate,
Effersoda , calcium
carbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum
hydroxide, and mixtures thereof. In some embodiments, the composition is
substantially free
of sucralfate. In other embodiments, the composition does not contain an amino
acid buffer.
In still other embodiments, the composition is a combination of two or more
antacids,
wherein at least two of the antacids are not amino acids.
Pharmaceutical formulations of the present invention may comprise varying
amounts
of antacid. For example, in some embodiments, the pharmaceutical formulation
comprises
about 100 to 3000 mg of antacid. In other embodiments, the pharmaceutical
formulation
comprises about 400 to about 1300 mg of antacid. In still other embodiments
the
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pharmaceutical formulation comprises about 5 mEq to about 30 mEq, or about 8
mEq to
about 20 mEq, or about 10 mEq to about 15 mEq of antacid. In further
embodiments, the
pharmaceutical formulations comprise about 13 mEq of antacid.
Pharmaceutical formulations of the present invention may be in the form of a
tablet,
(including a suspension tablet, a chewable tablet, a fast-melt tablet, a bite-
disintegration tablet,
a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a
powder (including a
sterile packaged powder, a dispensable powder, or an effervescent powder) a
capsule
(including both soft or hard capsules, e.g., capsules made from animal-derived
gelatin or
plant-derived HPMC) a lozenge, a sachet, a troche, pellets, granules, or an
aerosol. In some
embodiments, the pharmaceutical formulation is in the form of a powder for
suspension. In
other embodiments, the pharmaceutical formaultion is in the form of a tablet,
including but
not limited to, a chewable tablet. Additionally, pharmaceutical formulations
of the present
invention may be administered as a single capsule or in multiple capsule
dosage form. In
some embodiments, the pharmaceutical formulation is administered in two, or
three, or four,
capsules.
In various embodiments of the present invention, the proton pump inhibitor may
be
microencapsulated with a material that enhances the shelf life of the
pharmaceutical
formulation. In some embodiments, the material that enhances the shelf life of
the
pharmaceutical formulation is selected from the group consisting of cellulose
hydroxypropyl
ethers; low-substituted hydroxypropyl ethers; cellulose hydroxypropyl methyl
ethers;
methylcellulose polymers; ethylcelluloses and mixtures thereof; polyvinyl
alcohol;
hydroxyethylcelluloses; carboxymethylcelluloses and salts of
carboxymethylcelluloses;
polyvinyl alcohol and polyethylene glycol co-polymers; monoglycerides;
triglycerides;
polyethylene glycols, modified food starch, acrylic polymers; mixtures of
acrylic polymers
with cellulose ethers; cellulose acetate phthalate; sepifilms, cyclodextrins;
and mixtures
thereof. In other embodiments, the material that enhances the shelf life of
the pharmaceutical
formulation further comprise an antioxidant, sodium bicarbonate, or a
plasticizer.
In various embodiments, the pharmaceutical formulations of the present
invention
further comprise or more excipients selected from the group consisting of
parietal cell
activators, organic solvents, erosion facilitators, flavoring agents,
sweetening agents,
diffusion facilitators, antioxidants and carrier materials selected from
binders, suspending
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agents, disintegration agents, filling agents, surfactants, solubilizers,
stabilizers, lubricants,
wetting agents, diluents, anti-adherents, and antifoaming agents.
DESCRIPTION OF THE FIGURES
Figure 1 shows a comparison of buffer systems comprising various mixtures of
NaHCO3 and
Mg(OH)2-
Figure 2 shows a comparison of buffer systems comprising various mixtures of
NaHCO3 and
Mg(OH)2-
Figure 3 shows the particle size effect of magnesium hydroxide on in-vitro/in-
vivo
neutralization.
Figure 4 shows the particle size effect of magnesium hydroxide on the
pharmacokinetics of
various formulations.
Figure 5 shows the binder effect on various pharmaceutical formulations.
Figure 6 shows the capsule dissolution effect with 5% binder as compared to a
powder for
suspension.
Figure 7 shows the pH study results of high/low Ac-Di-Sol (disintegrant).
Figure 8 shows the pharmacokinetic study results of high/low Ac-Di-Sol
(disintegrant) as
compared to Prilosec.
Figure 9 shows the pharmacokinetic profiles for six different pharmaceutical
formulations.
Figure 10 is a summary of all the CTM lots with the ANC present in the
individual
pharmaceutical formulations.
Figure 11 is a summary of the pharmacokinetics of various formulations.
Figure 12 shows the capsule stability of SAN-10E, SAN- IOBB, and SAN- 1 OB.
Figure 13 compares the concentration/time curve for Prilosec to the
concentration/time
curve of SAN- IOK (10.5 mEq of Sodium Bicarbonate and 40 mg omeprazole).
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to methods, kits, combinations, and
compositions
for treating a condition or disorder where treatment with an acid labile
proton pump inhibitor
is indicated. Also provided are methods, kits, combinations, and compositions
for treating,
preventing or reducing the risk of developing a gastrointestinal disorder or
disease, or the
symptoms associated with, or related to a gastrointestinal disorder or disease
in a subject in
need thereof.
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While the present invention may be embodied in many different forms, several
specific embodiments are discussed herein with the understanding that the
present disclosure
is to be considered only as an exemplification of the principles of the
invention, and it is not
intended to limit the invention to the embodiments illustrated. For example,
where the
present invention is illustrated herein with particular reference to
omeprazole,
hydroxyomeprazole, esomeprazole, tenatoprazole, lansoprazole, pantoprazole,
rabeprazole,
dontoprazole, habeprazole, periprazole, ransoprazole, pariprazole, or
leminoprazole, it will be
understood that any other proton pump inhibiting agent, if desired, can be
substituted in
whole or in part for such agents in the methods, kits, combinations, and
compositions herein
described.
To more readily facilitate an understanding of the invention and its preferred
embodiments, the meanings of terms used herein will become apparent from the
context of
this specification in view of common usage of various terms and the explicit
definitions of
other terms provided in the glossary below or in the ensuing description.
GLOSSARY
As used herein, the terms "comprising," "including," and "such as" are used in
their
open, non-limiting sense.
The term "about" is used synonymously with the term "approximately." As one of
ordinary skill in the art would understand, the exact boundary of "about" will
depend on the
component of the composition. Illustratively, the use of the term "about"
indicates that
values slightly ouside the cited values, i. e., plus or minus 0.1 % to 10%,
which are also
effective and safe.
The phrase "acid-labile pharmaceutical agent" refers to any pharmacologically
active
drug subject to acid catalyzed degradation.
"Anti-adherents," "glidants," or "anti-adhesion" agents prevent components of
the
formulation from aggregating or sticking and improve flow characteristics of a
material.
Such compounds include, e.g., colloidal silicon dioxide such as Cab-o-sil ;
tribasic calcium
phosphate, talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium
stearate, calcium
stearate, sodium stearate, kaolin, and micronized amorphous silicon dioxide
(Syloid )and the
like.
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"Antifoaming agents" reduce foaming during processing which can result in
coagulation of aqueous dispersions, bubbles in the finished film, or generally
impair
processing. Exemplary anti-foaming agents include silicon emulsions or
sorbitan
sesquoleate.
"Antioxidants" include, e.g., butylated hydroxytoluene (BHT), sodium
ascorbate, and
tocopherol.
"Binders" impart cohesive qualities and include, e.g., alginic acid and salts
thereof;
cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g.,
Methocel ),
hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose
(e.g.,
Klucel ), ethylcellulose (e.g., Ethocel ), and microcrystalline cellulose
(e.g., Avicel );
microcrystalline dextrose; amylose; magnesium aluminum silicate;
polysaccharide acids;
bentonites; gelatin; polyvinylpyrrolidone/vinyl acetate copolymer;
crospovidone; povidone;
starch; pregelatinized starch; tragacanth, dextrin, a sugar, such as sucrose
(e.g., Dipac ),
glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab ), and
lactose; a natural
or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol
husks,
polyvinylpyrrolidone (e.g., Polyvidone CL, Kollidon CL, Polyplasdone XL-10),
larch
arabogalactan, Veegum , polyethylene glycol, waxes, sodium alginate, and the
like.
"Bioavailability" refers to the extent to which an active moiety, e.g., drug,
prodrug, or
metabolite, is absorbed into the general circulation and becomes available at
the site of drug
action in the body. Thus, a proton pump inhibitor administered through IV is
100%
bioavailable. "Oral bioavailability" refers to the extent to which the proton
pump inhibitor
(or other active moiety) is absorbed into the general circulation and becomes
available at the
site of drug action in the body when the pharmaceutical composition is taken
orally.
"Bioequivalence" or "bioequivalent" means that the area under the serum
concentration time curve (AUC) and the peak serum concentration (Cmax) are
each within
80% and 120%.
"Carrier materials" include any commonly used excipients in pharmaceutics and
should be selected on the basis of compatibility with the proton pump
inhibitor and the
release profile properties of the desired dosage form. Exemplary carrier
materials include,
e.g., binders, suspending agents, disintegration agents, filling agents,
surfactants, solubilizers,
stabilizers, lubricants, wetting agents, diluents, and the like.
"Pharmaceutically compatible
carrier materials" may comprise, e.g., acacia, gelatin, colloidal silicon
dioxide, calcium
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glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium
silicate, sodium
caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium
phosphate,
sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride,
pregelatinized starch, and
the like. See, e.g., Remington: The Science and Practice of Pharmacy,
Nineteenth Ed
(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's
Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975;
Liberman, H.A.
and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,
N.Y.,
1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.
(Lippincott Williams & Wilkins1999).
"Character notes" include, e.g., aromatics, basis tastes, and feeling factors.
The
intensity of the character note can be scaled from 0-none, 1 -slight, 2-
moderate, or 3-strong.
A "derivative" is a compound that is produced from another compound of similar
structure by the replacement of substitution of an atom, molecule or group by
another suitable
atom, molecule or group. For example, one or more hydrogen atom of a compound
may be
substituted by one or more alkyl, acyl, amino, hydroxyl, halo, haloalkyl,
aryl, heteroaryl,
cycloaolkyl, heterocycloalkyl, or heteroalkyl group to produce a derivative of
that compound.
"Diffusion facilitators" and "dispersing agents" include materials that
control the
diffusion of an aqueous fluid through a coating. Exemplary diffusion
facilitators/dispersing
agents include, e.g., hydrophilic polymers, electrolytes, Tween 60 or 80,
PEG and the like.
Combinations of one or more erosion facilitator with one or more diffusion
facilitator can
also be used in the present invention.
"Diluents" increase bulk of the composition to facilitate compression. Such
compounds include e.g., lactose; starch; mannitol; sorbitol; dextrose;
microcrystalline
cellulose such as Avicel ; dibasic calcium phosphate; dicalcium phosphate
dihydrate;
tricalcium phosphate; calcium phosphate; anhydrous lactose; spray-dried
lactose;
pregelatinzed starch; compressible sugar, such as Di-Pac (Amstar); mannitol;
hydroxypropylmethylcellulose; sucrose-based diluents; confectioner's sugar;
monobasic
calcium sulfate monohydrate; calcium sulfate dihydrate; calcium lactate
trihydrate; dextrates;
hydrolyzed cereal solids; amylose; powdered cellulose; calcium carbonate;
glycine; kaolin;
mannitol; sodium chloride; inositol; bentonite; and the like.
The term "disintegrate" includes both the dissolution and dispersion of the
dosage
form when contacted with gastrointestinal fluid.
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"Disintegration agents" facilitate the breakup or disintegration of a
substance.
Examples of disintegration agents include a starch, e.g., a natural starch
such as corn starch or
potato starch, a pregelatinized starch such as National 1551 or Amijel , or
sodium starch
glycolate such as Promogel or Explotab ; a cellulose such as a wood product,
methylcrystalline cellulose, e.g., Avicel , Avicel PH101, Avicel PH102,
Avicel PH105,
Elcema P 100, Emcocel , Vivacel , Ming Tia , and Solka-Floc ,
methylcellulose,
croscarmellose, or a cross-linked cellulose, such as cross-linked sodium
carboxymethylcellulose (Ac-Di-Sol ), cross-linked carboxymethylcellulose, or
cross-linked
croscarmellose; a cross-linked starch such as sodium starch glycolate; a cross-
linked polymer
such as crospovidone; a cross-linked polyvinylpyrrolidone; alginate such as
alginic acid or a
salt of alginic acid such as sodium alginate; a clay such as Veegum HV
(magnesium
aluminum silicate); a gum such as agar, guar, locust bean, Karaya, pectin, or
tragacanth;
sodium starch glycolate; bentonite; a natural sponge; a surfactant; a resin
such as a cation-
exchange resin; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate in
combination starch;
and the like.
"Drug absorption" or "absorption" refers to the process of movement from the
site of
administration of a drug toward the systemic circulation, e.g., into the
bloodstream of a
subject.
An "enteric coating" is a substance that remains substantially intact in the
stomach but
dissolves and releases the drug once the small intestine is reached.
Generally, the enteric
coating comprises a polymeric material that prevents release in the low pH
environment of
the stomach but that ionizes at a slightly higher pH, typically a pH of 4 or
5, and thus
dissolves sufficiently in the small intestines to gradually release the active
agent therein.
The "enteric form of the proton pump inhibitor" is intended to mean that some
or
most of the proton pump inhibitor has been enterically coated to ensure that
at least some of
the drug is released in the proximal region of the small intestine (duodenum),
rather than the
acidic environment of the stomach.
"Erosion facilitators" include materials that control the erosion of a
particular material
in gastrointestinal fluid. Erosion facilitators are generally known to those
of ordinary skill in
the art. Exemplary erosion facilitators include, e.g., hydrophilic polymers,
electrolytes,
proteins, peptides, and amino acids.
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"Filling agents" include compounds such as lactose, calcium carbonate, calcium
phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline
cellulose, cellulose
powder, dextrose; dextrates; dextran, starches, pregelatinized starch,
sucrose, xylitol, lactitol,
mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
"Flavoring agents" or "sweeteners" useful in the pharmaceutical compositions
of the
present invention include, e.g., acacia syrup, acesulfame K, alitame, anise,
apple, aspartame,
banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate,
camphor, caramel,
cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch,
citrus cream,
cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate,
dextrose, eucalyptus,
eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza
(licorice) syrup, grape,
grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium
glyrrhizinate
(MagnaSweet ), maltol, mannitol, maple, marshmallow, menthol, mint cream,
mixed berry,
neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream,
Prosweet
Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint,
spearmint cream,
strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin,
saccharin,
aspartame, acesulfame potassium, mannitol, talin, sylitol, sucralose,
sorbitol, Swiss cream,
tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon,
wild cherry,
wintergreen, xylitol, or any combination of these flavoring ingredients, e.g.,
anise-menthol,
cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon,
lemon-lime,
lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures
thereof.
"Gastrointestinal fluid" is the fluid of stomach secretions of a subject or
the saliva of a
subject after oral administration of a composition of the present invention,
or the equivalent
thereof. An "equivalent of stomach secretion" includes, e.g., an in vitro
fluid having similar
content and/or pH as stomach secretions such as a I% sodium dodecyl sulfate
solution or
0.1N HCl solution in water.
"Half-life" refers to the time required for the plasma drug concentration or
the amount
in the body to decrease by 50% from its maximum concentration.
"Lubricants" are compounds that prevent, reduce or inhibit adhesion or
friction of
materials. Exemplary lubricants include, e.g., stearic acid; calcium
hydroxide; talc; sodium
stearyl fumerate; a hydrocarbon such as mineral oil, or hydrogenated vegetable
oil such as
hydrogenated soybean oil (Sterotex ); higher fatty acids and their alkali-
metal and alkaline
earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid,
sodium stearates,
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glycerol, talc, waxes, Stearowet , boric acid, sodium benzoate, sodium
acetate, sodium
chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such
as
CarbowaxTM, sodium oleate, glyceryl behenate, polyethylene glycol, magnesium
or sodium
lauryl sulfate, colloidal silica such as SyloidTM, Carb-O-Sil , a starch such
as corn starch,
silicone oil, a surfactant, and the like.
A "measurable serum concentration" or "measurable plasma concentration"
describes
the blood serum or blood plasma concentration, typically measured in mg, g,
or ng of
therapeutic agent per ml, dl, or 1 of blood serum, of a therapeutic agent that
is absorbed into
the bloodstream after administration. One of ordinary skill in the art would
be able to
measure the serum concentration or plasma concentration of a proton pump
inhibitor or a
prokinetic agent. See, e.g., Gonzalez H. et al., J. Chromatogr. B. Analyt.
Technol. Biomed.
Life Sci., vol. 780, pp 459-65, (Nov. 25, 2002).
"Parietal cell activators" or "activators" stimulate the parietal cells and
enhance the
pharmaceutical activity of the proton pump inhibitor. Parietal cell activators
include, e.g.,
chocolate; alkaline substances such as sodium bicarbonate; calcium such as
calcium
carbonate, calcium gluconate, calcium hydroxide, calcium acetate and calcium
glycerophosphate; peppermint oil; spearmint oil; coffee; tea and colas (even
if decaffeinated);
caffeine; theophylline; theobromine; amino acids (particularly aromatic amino
acids such as
phenylalanine and tryptophan); and combinations thereof.
"Pharmacodynamics" refers to the factors which determine the biologic response
observed relative to the concentration of drug at a site of action.
"Phanmacokinetics" refers to the factors which determine the attainment and
maintenance of the appropriate concentration of drug at a site of action.
"Plasma concentration" refers to the concentration of a substance in blood
plasma or
blood serum of a subject. It is understood that the plasma concentration of a
therapeutic
agent may vary many-fold between subjects, due to variability with respect to
metabolism of
therapeutic agents. In accordance with one aspect of the present invention,
the plasma
concentration of a proton pump inhibitors and/or prokinetic agent may vary
from subject to
subject. Likewise, values such as maximum plasma concentration (Cma,J or time
to reach
maximum serum concentration (T,,,aX), or area under the serum concentration
time curve
(AUC) may vary from subject to subject. Due to this variability, the amount
necessary to
constitute "a therapeutically effective amount" of proton pump inhibitor,
prokinetic agent, or
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other therapeutic agent, may vary from subject to subject. It is understood
that when mean
plasma concentrations are disclosed for a population of subjects, these mean
values may
include substantial variation.
"Plasticizers" are compounds used to soften the microencapsulation material or
film
coatings to make them less brittle. Suitable plasticizers include, e.g.,
polyethylene glycols
such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic
acid,
propylene glycol, oleic acid, and triacetin.
"Prevent" or "prevention" when used in the context of a gastric acid related
disorder
means no gastrointestinal disorder or disease development if none had
occurred, or no further
gastrointestinal disorder or disease development if there had already been
development of the
gastrointestinal disorder or disease. Also considered is the ability of one to
prevent some or
all of the symptoms associated with the gastrointestinal disorder or disease.
A "prodrug" refers to a drug or compound in which the pharmacological action
results from conversion by metabolic processes within the body. Prodrugs are
generally drug
precursors that, following administration to a subject and subsequent
absorption, are
converted to an active, or a more active species via some process, such as
conversion by a
metabolic pathway. Some prodrugs have a chemical group present on the prodrug
which
renders it less active and/or confers solubility or some other property to the
drug. Once the
chemical group has been cleaved and/or modified from the prodrug the active
drug is
generated. Prodrugs may be designed as reversible drug derivatives, for use as
modifiers to
enhance drug transport to site-specific tissues. The design of prodrugs to
date has been to
increase the effective water solubility of the therapeutic compound for
targeting to regions
where water is the principal solvent. See, e.g., Fedorak et al., Am. J.
Physiology, 269:G210-
218 (1995); McLoed et al., Gastroenterol., 106:405-413 (1994); Hochhaus et
al., Biomed.
Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. I Pharmaceutics,
37, 87 (1987);
J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., I
Pharm. Sci., 64:181-
210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems,
Vol. 14 of the
A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug
Design,
American Pharmaceutical Association and Pergamon Press, 1987.
"Proton pump inhibitor product" refers to a product sold on the market. Proton
pump
inhibitor products include, for example, Priolosec , Nexium , Prevacid ,
Protonic , and
Aciphex .
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"Serum concentration" refers to the concentration of a substance such as a
therapeutic
agent, in blood plasma or blood serum of a subject. It is understood that the
serum
concentration of a therapeutic agent may vary many-fold between subjects, due
to variability
with respect to metabolism of therapeutic agents. In accordance with one
aspect of the
present invention, the serum concentration of a proton pump inhibitors and/or
prokinetic
agent may vary from subject to subject. Likewise, values such as maximum serum
concentration (CR,a,,) or time to reach maximum serum concentration (Tma,.),
or total area
under the serum concentration time curve (AUC) may vary from subject to
subject. Due to
this variability, the amount necessary to constitute "a therapeutically
effective amount" of
proton pump inhibitor, prokinetic agent, or other therapeutic agent, may vary
from subject to
subject. It is understood that when mean serum concentrations are disclosed
for a population
of subjects, these mean values may include substantial variation.
"Solubilizers" include compounds such as citric acid, succinic acid, fumaric
acid,
malic acid, tartaric acid, maleic acid, glutaric acid, sodium bicarbonate,
sodium carbonate and
the like.
"Stabilizers" include compounds such as any antioxidation agents, buffers,
acids, and
the like.
"Suspending agents" or "thickening agents" include compounds such as
polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone
K17,
polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30; polyethylene glycol,
e.g., the
polyethylene glycol can have a molecular weight of about 300 to about 6000, or
about 3350
to about 4000, or about 7000 to about 5400; sodium carboxymethylcellulose;
methylcellulose;
hydroxy-propylmethylcellulose; polysorbate-80; hydroxyethylcellulose; sodium
alginate;
gums, such as, e.g., gum tragacanth and gum acacia; guar gum; xanthans,
including xanthan
gum; sugars; cellulosics, such as, e.g., sodium carboxymethylcellulose,
methylcellulose,
sodium carboxymethylcellulose, hydroxypropylmethylcellulose,
hydroxyethylcellulose;
polysorbate-80; sodium alginate; polyethoxylated sorbitan monolaurate;
polyethoxylated
sorbitan monolaurate; povidone and the like.
"Surfactants" include compounds such as sodium lauryl sulfate, sorbitan
monooleate,
polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts,
glyceryl
monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic
(BASF);
and the like.
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A "therapeutically effective amount" or "effective amount" is that amount of a
pharmaceutical agent to achieve a pharmacological effect. The term
"therapeutically
effective amount" includes, for example, a prophylactically effective amount.
An "effective
amount" of a proton pump inhibitor is an amount effective to achieve a desired
pharmacologic effect or therapeutic improvement without undue adverse side
effects. For
example, an effective amount of a proton pump inhibitor refers to an amount of
proton pump
inhibitor that reduces acid secretion, or raises gastrointestinal fluid pH, or
reduces
gastrointestinal bleeding, or reduces the need for blood transfusion, or
improves survival rate,
or provides for a more rapid recovery from a gastric acid related disorder.
The effective
amount of a pharmaceutical agent will be selected by those skilled in the art
depending on the
particular patient and the disease level. It is understood that "an effect
amount" or "a
therapeutically effective amount" can vary from subject to subject, due to
variation in
metabolism of therapeutic agents such as proton pump inhibitors and/or
prokinetic agents,
age, weight, general condition of the subject, the condition being treated,
the severity of the
condition being treated, and the judgment of the prescribing physician.
"Total intensity of aroma" is the overall immediate impression of the strength
of the
aroma and includes both aromatics and nose feel sensations.
"Total intensity of flavor" is the overall immediate impression of the
strength of the
flavor including aromatics, basic tastes and mouth feel sensations.
"Treat" or "treatment" as used in the context of a gastric acid related
disorder refers to
any treatment of a disorder or disease associated with a gastrointestinal
disorder, such as
preventing the disorder or disease from occurring in a subject which may be
predisposed to
the disorder or disease, but has not yet been diagnosed as having the disorder
or disease;
inhibiting the disorder or disease, e.g., arresting the development of the
disorder or disease,
relieving the disorder or disease, causing regression of the disorder or
disease, relieving a
condition caused by the disease or disorder, or stopping the symptoms of the
disease or
disorder. Thus, as used herein, the term "treat" is used synonymously with the
term
"prevent."
"Wetting agents" include compounds such as oleic acid, glyceryl monostearate,
sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate,
polyoxyethylene sorbitan
monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl
sulfate, and
the like.
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WO 2005/115474 PCT/US2005/018585
PROTON PUMP INHIBITORS
The terms "proton pump inhibitor," "PPI," and "proton pump inhibiting agent"
can be
used interchangeably to describe any acid labile pharmaceutical agent
possessing
pharmacological activity as an inhibitor of H+/K+-ATPase. A proton pump
inhibitor may, if
desired, be in the form of free base, free acid, salt, ester, hydrate,
anhydrate, amide,
enantiomer, isomer, tautomer, prodrug, polymorph, derivative, or the like,
provided that the
free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug,
or any other
pharmacologically suitable derivative is therapeutically active.
In various embodiments, the proton pump inhibitor can be a substituted
bicyclic aryl-
imidazole, wherein the aryl group can be, e.g., a pyridine, a phenyl, or a
pyrimidine group
and is attached to the 4- and 5-positions of the imidazole ring. Proton pump
inhibitors
comprising a substituted bicyclic aryl-imidazoles include, but are not limited
to, omeprazole,
hydroxyomeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole,
dontoprazole,
habeprazole, perprazole, tenatoprazole, ransoprazole, pariprazole,
leminoprazole, or a free
base, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer,
polymorph, prodrug,
or derivative thereof. See, e.g., The Merck Index, Merck & Co. Rahway, N.J.
(2001).
Other proton pump inhibitors include but are not limited to: soraprazan
(Altana);
ilaprazole (U.S. Patent No. 5,703,097) (II-Yang); AZD-0865 (AstraZeneca); YH-
1885 (PCT
Publication WO 96/05177) (SB-641257) (2-pyrimidinamine, 4-(3,4-dihydro-l-
methyl-2(1H)-
isoquinolinyl)-N-(4-fluorophenyl)-5,6-dimethyl-monohydrochloride)(YuHan); BY-
112
(Altana); SPI-447 (Imidazo(1,2-a)thieno(3,2-c)pyridin-3-amine,5-methyl-2-(2-
methyl-3-
thienyl) (Shinnippon); 3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-
pyrano(2,3-c)-
imidazo(1,2-a)pyridine (PCT Publication WO 95/27714) (AstraZeneca);
Pharmaprojects No.
4950 (3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydro-pyrano(2,3-c)-
imidazo(1,2-
a)pyridine) (AstraZeneca, ceased) WO 95/27714; Pharmaprojects No. 4891 (EP
700899)
(Aventis); Pharmaprojects No. 4697 (PCT Publication WO 95/32959)
(AstraZeneca); H-
335/25 (AstraZeneca); T-330 (Saitama 335) (Pharmacological Research Lab);
Pharmaprojects No. 3177 (Roche); BY-574 (Altana); Pharmaprojects No. 2870
(Pfizer); AU-
1421 (EP 264883) (Merck); AU-2064 (Merck); AY-28200 (Wyeth); Pharmaprojects
No.
2126 (Aventis); WY-26769 (Wyeth); pumaprazole (PCT Publication WO 96/05199)
(Altana);
YH-1238 (YuHan); Pharmaprojects No. 5648 (PCT Publication WO 97/32854)
(Dainippon);
BY-686 (Altana); YM-020 (Yamanouchi); GYKI-34655 (Ivax); FPL-65372 (Aventis);
24
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WO 2005/115474 PCT/US2005/018585
Pharmaprojects No. 3264 (EP 509974) (AstraZeneca); nepaprazole (Toa Eiyo); HN-
1 1203
(Nycomed Pharma); OPC-22575; pumilacidin A (BMS); saviprazole (EP 234485)
(Aventis);
SKandF-95601 (GSK, discontinued); Pharmaprojects No. 2522 (EP 204215)
(Pfizer); S-3337
(Aventis); RS-13232A (Roche); AU-1363 (Merck); SKandF-96067 (EP 259174)
(Altana);
SUN 8176 (Daiichi Phama); Ro-18-5362 (Roche); ufiprazole (EP 74341)
(AstraZeneca); and
Bay-p-1455 (Bayer); or a free base, free acid, salt, hydrate, ester, amide,
enantiomer, isomer,
tautomer, polymorph, prodrug, or derivative of these compounds.
Still other proton pump inhibitors contemplated by the present invention
include those
described in the following U.S. Patent Nos: 4,628,098; 4,689,333; 4,786,505;
4,853,230;
4,965,269; 5,021,433; 5,026,560; 5,045,321; 5,093,132; 5,430,042; 5,433,959;
5,576,025;
5,639,478; 5,703,110; 5,705,517; 5,708,017; 5,731,006; 5,824,339; 5,855,914;
5,879,708;
5,948,773; 6,017,560; 6,123,962; 6,187,340; 6,296,875; 6,319,904; 6,328,994;
4,255,431;
4,508,905; 4,636,499; 4,738,974; 5,690,960; 5,714,504; 5,753,265; 5,817,338;
6,093,734;
6,013,281; 6,136,344; 6,183,776; 6,328,994; 6,479,075; 6,559,167.
Other substituted bicyclic aryl-imidazole compounds as well as their salts,
hydrates,
esters, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs, and
derivatives may
be prepared using standard procedures known to those skilled in the art of
synthetic organic
chemistry. See, e.g., March, Advanced Organic Chemistry: Reactions, Mechanisms
and
Structure, 4th Ed. (New York: Wiley-Interscience, 1992); Leonard et al.,
Advanced Practical
Organic Chemistry (1992); Howarth et al., Core Organic Chemistry (1998); and
Weisermel
et al., Industrial Organic Chemistry (2002).
"Pharmaceutically acceptable salts," or "salts," include, e.g., the salt of a
proton pump
inhibitor prepared from formic, acetic, propionic, succinic, glycolic,
gluconic, lactic, malic,
tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic,
glutamic, benzoic,
anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic,
mandelic, embonic,
methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,
toluenesulfonic, 2-
hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, /3-
hydroxybutyric,
galactaric and galacturonic acids.
In one embodiment, acid addition salts are prepared from the free base using
conventional methodology involving reaction of the free base with a suitable
acid. Suitable
acids for preparing acid addition salts include both organic acids, e.g.,
acetic acid, propionic
acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid,
succinic acid, maleic
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WO 2005/115474 PCT/US2005/018585
acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,
mandelic acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic
acid, and the like,
as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid,
phosphoric acid, and the like.
In other embodiments, an acid addition salt is reconverted to the free base by
treatment with a suitable base. In a further embodiment, the acid addition
salts of the proton
pump inhibitors are halide salts, which are prepared using hydrochloric or
hydrobromic acids.
In still other embodiments, the basic salts are alkali metal salts, e.g.,
sodium salt.
Salt forms of proton pump inhibiting agents include, but are not limited to: a
sodium
salt form such as esomeprazole sodium, omeprazole sodium, rabeprazole sodium,
pantoprazole sodium; or a magnesium salt form such as esomeprazole magnesium
or
omeprazole magnesium, described in U.S. Patent No. 5,900,424; a calcium salt
form; or a
potassium salt form such as the potassium salt of esomeprazole, described in
U.S. Patent
Application No. 02/0198239 and U.S. Patent No. 6,511,996. Other salts of
esomeprazole are
described in U.S. 4,738,974 and U.S. 6,369,085. Salt forms of pantoprazole and
lansoprazole
are discussed in U.S. Pat. Nos. 4,758,579 and 4,628,098, respectively.
In one embodiment, preparation of esters involves fictionalization of hydroxyl
and/or
carboxyl groups which may be present within the molecular structure of the
drug. In one
embodiment, the esters are acyl-substituted derivatives of free alcohol
groups, e.g., moieties
derived from carboxylic acids of the formula RCOORI where RI is a lower alkyl
group.
Esters can be reconverted to the free acids, if desired, by using conventional
procedures such
as hydrogenolysis or hydrolysis.
"Amides" may be prepared using techniques known to those skilled in the art or
described in the pertinent literature. For example, amides may be prepared
from esters, using
suitable amine reactants, or they may be prepared from an anhydride or an acid
chloride by
reaction with an amine group such as ammonia or a lower alkyl amine.
"Tautomers" of substituted bicyclic aryl-imidazoles include, e.g., tautomers
of
omeprazole such as those described in U.S. Patent Nos.: 6,262,085; 6,262,086;
6,268,385;
6,312,723; 6,316,020; 6,326,384; 6,369,087; and 6,444,689; and U.S. Patent
Publication No.
02/0156103.
An exemplary "isomer" of a substituted bicyclic aryl-imidazole is the isomer
of
omeprazole including but not limited to isomers described in: Oishi et al.,
Acta Cryst. (1989),
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WO 2005/115474 PCT/US2005/018585
C45, 1921-1923; U.S. Patent No. 6,150,380; U.S. Patent Publication No.
02/0156284; and
PCT Publication No. WO 02/085889.
Exemplary "polymorphs" include, but are not limited to, those described in PCT
Publication No. WO 92/08716, and U.S. Patent Nos. 4,045,563; 4,182,766;
4,508,905;
4,628,098; 4,636,499; 4,689,333; 4,758,579; 4,783,974; 4,786,505; 4,808,596;
4,853,230;
5,026,560; 5,013,743; 5,035,899; 5,045,321; 5,045,552; 5,093,132; 5,093,342;
5,433,959;
5,464,632; 5,536,735; 5,576,025; 5,599,794; 5,629,305; 5,639,478; 5,690,960;
5,703,110;
5,705,517; 5,714,504; 5,731,006; 5,879,708; 5,900,424; 5,948,773; 5,997,903;
6,017,560;
6,123,962; 6,147,103; 6,150,380; 6,166,213; 6,191,148; 5,187,340; 6,268,385;
6,262,086;
6,262,085; 6,296,875; 6,316,020; 6,328,994; 6,326,384; 6,369,085; 6,369,087;
6,380,234;
6,428,810; 6,444,689; and 6,462,0577.
Micronized Proton Pump Inhibitor
Particle size of the proton pump inhibitor can affect the solid dosage form in
numerous ways. Since decreased particle size increases in surface area (S),
the particle size
reduction provides an increase in the rate of dissolution (dM/dt) as expressed
in the Noyes-
Whitney equation below:
dM/dt = dS / h(Cs-C)
M =mass of drug dissolved; t = time; D = diffusion coefficient of drug; S =
effective surface
area of drug particles; H= stationary layer thickness; Cs = concentration of
solution at
saturation; and C = concentration of solution at time t.
Because omeprazole, as well as other proton pump inhibitors, has poor water
solubility, to aid the rapid absorption of the drug product, various
embodiments of the present
invention use micronized proton pump inhibitor is used in the drug product
formulation.
In various embodiments of the present invention, the proton pump inhibitor is
micronized. In some embodiments, the average particle size of at least about
90% the
micronized proton pump inhibitor is less than about 40 gm, or less than about
35 gm, or less
than about 30 gm, or less than about 25 gm, or less than about 20 gm, or less
than about 15
gm, or less than about 10 gm. In other embodiments, at least 80% of the
micronized proton
pump inhibitor has an average particle size of less than about 40 gm, or less
than about 35
gm, or less than about 30 gm, or less than about 25 gm, or less than about 20
gm, or less than
about 15 gm, or less than about 10 gm. In still other embodiments, at least
70% of the
27
CA 02566655 2012-08-14
micronized proton pump inhibitor has an average particle size of less than
about 40 m, or
less than about 35 pm, or less than about 30 pm, or less than about 25 pm, or
less than about
20 m, or less than about 15 pm, or less than about 10 W.
Compositions are provided wherein the micronized proton pump inhibitor is of a
size
which allows greater than 75% of the proton pump inhibitor to be released
within about I
hour, or within about 50 minutes, or within about 40 minutes, or within about
30 minutes, or
within about 20 minutes, or within about 10 minutes, or within about 5 minutes
of dissolution
testing. In another embodiment of the invention, the micronized proton pump
inhibitor is of a
size which allows greater than 90% of the proton pump inhibitor to be released
within about 1
hour, or within about 50 minutes, or within about 40 minutes, or within about
30 minutes, or
within about 20 minutes, or within about 10 minutes, or within about 5 minutes
of dissolution
testing. See U.S. Patent Application No. 10/893,092, filed July 16, 2004,
which claims
priority to U.S. Provisional Application No. 60/488,324 filed July 18, 2003,
Particle Size of Insoluble Materials
The particle size of the proton pump inhibitor, antacid and excipients is an
important
factor which can effect bioavailability, blend uniformity, segregation, and
flow properties. In
general, smaller particle sizes of a drug increases the bioabsorption rate of
the drug with
substantially poor water solubility by increasing the surface area. The
particle size of the drug
and excipients can also affect the suspension properties of the pharmaceutical
formulation.
For example, smaller particles are less likely to settle and therefore form
better suspensions.
In various embodiments, the average particle size of the dry powder (which can
be
administered directly, as a poweder for suspension, or used in a solid dosage
form) is less
than about 500 microns in diameter, or less than about 450 microns in
diameter, or less than
about 400 microns in diameter, or less than about 350 microns in diameter, or
less than about
300 microns in diameter, or less than about 250 microns in diameter, or less
than about 200
microns in diameter, or less than about 150 microns in diameter, or less than
about 100
microns in diameter, or less than about 75 microns in diameter, or less than
about 50 microns
in diameter, or less than about 25 microns in diameter, or less than about 15
microns in
diameter. In other embodiments, the average particle size of the aggregates is
between about
25 microns in diameter to about 300 microns in diameter. In still other
embodiments, the
average particle size of the aggregates is between about 25 microns in
diameter to about 150
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WO 2005/115474 PCT/US2005/018585
microns in diameter. And, in still further embodiments, the average particle
size of the
aggregates is between about 25 microns in diameter to about 100 microns in
diameter. The
term "average particle size" is intended to describe the average diameter of
the particles
and/or agglomerates used in the pharmaceutical formulation.
In another embodiment, the average particle size of the insoluble excipients
is
between about 5 m to about 500 m, or less than about 400 m, or less than
about 300 m,
or less than about 200 m, or less than about 150 m, or less than about 100
m, or less than
about 90 m, or less than about 80 m, or less than about 70 m, or less than
about 60 m, or
less than about 50 m, or less than about 40 m, or less than about 30 m, or
less than about
25 m, or less than about 20 m, or less than about 15 m, or less than about
10 m, or less
than about 5 m.
In other embodiments of the present invention, at least about 80% of the
particles
have a particle size of less than about 300 m, or less than about 250 m, or
less than about
200 m, or less than about 150 m, or less than about 100 m, or less than
about 500 m. In
another embodiment, at least about 85% of the dry powder particles have a
particle size of
less than about 300 m, or less than about 250 m, or less than about 200 m,
or less than
about 150 m, or less than about 100 m, or less than about 50 m. In still
other
embodiments of the present invention, at least about 90% of the dry powder
particles have a
particle size of less than about 300 m, or less than about 250 m, or less
than about 200 m,
or less than about 150 m, or less than about 100 m, or less than about 50
m. In yet another
embodiment, at least about 95% of the dry powder particles have a particle
size of less than
about 300 m, or less than about 250 m, or less than about 200 m, or less
than about 150
m, or less than about 100 m, or less than about 50 m.
In another embodiment, the particle size of other excipients is chosen to be
about the
same as the particle size of the antacid. In yet another embodiment, the
particle size of the
insoluable excipients is chosen to be about the same as the particle size of
the proton pump
inhibitor.
Several factors can be considered in choosing both the proper excipient and
its
quantity. For example, the excipient should be pharmaceutically acceptable.
Also, in some
examples, rapid dissolution and neutralization of gastric acid to maintain the
gastric pH at
about 6.5 for at least one hour. The excipients which will be in contact with
the proton pump
inhibitor, if any, should also be chemically compatible with the proton pump
inhibitor.
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WO 2005/115474 PCT/US2005/018585
"Chemically compatible" is intended to mean that the material does not lead to
more than
10% degradation of the proton pump inhibitor when stored at room temperature
for at least
about 1 year.
Parietal cell activators are administered in an amount sufficient to produce
the desired
stimulatory effect without causing untoward side effects to patients. In one
embodiment, the
parietal cell activator is administered in an amount of about 5 mg to about
2.5 grams per 20
mg dose of the proton pump inhibitor.
ANTACIDS
The pharmaceutical composition of the invention comprises one or more
antacids. A
class of antacids useful in the present invention include, but are not limited
to, antacids
possessing pharmacological activity as a base. In one embodiment, the antacid,
when
formulated or delivered with an proton pump inhibiting agent, functions to
substantially
prevent or inhibit the acid degradation of the proton pump inhibitor by
gastrointestinal fluid
for a period of time, e.g., for a period of time sufficient to preserve the
bioavailability of the
proton pump inhibitor administered. The antacid can be delivered before,
during and/or after
delivery of the proton pump inhibitor. In one aspect of the present invention,
the antacid
includes a salt of a Group IA metal (alkali metal), including, e.g., a
bicarbonate salt of a
Group IA metal, a carbonate salt of a Group IA metal; an alkaline earth metal
antacid (Group
IIA metal); an aluminum antacid; a calcium antacid; or a magnesium antacid.
Other antacids suitable for the present invention include, e.g., alkali metal
(a Group
IA metal including, but not limited to, lithium, sodium, potassium, rubidium,
cesium, and
francium) or alkaline earth metal (Group IIA metal including, but not limited
to, beryllium,
magnesium, calcium, strontium, barium, radium) carbonates, phosphates,
bicarbonates,
citrates, borates, acetates, phthalates, tartrate, succinates and the like,
such as sodium or
potassium phosphate, citrate, borate, acetate, bicarbonate and carbonate.
In various embodiments, a antacid includes an amino acid, an alkali metal salt
of an
amino acid, aluminum hydroxide, aluminum hydroxide/magnesium carbonate/calcium
carbonate co-precipitate, aluminum magnesium hydroxide, aluminum
hydroxide/magnesium
hydroxide co-precipitate, aluminum hydroxide/sodium bicarbonate coprecipitate,
aluminum
glycinate, calcium acetate, calcium bicarbonate, calcium borate, calcium
carbonate, calcium
citrate, calcium gluconate, calcium glycerophosphate, calcium hydroxide,
calcium lactate,
calcium phthalate, calcium phosphate, calcium succinate, calcium tartrate,
dibasic sodium
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WO 2005/115474 PCT/US2005/018585
phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium
hydrogen
phosphate, disodium succinate, dry aluminum hydroxide gel, L-arginine,
magnesium acetate,
magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium
carbonate,
magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium
lactate,
magnesium metasilicate aluminate, magnesium oxide, magnesium phthalate,
magnesium
phosphate, magnesium silicate, magnesium succinate, magnesium tartrate,
potassium acetate,
potassium carbonate, potassium bicarbonate, potassium borate, potassium
citrate, potassium
metaphosphate, potassium phthalate, potassium phosphate, potassium
polyphosphate,
potassium pyrophosphate, potassium succinate, potassium tartrate, sodium
acetate, sodium
bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium
gluconate, sodium
hydrogen phosphate, sodium hydroxide, sodium lactate, sodium phthalate, sodium
phosphate,
sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium
succinate,
sodium tartrate, sodium tripolyphosphate, Effersoda (mixture of sodium
bicarbonate and
sodium carbonate), synthetic hydrotalcite, tetrapotassium pyrophosphate,
tetrasodium
pyrophosphate, tripotassium phosphate, trisodium phosphate, and trometamol.
(See, e.g.,
lists provided in The Merck Index, Merck & Co. Rahway, N.J. (2001)). Certain
proteins or
protein hydrolysates that rapidly neutralize acids can serve as antacids in
the present
invention. Combinations of the above mentioned antacids may also be used in
the
pharmaceutical compositions described herein.
The antacids useful in the present invention also include antacids or
combinations of
antacids that interact with HCl (or other acids in the environment of
interest) faster than the
proton pump inhibitor interacts with the same acids. When placed in a liquid
phase, such as
water, these antacids produce and maintain a pH greater than the pKa of the
proton pump
inhibitor.
In various embodiments, the antacid is selected from sodium bicarbonate,
sodium
carbonate, calcium carbonate, magnesium oxide, magnesium hydroxide, magnesium
carbonate, and mixtures thereof.
Particle size of the buffer, especially that an insoluble buffer can affect
the onset of in-
vivo neutralization of the stomach acid. Since decreased particle size
increases in surface area,
the particle size reduction provides an increase in the rate of acid
neutralization, leading to
superior protection of PPI from gastric acid degradation. On the other hand,
extremely fine
particle size of buffer will result in the powder mixture that is difficult to
manufacture in
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WO 2005/115474 PCT/US2005/018585
commercial scale due to their poor flow and difficulties in processing (i.e.,
compression and
encapsulation).
In various embodiments of the present invention, the antacid is micronized. In
some
embodiments, particle size of at least 90% of antacid (D90) is less than about
300 gm, or less
than about 250 gm, or less than about 200 gm, or less than about 150 gm, or
less than about
100 gm. In other embodiments, at least 75% of the antacid (D75) has particle
size of less than
about 300 gm, or less than about 250 gm, or less than about 200 gm, or less
than about 150
gm, or less than about 100 gm.. In still other embodiments, at least 50% of
the antacid (D5o)
has particle size of less than about 300 gm, or less than about 250 gm, or
less than about 200
gm, or less than about 150 gm, or less than about 100 gm.
Spray dried antacid can also facilitate the speed of neutralization by fast
reacting with
acid upon contact. Sprayed dried antacid typically has spherical particle
shape which aids
with achieving homogeneous blend during manufacturing process. In one
embodiment the
antacid is spray dried with at least 15% of coating material such as
maltodextrin or starch. In
still other embodiment the antacid is spray dried with at least 10% of coating
material such as
maltodextrin or starch. Yet another embodiment the antacid is spray dried with
at least 15%
of coating material such as maltodextrin or starch.
KINETIC STOMACH MODEL
The acid neutralizing capacity and pH profile of various antacid combinations
can be
evaluated by using an in-vitro stomach model. Several of these simulated
dynamic models
are known in the art. See, e.g., Smyth et al., Correlation of In-Vivo
Methodology for
Evaluation of Antacids, J. Pharm. Sci. Vol. 65, 1045 (1976); Hobert, Fordham
et al., In-Vivo
Evaluation of Liquid Antacids, New England Journal of Med. 288, 923 (1973);
Johnson et al.,
The Chemical Testing of Antacids, Gut 5, 585 (1964); Clain et al., In-Vitro
Neutralizing
Capacity of Commercially Available Antacid Mixtures and Their Role in the
Treatment of
Peptic Ulcer, S. Afr. Med. J., 57, 158 (1980); Rossett et al., In -Vitro
Evaluation of Efficacy
of More Frequently Used Antacids with Particular Attention to Tablets,
Gastroentrology, 26,
490; Decktor et al., Comparative Effects of Liquid Antacids on Esophageal and
Gastric pH in
Patients with Heartburn , Am. J. of Therapeutics, 2, 481 (1995); Charles
Fuchs, Antacids:
Their Function, Formulation and Evaluation, Drug and Cosmetic Industry, 49,
692; Stewart
M. Beekman, Preparation and Properties of New Gastric Antacids I, Aluminium
Hydroxide-
Magnesium Carbonate Dried Gels, J. Am. Pharm. Assoc., 49, 191 (1960). For
example, a
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modified Fuch's model where the continuous influx of 0.5 mEq of acid is added
to initial 5.0
mEq of acid to simulate a fasting state of stomach can be used with the
present invention.
In various embodiments of the present invention, the antacid increases the
gastric pH to at
least about 3.5 for no more than about 90 minutes as measured by a simulated
stomach model
such as Fuch's kinetic in-vitro pH model. In other embodiments, the antacid
increases the pH
to at least about 3.5 for no more than about 60 minutes. In still other
embodiments, the
antacid increases the pH to at least about 3.5 for no more than 45 minutes.
Depending on the
buffer system used (i.e., type of antacid and amount) some embodiments of the
present
invention, the antacid increases the gastric pH to at least about 3.5 for no
more than about 30
minutes as measured by a simulated stomach model such as Fuchs' kinetic in-
vitro pH model.
In other embodiments, the antacid increases the gastric pH to at least about
3.5 for less than
about 25 minutes as measured by a simulated stomach model such as Fuch's
kinetic in-vitro
pH model. In yet other embodiments, the antacid increases the gastric pH to at
least about
3.5 for less than about 20 minutes, or less than about 15 minutes, or less
than about 10
minutes as measured by a stimulated stomach model such as Fuch's kinetic in-
vitro pH model.
In each of these embodiments, the antacid protects at least some of the proton
pump inhibitor
and a therapeutically effective amount of the proton pump inhibitor is
delivered to the subject.
In each of these embodiments, the antacid protects at least some of the proton
pump
inhibitor and a therapeutically effective amount of the proton pump inhibitor
is delivered to
the subject.
DISINTEGRANTS
Most PPIs are sparingly soluble in water and therefore exhibit a strong
correlation of
disintegration time to bioavailability. Thus, it is important to optimize the
disintegration time
in order to enhance in vivo dissolution of the drug. In order to release the
active ingredient
from a solid dosage form matrix as efficiently as possible, disintegrant is
often used in the
formulation, especially when the dosage forms are compressed with binder.
Disintegrants
help rupturing the dosage form matrix by swelling or capillary action when
moisture is
absorbed into the dosage form. Starch is the oldest disintegrants and 5-15%
level is suggested
(Remington, 20th Ed, p862). Super disintegrants such as Ac-di-Sol or
Crospovidones are
effective at lower levels (2-4%).
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Ac-Di-Sol is effective in both direct compression and wet granulation
formulations.
The amount of Ac-Di-Sol used in direct compression tableting may vary with
typical usage
levels between 1 and 3 percent. When added to granulations, generally the same
percent is
used as with a direct compression formulation. It is often added to both the
wet mass and the
dried granulations before compression. As with direct compression, the use
level typically
ranges from 1 to 3 percent with half of the material added to the wet mass and
half added to
the running powder. This promotes disintegration of both the granules and the
tablet.
The amount of Ac-Di-Sol used in capsule formulations generally ranges from 4 -
6
percent. Reduced interparticle contact within a capsule facilitates the need
for elevated levels
of disintegrant. Capsules filled on automatic dosater types of equipment, as
opposed to semi-
automatic or hand-filled machines, are more dense and have a harder structure
due to the
greater compressional forces needed to form the plug and successfully transfer
it into the
gelatin shell. Greater plug hardness results in greater effectiveness of Ac-Di-
Sol.
Solid Oral Dosage Forms
In some embodiments of the present invention, the phamaceutical formulation
has
greater than about 1 wt-% of a disintegrant. In various embodiments of the
present invention,
the pharmaceutical formulations have between about 1 wt-% to about 11 wt-% of
a
disintegrant. In some embodiments the disintegrant is Ac-Di-Sol. In other
embodiments the
disintegrant is sodium starch glycolated such as Promogel or Explotab . In
still other
embodiments, the pharmaceutical formulations have between about 2 wt-% to
about 8 wt-%
disintegrant. In yet other embodiments, the pharmaceutical formualtions have
greater than
about 2 wt-% disintegrant.
Because sodium bicarbonate has effervescent characteristic when mixed with
acid
such as gastric fluid, in some embodiments the pharmaceutical formulations of
the present
invention can comprise at least about 400 mgs of sodium bicarbonate and
greater than about
1 wt-% of a disintegrant. In some embodiments, the pharmaceutical formulation
comprises
about 2 wt-% disintegrant, or about 3 wt-% disintegrant, or about 4 wt-%
disintegrant. In yet
other embodiments, the pharmaceutical formulation comprises less than 8 wt-%
disintegrant.
In other embodiments, the pharmaceutical formulations have less than about 5
wt-%
disintegrant, or less than about 4 wt-% disintegrant, or less than about 3 wt-
% disintegrant, or
less than about 2 wt-% disintegrant, or less than about 1 wt-% disintegrant.
In other
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embodiments, the sodium bicarbonate helps facilitate the disintegration of the
capsule
product.
In some embodiments of the present invention, the wt-% of disintegrant can be
decreased and the amount of sodium bicarbonate increased to achieve the
desired
bioavailability of the proton pump inhibitor. In other embodiments, the wt-%
of disintegrant
can be increased and the amount of sodium bicarbonate decreased.
BINDERS
Binders impart a cohesiveness to solid oral dosage form formulations: for
powder
filled capsule formulation, they aid in plug formation that can be filled into
a hard sell
capsules and for tablet formulation, they ensure the tablet remaining intact
after compression.
Materials commonly used as binders include starch gelatin, and sugars such as
sucrose,
glucose, dextrose, molasses, and lactose. The quantity of binder used
influences the
characteristics of the dosage form and/or manufacturing processes. For
example, dosator
type encapsulators (e.g. Zanasi machine) normally requires the filling
material to be
mechanically strong plugs whereas dosing disc type encapsulators (e.g., HK
machine) do not
require the same degree of high plug breaking force. In general, binder level
of 1-10% are
used in powder-filled hard gel capsule formulations. Binder usage level in
tablet
formulations varies whether direct compression, wet granulation, or usage of
other excipients
such as fillers which itself can act as moderate binder. Formulators skilled
in art can
determine the binder level for the formulations, but binder usage level of 2-
25% in tablet
formulations is common.
Solid Oral Dosage Forms
In some embodiments of the present invention, the wt-% of the disintegrant is
at least
equivalent to the wt -% of the binder. For example, formulations of the
present invention may
comprise about 5 wt-% of disintegrant and about 2 wt-% of a binder or about 3
wt-% of a
disintegrant and about 3 wt-% of a binder. In other embodiments, the solid
oral dosage form
does not comprise a binder. In some embodiments, the solid oral dosage form
comprises
significantly more disintegrant than binder. For example, the binder may be
present in an
amount of less than 2 wt-% while the disintegrant is present in an amount of
greater than 5
wt-%. In other embodiments, the binder and disintegrant are present in the
formulation in
CA 02566655 2012-08-14
substantially the same amount. For example, the binder may be present in an
amount of
about 2 wt-% and the disintegrant may be present in anamout of about 3 wt-%.
MICROENCAPSULATION
In accordance with one aspect of the present invention, compositions may
include
microencapsulation of the proton pump inhibitor or the antacid, in order to
enhance the shelf
life of the composition and/or enhance the taste of the pharmaceutical
composition. See U.S.
Application No. 10/893,203, filed July 16, 2004, which claims priority to U.S.
Provisional
Application No. 60/488,321 filed July 18, 2001.
Materials useful for enhancing the shelf life and/or masking the taste of the
pharmaceutical compositions of the present invention include materials
compatible with the
proton pump inhibitor of the pharmaceutical compositions which sufficiently
isolate the
proton pump inhibitor from other non-compatible excipients. Materials
compatible with the
proton pump inhibitors of the present invention are those that enhance the
shelf life of the
proton pump inhibitor, i.e., by slowing or stopping degradation of the proton
pump inhibitor.
Exemplary micro encapsulation materials useful for enhancing the shelf life of
pharmaceutical compositions comprising a proton pump inhibitor include, but
are not limited
to: hydroxypropyl cellulose ethers (HPC) such as Klucel or Nisso HPC; low-
substituted
hydroxypropyl cellulose ethers (L-HPC); hydroxypropyl methyl cellulose ethers
(HPMC)
such as Seppifilm-LC, Pharmacoat , Metolose SR, Methocel -E, Opadry YS,
PrimaFlo,
Benecel MP824, and Benecel MP843; methylcellulose polymers such as Methocel -A
and
Metolose ; Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel ,
Aqualon -EC,
Surelease ; Polyvinyl alcohol (PVA) such as Opadry AMB; hydroxyethylcelluloses
such as
Natrosol ; carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC)
such as
Aqualon -CMC; polyvinyl alcohol and polyethylene glycol co-polymers such as
Kollicoat
IR ; monoglyceri des (Myverol), triglycerides (KLX), polyethylene glycols,
modified food
starch, acrylic polymers and mixtures of acrylic polymers with cellulose
ethers such as
Eudragit EPO, Eudragit RD100, and Eudragit E100; cellulose acetate
phthalate; sepifilms
such as mixtures of HPMC and stearic acid, cyclodextrins; and mixtures of
these materials.
In various embodiments, an antacid such as sodium bicarbonate or sodium
carbonate
is incorporated into the microencapsulation material. In other embodiments, an
antioxidant
such as BHT is incorporated into the microencapsulation material. In still
other embodiments,
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plasticizers such as polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600,
PEG 1450, PEG
3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin
are incorporated
into the microencapsulation material. In other embodiments, the
microencapsulating material
useful for enhancing the shelf life of the pharmaceutical compositions is from
the USP or the
National Formulary (NF). In yet other embodiments, the microencapsulation
material is
Klucel. In still other embodiments, the microencapsulation material is
methocel.
In further embodiments, one or more other compatible materials are present in
the
microencapsulation material. Exemplary materials include, but are not limited
to, pH
modifiers, parietal cell activators, erosion facilitators, diffusion
facilitators, anti-adherents,
anti-foaming agents, antioxidants, flavoring agents, and carrier materials
such as binders,
suspending agents, disintegration agents, filling agents, surfactants,
solubilizers, stabilizers,
lubricants, wetting agents, and diluents.
According to one aspect of the invention, some of the proton pump inhibitor is
coated.
The coating may be, for example, a gastric resistant coating such as an
enteric coating (See,
e.g, WO 91/16895 and WO 91/16886), a controlled-release coating, an enzymatic-
controlled
coating, a film coating, a sustained-release coating, an immediate-release
coating, or a
delayed-release coating. According to another aspect of the invention, the
coating may be
useful for enhancing the stability of the pharmaceutical compositions of the
present invention.
In addition to microencapsulating the proton pump inhibitors with a material
as
described herein, the pharmaceutical compositions of the present invention may
also
comprise one or more flavoring agents. In some embodiments, one or more
flavoring agents
are mixed with the taste-masking material prior to microencapsulating the
proton pump
inhibitor and/or antacid. In other embodiments, the flavoring agent is mixed
with non-
compatible excipients during the formulation process and is therefore not in
contact with the
proton pump inhibitor and/or antacid, and not part of the microencapsulation
material.
"Flavoring agents" or "sweeteners" useful in the pharmaceutical compositions
of the
present invention include, e.g., acacia syrup, acesulfame K, alitame, anise,
apple, aspartame,
banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate,
camphor, caramel,
cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch,
citrus cream,
cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate,
dextrose, eucalyptus,
eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza
(licorice) syrup, grape,
grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium
glyrrhizinate
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(MagnaSweet ), maltol, mannitol, maple, marshmallow, menthol, mint cream,
mixed berry,
neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream,
Prosweet
Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint,
spearmint cream,
strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin,
saccharin,
aspartame, acesulfame potassium, mannitol, talin, sucralose, sorbitol, swiss
cream, tagatose,
tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry,
wintergreen,
xylitol, or any combination of these flavoring ingredients, e.g., anise-
menthol, cherry-anise,
cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime,
lemon-mint,
menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. In other
embodiments, sodium chloride is incorporated into the pharmaceutical
composition. Based
on the proton pump inhibitor, antacid, and excipients, as well as the amounts
of each one, one
of skill in the art would be able to determine the best combination of flavors
to provide the
optimally flavored product for consumer demand and compliance. See, e.g., Roy
et al.,
Modifying Bitterness: Mechanism, Ingredients, and Applications (1997).
METHODS OF MICROENCAPSULA TION
The proton pump inhibitor and/or antacid may be microencapsulated by methods
known by one of ordinary skill in the art. Such known methods include, e.g.,
spray drying
processes, spinning disk-solvent processes, hot melt processes, spray chilling
methods,
fluidized bed, electrostatic deposition, centrifugal extrusion, rotational
suspension separation,
polymerization at liquid-gas or solid-gas interface, pressure extrusion, or
spraying solvent
extraction bath. In addition to these, several chemical techniques, e.g.,
complex coacervation,
solvent evaporation, polymer-polymer incompatibility, interfacial
polymerization in liquid
media, in situ polymerization, in-liquid drying, and desolvation in liquid
media could also be
used.
The spinning disk method allows for: 1) an increased production rate due to
higher
feed rates and use of higher solids loading in feed solution, 2) the
production of more
spherical particles, 3) the production of a more even coating, and 4) limited
clogging of the
spray nozzle during the process.
Spray drying is often more readily available for scale-up. In various
embodiments,
the material used in the spray-dry encapsulation process is emulsified or
dispersed into the
core material in a concentrated form, e.g., 10-60 % solids. The
microencapsulation material
is, in one embodiment, emulsified until about 1 to 3 m droplets are obtained.
Once a
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dispersion of proton pump inhibitor and encapsulation material are obtained,
the emulsion is
fed as droplets into the heated chamber of the spray drier. In some
embodiments, the droplets
are sprayed into the chamber or spun off a rotating disk. The microspheres are
then dried in
the heated chamber and fall to the bottom of the spray drying chamber where
they are
harvested.
In some embodiments of the present invention, the microspheres have irregular
geometries. In other embodiments, the microspheres are aggregates of smaller
particles.
In various embodiments, the proton pump inhibitor and/or antacid are present
in the
microspheres in an amount greater than 1%, greater than 2.5%, greater than 5%,
greater than
10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%,
greater than
35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%,
greater than
60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%,
greater than
85%, greater than 90 % greater than 95% or greater than 98% weight percent of
the proton
pump inhibitor to the microencapsulation material used to enhance the
stability of the
pharmaceutical composition or the taste-masking material.
STABILITY
A pharmaceutical formulation of the present invention is stable if, e.g., the
proton
pump inhibitor has less than about 0.5% degradation after one month of storage
at room
temperature, or less than about 1% degradation after one month at room
temperature, or less
than about 1.5% degradation after one month of storage at room temperature, or
less than
about 2% degradation after one month storage at room temperature, or less than
about 2.5%
degradation after one month of storage at room temperature, or less than about
3%
degradation after one month of storage at room temperature.
In other embodiments, a pharmaceutical formulation of the present invention
may
have stable if the pharmaceutical formulation contains less than about 5%
total impurities
after about 3 years of storage, or after about 2.5 years of storage, or about
2 years of storage,
or about 1.5 years of storage, or about 1 year of storage, or after 11 months
of storage, or
after 10 months of storage, or after 9 months of storage, or after 8 months of
storage, or after
7 months of storage, or after 6 months of storage, or after 5 months of
storage, or after 4
months of storage, or after 3 months of storage, or after 2 months of storage,
or after 1 month
of storage.
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In further embodiments, pharmaceutical formulations of the present invention
may
contain microencapsulated omeprazole and have enhanced shelf life stability if
the
pharmaceutical formulation contains less degradation of the proton pump
inhibitor than
proton pump inhibitor in the same formulation which is not microencapsulated,
or "bare". For
example, if bare proton pump inhibitor in the pharmaceutical formulation
degrades at room
temperature by more than about 2% after one month of storage and the
microencapsulated
material degrades at room temperature by less than about 2% after one month of
storage, then
the proton pump inhibitor has been microencapsulated with a compatible
material that
enhances the shelf life of the pharmaceutical formulation.
DOSAGE
The proton pump inhibiting agent is administered and dosed in accordance with
good
medical practice, taking into account the clinical condition of the individual
patient, the site
and method of administration, scheduling of administration, and other factors
known to
medical practitioners. In human therapy, it is important to provide a dosage
form that
delivers the required therapeutic amount of the therapeutic agent in vivo, and
renders
therapeutic agent bioavailable in a rapid manner. In addition to the dosage
forms described
herein, the dosage forms are also described by Phillips et al. in U.S. Patent
Nos. 5,840,737,
6,489,346, 6,699,885 and 6,645,988.
The percent of intact drug that is absorbed into the bloodstream is not
narrowly
critical, as long as a therapeutically effective amount, e.g., a
gastrointestinal-disorder-
effective amount of a proton pump inhibiting agent, is absorbed following
administration of
the pharmaceutical composition to a subject. Gastrointestinal-disorder-
effective amounts
may be found in U.S. Patent No. 5,622,719. It is understood that the amount of
proton pump
inhibiting agent and/or antacid that is administered to a subject is dependent
on a number of
factors, e.g., the sex, general health, diet, and/or body weight of the
subject.
Illustratively, administration of a substituted bicyclic aryl-imidazole to a
young child
or a small animal, such as a dog, a relatively low amount of the proton pump
inhibitor, e.g.,
about 1 mg to about 30 mg, will often provide blood serum concentrations
consistent with
therapeutic effectiveness. Where the subject is an adult human or a large
animal, such as a
horse, achievement of a therapeutically effective blood serum concentration
will require
larger dosage units, e.g., about 10 mg, about 15 mg, about 20 mg, about 30 mg,
about 40 mg,
about 80 mg, or about 120 mg dose for an adult human, or about 150 mg, or
about 200 mg, or
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about 400 mg, or about 800 mg, or about 1000 mg dose, or about 1500 mg dose,
or about
2000 mg dose, or about 2500 mg dose, or about 3000 mg dose or about 3200 mg
dose or
about 3500 mg dose for an adult horse.
In various other embodiments of the present invention, the amount of proton
pump
inhibitor administered to a subject is, e.g., about 0.5-2 mg/Kg of body
weight, or about 0.5
mg/Kg of body weight, or about 1 mg/Kg of body weight, or about 1.5 mg/Kg of
body weight,
or about 2 mg/Kg of body weight.
Treatment dosages generally may be titrated to optimize safety and efficacy.
Typically, dosage-effect relationships from in vitro and/or in vivo tests
initially can provide
useful guidance on the proper doses for subject administration. In terms of
treatment
protocols, it should be appreciated that the dosage to be administered will
depend on several
factors, including the particular agent that is administered, the route chosen
for administration,
and the condition of the particular subject.
In various embodiments, unit dosage forms for humans contain about 1 mg to
about
120 mg, or about 1 mg, or about 5 mg, or about 10 mg, or about 15 mg, or about
20 mg, or
about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg,
or about 80
mg, or about 90 mg, or about 100 mg, or about 110 mg, or about 120 mg of a
proton pump
inhibitor.
In a further embodiment of the present invention, the pharmaceutical
composition is
administered in an amount to achieve a measurable serum concentration of a non-
acid
degraded proton pump inhibiting agent greater than about 100 ng/ml within
about 30 minutes
after administration of the pharmaceutical composition. In another embodiment
of the
present invention, the pharmaceutical composition is administered to the
subject in an amount
to achieve a measurable serum concentration of a non-acid degraded or non-acid
reacted
proton pump inhibiting agent greater than about 100 ng/ml within about 15
minutes after
administration of the pharmaceutical composition. In yet another embodiment,
the
pharmaceutical composition is administered to the subject in an amount to
achieve a
measurable serum concentration of a non-acid degraded or non-acid reacted
proton pump
inhibiting agent greater than about 100 ng/ml within about 10 minutes after
administration of
the pharmaceutical composition.
In another embodiment of the present invention, the composition is
administered to
the subject in an amount to achieve a measurable serum concentration of the
proton pump
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inhibiting agent greater than about 150 ng/ml within about 15 minutes and to
maintain a
serum concentration of the proton pump inhibiting agent of greater than about
150 ng/ml
from about 15 minutes to about 1 hour after administration of the composition.
In yet another
embodiment of the present invention, the composition is administered to the
subject in an
amount to achieve a measurable serum concentration of the proton pump
inhibiting agent
greater than about 250 ng/ml within about 15 minutes and to maintain a serum
concentration
of the proton pump inhibiting agent of greater than about 250 ng/ml from about
15 minutes to
about 1 hour after administration of the composition. In another embodiment of
the present
invention, the composition is administered to the subject in an amount to
achieve a
measurable serum concentration of the proton pump inhibiting agent greater
than about 350
ng/ml within about 15 minutes and to maintain a serum concentration of the
proton pump
inhibiting agent of greater than about 350 ng/ml from about 15 minutes to
about 1 hour after
administration of the composition. In another embodiment of the present
invention, the
composition is administered to the subject in an amount to achieve a
measurable serum
concentration of the proton pump inhibiting agent greater than about 450 ng/ml
within about
15 minutes and to maintain a serum concentration of the proton pump inhibiting
agent of
greater than about 450 ng/ml from about 15 minutes to about 1 hour after
administration of
the composition.
In another embodiment of the present invention, the composition is
administered to
the subject in an amount to achieve a measurable serum concentration of the
proton pump
inhibiting agent greater than about 150 ng/ml within about 30 minutes and to
maintain a
serum concentration of the proton pump inhibiting agent of greater than about
150 ng/ml
from about 30 minutes to about 1 hour after administration of the composition.
In yet another
embodiment of the present invention, the composition is administered to the
subject in an
amount to achieve a measurable serum concentration of the proton pump
inhibiting agent
greater than about 250 ng/ml within about 30 minutes and to maintain a serum
concentration
of the proton pump inhibiting agent of greater than about 250 ng/ml from about
30 minutes to
about 1 hour after administration of the composition. In another embodiment of
the present
invention, the composition is administered to the subject in an amount to
achieve a
measurable serum concentration of the proton pump inhibiting agent greater
than about 350
ng/ml within about 30 minutes and to maintain a serum concentration of the
proton pump
inhibiting agent of greater than about 350 ng/ml from about 30 minutes to
about 1 hour after
administration of the composition. In another embodiment of the present
invention, the
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composition is administered to the subject in an amount to achieve a
measurable serum
concentration of the proton pump inhibiting agent greater than about 450 ng/ml
within about
30 minutes and to maintain a serum concentration of the proton pump inhibiting
agent of
greater than about 450 ng/ml from about 30 minutes to about 1 hour after
administration of
the composition.
In still another embodiment of the present invention, the composition is
administered
to the subject in an amount to achieve a measurable serum concentration of a
non-acid
degraded or non-acid reacted proton pump inhibiting agent greater than about
500 ng/ml
within about 1 hour after administration of the composition. In yet another
embodiment of
the present invention, the composition is administered to the subject in an
amount to achieve
a measurable serum concentration of a non-acid degraded or non-acid reacted
proton pump
inhibiting agent greater than about 300 ng/ml within about 45 minutes after
administration of
the composition.
In one embodiment of the present invention, the composition is administered to
a
subject in a gastrointestinal-disorder-effective amount, that is, the
composition is
administered in an amount that achieves a therapeutically-effective dose of a
proton pump
inhibiting agent in the blood serum of a subject for a period of time to
elicit a desired
therapeutic effect. Illustratively, in a fasting adult human (fasting for
generally at least 10
hours) the composition is administered to achieve a therapeutically-effective
dose of a proton
pump inhibiting agent in the blood serum of a subject within about 45 minutes
after
administration of the composition. In another embodiment of the present
invention, a
therapeutically-effective dose of the proton pump inhibiting agent is achieved
in the blood
serum of a subject within about 30 minutes from the time of administration of
the
composition to the subject. In yet another embodiment, a therapeutically-
effective dose of
the proton pump inhibiting agent is achieved in the blood serum of a subject
within about 20
minutes from the time of administration to the subject. In still another
embodiment of the
present invention, a therapeutically-effective dose of the proton pump
inhibiting agent is
achieved in the blood serum of a subject at about 15 minutes from the time of
administration
of the composition to the subject.
In further embodiments, the oral bioavailability of the proton pump inhibitor
is at least
about 25%. In other embodiments, the oral bioavailability of the proton pump
inhibitor is at
least about 30%. In still other embodiments, the oral bioavailability of the
proton pump
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inhibitor is at least 35%, or at least 40%, or at least 45%, or at least 50%,
or at least 55%
bioavailable, or at least 60%.
In alternative embodiments, the pharmaceutical composition comprises at least
about
mEq of antacid and is bioequivalent to a proton pump inhibitor product such as
Priolosec ,
Nexium , Prevacid , Protonic , or Aciphex . In other embodiments, the
pharmaceutical
composition comprises between about 5 mEq to about 30 mEq of antacid and is
bioequivalent
to a proton pump inhibitor product such as Priolosec , Nexium , Prevacid ,
Protonic , or
Aciphex . In still other embodiments, the pharmaceutical composition comprises
between
about 5 mEq to about 30 mEq, or about 5 mEq, or about 7 mEq, or about 10 mEq,
or about
13 mEq, or about 15 mEq, or about 17 mEq, or about 20 mEq, or about 22 mEq, or
about 25
mEq, or about 27 mEq, or about 30 mEq of antacid and is bioequivalent to a
proton pump
inhibitor product such as Priolosec , Nexium , Prevacid , Protonic , or
Aciphex .
"Bioequivalent" is intended to mean that the area under the serum
concentration time curve
(AUC) and the peak serum concentration (Cmax) are each within 80% and 120%.
In alternative embodiments, the pharmaceutical composition comprises at least
about
5 mEq of antacid and is Bioequivalent to a proton pump inhibitor product such
as Priolosec ,
Nexium , Prevacid , Protonic , or Aciphex . In other embodiments, the
pharmaceutical
composition comprises between about 5 mEq to about 11 mEq of antacid and is
bioequivalent
to a proton pump inhibitor product such as Priolosec , Nexium , Prevacid ,
Protonic 'O, or
Aciphex . In still other embodiments, the pharmaceutical composition comprises
between
about 5 mEq to about 11 mEq, or about 5 mEq, or about 6 mEq, or about 7 mEq,
or about 8
mEq, or about 9 mEq, or about 10 mEq, or about 11 mEq of antacid and is
bioequivalent to a
proton pump inhibitor product such as Priolosec , Nexium , Prevacid , Protonic
, or
Aciphex .
In other embodiments, when administered to a subject, the pharmaceutical
composition has an area under the serum concentration time curve (AUC) for the
proton
pump inhibitor that is equivalent to the area under the serum concentration
time curve (AUC)
for the proton pump inhibitor when the enteric form of the proton pump
inhibitor is delivered
without antacid. "Equivalent" is intended to mean that the area under the
serum
concentration time curve (AUC) for the proton pump inhibitor is within 30%
of the area
under the serum concentration time curve (AUC) when the same dosage amount of
the proton
pump inhibitor is enterically coated and delivered to the subject with less
than 1 mEq of
antacid. The "enteric form of the proton pump inhibitor" is intended to mean
that some or
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most of the proton pump inhibitor has been enterically coated to ensure that
at least some of
the drug is released in the proximal region of the small intestine (duodenum),
rather than the
acidic environment of the stomach.
In yet other embodiments, the pharmaceutical compositions provide a release
profile
of the proton pump inhibitor, using USP dissolution methods, whereby greater
than about
50% of the proton pump inhibitor is released from the composition within about
2 hours; or
greater than 50% of the proton pump inhibitor is released from the composition
within about
1.5 hours; or greater than 50% of the proton pump inhibitor is released from
the composition
within about 1 hour after exposure to gastrointestinal fluid. In another
embodiment, greater
than about 60% of the proton pump inhibitor is released from the composition
within about 2
hours; or greater than 60% of the proton pump inhibitor is released from the
composition
within about 1.5 hours; or greater than 60% of the proton pump inhibitor is
released from the
composition within about 1 hour after exposure to gastrointestinal fluid. In
yet another
embodiment, greater than about 70% of the proton pump inhibitor is released
from the
composition within about 2 hours; or greater than 70% of the proton pump
inhibitor is
released from the composition within about 1.5 hours; or greater than 70% of
the proton
pump inhibitor is released from the composition within about 1 hour after
exposure to
gastrointestinal fluid.
Compositions contemplated by the present invention provide a therapeutic
effect as
proton pump inhibiting agent medications over an interval of about 5 minutes
to about 24
hours after administration, enabling, for example, once-a-day, twice-a-day, or
three times a
day administration if desired. Generally speaking, one will desire to
administer an amount of
the compound that is effective to achieve a serum level commensurate with the
concentrations found to be effective in vivo for a period of time effective to
elicit a
therapeutic effect. Determination of these parameters is well within the skill
of the art.
DOSAGE FORMS
The pharmaceutical compositions of the present invention contain desired
amounts of
proton pump inhibitor and antacid and can be in the form of. a tablet,
(including a suspension
tablet, a chewable tablet, a fast-melt tablet, a bite-disintegration tablet, a
rapid-disintegration
tablet, an effervescent tablet, or a caplet), a pill, a powder (including a
sterile packaged
powder, a dispensable powder, or an effervescent powder) a capsule (including
both soft or
hard capsules, e.g., capsules made from animal-derived gelatin or plant-
derived HPMC) a
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lozenge, a sachet, a troche, pellets, granules, or an aerosol. The
pharmaceutical compositions
of the present invention can be manufactured by conventional pharmacological
techniques.
In some embodiments, the pharmaceutical compositions of the present invention
contain desired amounts of proton pump inhibiting inhibitor and antacid and
are in a solid
dosage form. In other embodiments, the pharmaceutical compositions of the
present
invention contain desired amounts of proton pump inhibitor and antacid and are
administered
in the form of a capsule (including both soft or hard capsules, e.g., capsules
made from
animal-derived gelatineor plant-derived HPMC). The pharmaceutical compositions
of the
present invention can be manufactured by conventional pharmacological
techniques.
Conventional pharmacological techniques include, e.g., one or a combination of
methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-
aqueous
granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al.,
The Theory and
Practice of Industrial Pharmacy (1986). Other methods include, e.g., prilling,
spray drying,
pan coating, melt granulation, granulation, wurster coating, tangential
coating, top spraying,
extruding, coacervation and the like.
In one embodiment, the proton pump inhibitor is microencapsulated prior to
being
formulated into one of the above forms. In another embodiment, some of the
proton pump
inhibitor is microencapsulated prior to being formulated. In another
embodiment, some or all
of the antacid is microencapsulated prior to being formulated. In still
another embodiment,
some or most of the proton pump inhibitor is coatedprior to being further
formulated by using
standard coating procedures, such as those described in Remington's
Pharmaceutical Sciences,
20th Edition (2000). In yet other embodiments contemplated by the present
invention, a film
coating is provided around the pharmaceutical composition.
In other embodiments, the pharmaceutical compositions further comprise one or
more
additional materials such as a pharmaceutically compatible carrier, binder,
filling agent,
suspending agent, flavoring agent, sweetening agent, disintegrating agent,
surfactant,
preservative, lubricant, colorant, diluent, solubilizer, moistening agent,
stabilizer, wetting
agent, anti-adherent, parietal cell activator, anti-foaming agent,
antioxidant, chelating agent,
antifungal agent, antibacterial agent, or one or more combination thereof.
In other embodiments, one or more layers of the pharmaceutical formulation are
plasticized. Illustratively, a plasticizer is generally a high boiling point
solid or liquid.
Suitable plasticizers can be added from about 0.01% to about 50% by weight
(w/w) of the
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coating composition. Plasticizers include, e.g., diethyl phthalate, citrate
esters, polyethylene
glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol,
polyethylene glycol,
triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and
castor oil.
Exemplary Solid Oral Dosage Compositions
Solid oral dosage compositions, e.g., tablets, chewable tablets, effervescent
tablets,
caplets, and capsules, can be prepared, for example, by mixing the proton pump
inhibitor, one
or more antacid, and pharmaceutical excipients to form a bulk blend
composition. When
referring to these bulk blend compositions as homogeneous, it is meant that
the proton pump
inhibitor and antacid are dispersed evenly throughout the composition so that
the composition
may be readily subdivided into equally effective unit dosage forms, such as
tablets, pills, and
capsules. The individual unit dosages may also comprise film coatings, which
disintegrate
upon oral ingestion or upon contact with diluent.
Compressed tablets are solid dosage forms prepared by compacting the bulk
blend
compositions described above. In various embodiments, compressed tablets of
the present
invention will comprise one or more functional excipients such as binding
agents and/or
disintegrants. In other embodiments, the compressed tablets will comprise a
film surrounding
the final compressed tablet. In other embodiments, the compressed tablets
comprise one or
more excipients and/or flavoring agents.
A chewable tablet may be prepared by compacting bulk blend compositions,
described above. In one embodiment, the chewable tablet comprises a material
useful for
enhancing the shelf life of the pharmaceutical composition. In another
embodiment, the
microencapsulated material has taste-masking properties. In various other
embodiments, the
chewable tablet comprises one or more flavoring agents and one or more taste-
masking
materials. In yet other embodiments the chewable tablet comprised both a
material useful for
enhancing the shelf life of the pharmaceutical formulation and one or more
flavoring agents.
In various embodiments, the proton pump inhibitor, antacid, and optionally one
or
more excipients, are dry blended and compressed into a mass, such as a tablet
or caplet,
having a hardness sufficient to provide a pharmaceutical composition that
substantially
disintegrates within less than about 30 minutes, less than about 35 minutes,
less than about 40
minutes, less than about 45 minutes, less than about 50 minutes, less than
about 55 minutes,
or less than about 60 minutes, after oral administration, thereby releasing
the antacid and the
proton pump inhibitor into the gastrointestinal fluid. When at least 50% of
the
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pharmaceutical composition has disintegrated, the compressed mass has
substantially
disintegrated.
A capsule may be prepared by placing any of the bulk blend compositions
described
above, into a capsule. In some embodiments of the present invention, the
therapeutic dose is
split into multiple (e.g., two, three, or four) capsules. In some embodiments,
the entire dose
of the proton pump inhibitor and antacid are delivered in a capsule form. For
example, the
capsule may comprise between about 10 mg to about 120 mg of a proton pump
inhibitor and
between about 5 mEq to about 30 mEq of antacid. In some embodiments, the
antacid may be
selected from sodium bicarbonate, magnesium hydroxide, calcium carbonate,
magnesium
oxide, and mixtures thereof. In alternative embodiments the capsule comprises
5 mEq to
about 30 mEq of sodium bicarbonate.
Exemplary Powder Compositions
A powder for suspension may be prepared by combining at least one acid labile
proton pump inhibitor and between about 5 mEq to about 11 mEq of antacid. In
various
embodiments, the powder may comprise one or more pharmaceutical excipients and
flavors.
A powder for suspension may be prepared, for example, by mixing the proton
pump inhibitor,
one or more antacids, and optional pharmaceutical excipients to form a bulk
blend
composition. This bulk blend is uniformly subdivided into unit dosage
packaging or multi-
dosage packaging units. The term "uniform" means the homogeneity of the bulk
blend is
substantially maintained during the packaging process.
In some embodiments, some or all of the proton pump inhibitor is micronized.
Additional embodiments of the present invention also comprise a suspending
agent and/or a
wetting agent.
Effervescent powders are also prepared in accordance with the present
invention.
Effervescent salts have been used to disperse medicines in water for oral
administration.
Effervescent salts are granules or coarse powders containing a medicinal agent
in a dry
mixture, usually composed of sodium bicarbonate, citric acid and/or tartaric
acid. When salts
of the present invention are added to water, the acids and the base react to
liberate carbon
dioxide gas, thereby causing "effervescence." Examples of effervescent salts
include, e.g.,
the following ingredients: sodium bicarbonate or a mixture of sodium
bicarbonate and
sodium carbonate, citric acid and/or tartaric acid. Any acid-base combination
that results in
the liberation of carbon dioxide can be used in place of the combination of
sodium
48
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bicarbonate and citric and tartaric acids, as long as the ingredients were
suitable for
pharmaceutical use and result in a pH of about 6.0 or higher.
The method of preparation of the effervescent granules of the present
invention
employs three basic processes: wet granulation, dry granulation and fusion.
The fusion
method is used for the preparation of most commercial effervescent powders. It
should be
noted that, although these methods are intended for the preparation of
granules, the
formulations of effervescent salts of the present invention could also be
prepared as tablets,
according to known technology for tablet preparation.
Powder for Suspension
In some embodiments, compositions are provided comprising a pharmaceutical at
least one proton pump inhibitor, about 5 mEq to about 11 mEq of an antacid,
and at least one
suspending agent for oral administration to a subject. The composition may be
a powder for
suspension, and upon admixture with water, a substantially uniform suspension
is obtained.
See U.S. Patent Application No. 10/893,092, filed July 16, 2004, which claims
priority to U.S.
Provisional Application No. 60/488,324 filed July 18, 2003; .
A suspension is "substantially uniform" when it is mostly homogenous, that is,
when
the suspension is composed of approximately the same concentration of proton
pump
inhibitor at any point throughout the suspension. A suspension is determined
to be composed'
of approximately the same concentration of proton pump inhibitor throughout
the suspension
when there is less than about 20%, less than about 15%, less than about 13%,
less than about
11%, less than about 10%, less than about 8%, less than about 5%, or less than
about 3%
variation in concentration among samples taken from various points in the
suspension.
The concentration at various points throughout the suspension can be
determined by
any suitable means known in the art. For example, one suitable method of
determining
concentration at various points involves dividing the suspension into three
substantially equal
sections: top, middle and bottom. The layers are divided starting at the top
of the suspension
and ending at the bottom of the suspension. Any number of sections suitable
for determining
the uniformity of the suspension can be used, such as for example, two
sections, three
sections, four sections, five sections, or six or more sections.
In one embodiment, the composition comprises at least one proton pump
inhibitor,
between about 5 mEq to about 11 mEq of antacid, and a gum suspending agent,
wherein the
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average particle size of the insoluble material is less than about 200 gm. In
some
embodiments, the average particle size of the insoluble material is less than
about 100 m. In
other embodiments, the average particle size of the insoluble material is less
than about 50
m. The composition is a powder for suspension, and upon admixture with water,
a first
suspension is obtained that is substantially more uniform when compared to a
second
suspension comprising the proton pump inhibitor, the antacid, and suspending
agent, wherein
the suspending agent is not xanthan gum.
In another embodiment, the composition comprises omeprazole, sodium
bicarbonate
and xanthan gum. The composition is a powder for suspension, and upon
admixture with
water, a substantially uniform suspension is obtained. In yet another
embodiment, the
composition is a powder for suspension and comprises omeprazole, about 5 mEq
to about 11
mEq sodium bicarbonate, xanthan gum, and at least one sweetener or flavoring
agent.
COMBINATION THERAPY
The compositions and methods described herein may also be used in conjunction
with
other well known therapeutic reagents that are selected for their particular
usefulness against
the condition that is being treated. In general, the compositions described
herein and, in
embodiments where combinational therapy is employed, other agents do not have
to be
administered in the same pharmaceutical composition, and may, because of
different physical
and chemical characteristics, have to be administered by different routes. The
determination
of the mode of administration and the advisability of administration, where
possible, in the
same pharmaceutical composition, is well within the knowledge of the skilled
clinician. The
initial administration can be made according to established protocols known in
the art, and
then, based upon the observed effects, the dosage, modes of administration and
times of
administration can be modified by the skilled clinician.
The particular choice of compounds used will depend upon the diagnosis of the
attending physicians and their judgment of the condition of the patient and
the appropriate
treatment protocol. The compounds may be administered concurrently (e.g.,
simultaneously,
essentially simultaneously or within the same treatment protocol) or
sequentially, depending
upon the nature of the proliferative disease, the condition of the patient,
and the actual choice
of compounds used. The determination of the order of administration, and the
number of
repetitions of administration of each therapeutic agent during a treatment
protocol, is well
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within the knowledge of the skilled physician after evaluation of the disease
being treated and
the condition of the patient.
It is understood that the dosage regimen to treat, prevent, or ameliorate the
condition(s)
for which relief is sought, can be modified in accordance with a variety of
factors. These
factors include the type of gastric acid disorder from which the subject
suffers, the proton
pump inhibitor being administered, as well as the age, weight, sex, diet, and
medical
condition of the subject. Thus, the dosage regimen actually employed can vary
widely and
therefore can deviate from the dosage regimens set forth herein. For example,
proton pump
inhibitors can be formulated to deliver rapid relief as well as sustained
relief of a gastric acid
related disorder.
The pharmaceutical agents which make up the combination therapy disclosed
herein
may be a combined dosage form or in separate dosage forms intended for
substantially
simultaneous administration. The pharmaceutical agents that make up the
combination
therapy may also be administered sequentially, with either therapeutic
compound being
administered by a regimen calling for two-step administration. The two-step
administration
regimen may call for sequential administration of the active agents or spaced-
apart
administration of the separate active agents. The time period between the
multiple
administration steps may range from, a few minutes to several hours, depending
upon the
properties of each pharmaceutical agent, such as potency, solubility,
bioavailability, plasma
half-life and kinetic profile of the pharmaceutical agent. Circadian variation
of the target
molecule concentration may also determine the optimal dose interval.
In some embodiments, the present methods, kits, and compositions can be used
in
combination with another pharmaceutical agent that is indicated for treating
or preventing a
gastrointestinal disorder, such as, for example, an anti-bacterial agent, an
alginate, a
prokinetic agent, or an H2-antagonist which are commonly administered to
minimize the pain
and/or complications related to this disorder. These drugs have certain
disadvantages
associated with their use. Some of these drugs are not completely effective in
the treatment
of the aforementioned conditions and/or produce adverse side effects, such as
mental
confusion, constipation, diarrhea, and thrombocytopenia.
In other embodiments, the present methods, kits, and compositions can be used
in
combination with other pharmaceutical agents, including but not limited to:
NSAIDs
including but not limited to aminoarylcarboxylic acid derivatives such as
enfenamic acid,
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etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid,
niflumic acid,
talniflumate, terofenamate, and tolfenamic acid; arylacetic acid derivatives
such as
aceclofenac, acemetacin, aiclofenac, amfenac, amtolmetin guacil, bromfenac,
bufexamac,
cinmetacin, clopirac, diclofenac sodium, etodolac, felbinac, fenclozic acid,
fentiazac,
glucametacin, ibufenac, indomethacin, isofezolac isoxepac, lonazolac,
metiazinic acid,
mofezolac, oxametacine, pirazolac, proglumetacin, sulindac, tiaramide,
tolmetin, tropesin,
and zomepirac; arylbutyric acid derivatives such as bumadizon, butibufen,
fenbufen,
xenbucin; arylcarboxylic acids such as clidanac, ketorolac, tinoridine;
arylpropionic acid
derivatives such as alminoprofen, benoxaprofin, bermoprofen, bucloxic acid,
carprofen,
fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen,
ketoprofen,
loxoprofen, naproxen, oxaprozin, piketoprofin, pirprofen, pranoprofen,
protizinic acid,
suprofen, tiaprofenic acid, ximoprofen, and zaltoprofen; pyrazoles such as
difenamizole, and
epirozole; pyrazolones such as apazone, benzpiperylon, feprazone,
mofebutazone, morazone,
oxyphenbutazone, phenylbutazone, pipebuzone, propyphenazone, prostaglandins,
ramifenazone, suxibuzone, and thiazolinobutazone; salicylic acid derivatives
such as
acetaminosalol, aspirin, benorylate, bromosaligenin, calcium acetylsalicylate,
diflunisal,
etersalate, fendosal, gentisic acid, glycol salicylate, imidazole salicylate,
lysine
acetylsalicylate, mesalamine, morpholine salicylate, 1-naphtyl salicylate,
olsalazine,
parsalmide, phenyl acetylsalicylate, phenyl salicylate, salacetamide,
salicylamide o-acetic
acid, salicylsulfuric acid, salsalate, sulfasalazine; thiazinecarboxamides
such as ampiroxicam,
droxicam, isoxicam, lomoxicam, piroxicam, and tenoxicam; cyclooxygenase-Il
inhibitors
("COX-II") such as Celebrex (Celecoxib), Vioxx, Relafen, Lodine, and Voltaren
and others,
such as epsilon-acetamidocaproic acid, s-adenosylmethionine, 3-amino-4-
hydroxybutytic
acid, amixetrine, bendazac, benzydamine, a-bisabolol, bucololome,
difenpiramide, ditazol,
emorfazone, fepradinol, guaiazulene, nabumetone, nimesulide, oxaceprol,
paranyline,
perisoxal, proquazone, tenidap and zilenton; sleep aids including but not
limited to a
benzodiazepine hypnotic, non-benzodiazepine hypnotic, antihistamine hypnotic,
antidepressant hypnotic, herbal extract, barbiturate, peptide hypnotic,
triazolam, brotizolam,
loprazolam, lormetazepam, flunitrazepam, flurazepam, nitrazepam, quazepam,
estazolam,
temazepam, lorazepam, oxazepam, diazepam, halazepam, prazepam, alprazolam,
chlordiazepoxide, clorazepate, an imidazopyridine or pyrazolopyrimidine
hypnotic, zolpidem
or zolpidem tartarate, zopiclone, eszopiclone, zaleplon, indiplone,
diphenhydramine,
doxylamine, phenyltoloxamine, pyrilamine, doxepin, amtriptyline, trimipramine,
trazodon,
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nefazodone, buproprion, bupramityiptyline, an herbal extract such as valerian
extract or
amentoflavone, a hormone such as melatonin,or gabapeptin; motility agents,
including but
not limited to 5-HT inhibitors such as cisapride, domperidone, and
metoclopramide, and
agents useful for treating irritable bowel syndrome.
EXAMPLES
The present invention is further illustrated by the following examples, which
should
not be construed as limiting in any way. The experimental procedures to
generate the data
shown are discussed in more detail below. For all formulations herein,
multiple doses may
be proportionally compounded as is known in the art. The coatings, layers and
encapsulations are applied in conventional ways using equipment customary for
these
purposes.
The invention has been described in an illustrative manner, and it is to be
understood
that the terminology used is intended to be in the nature of description
rather than of
limitation.
Example 1: Modified Fuchs Model for Antacid Selection
Samples were prepared and analyzed using a method that is a variation of the
Fuchs'
procedure described in the literature. The procedure described simulates a
gastric
environment with continuous acid influx. A description of experimental set-up
and sample
analysis is provided below. Changes may be made to these instructions after
initial sample
evaluation to optimize sample analysis and collection of relevant information.
Set-W:
1. A glass sample vessel (-150 mL capacity) containing 50 mL of a standardized
solution of 0.1 N HC1 was placed into a water bath set at 37 C ( 2 C).
2. A second glass vessel containing > 70 mL of a standardized solution of 1.0
N HCl
was placed into the same water bath.
3. The stir paddle was then placed into the sample vessel and set at an
appropriate speed.
The speed of the stir paddle was recorded and used for all samples analyzed.
The
speed of the paddle should be adequate to dissolve the sample and added acid
without
causing interference with the pH measurement or splashing of the solution.
4. Prior to the start of each sample analysis, the tubing was primed and it
was verified
that the flow rate with 1.0 N HCl was 0.5 mVmin and the temperature was 37 C (
2
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C). The pump and tubing were then set-up to allow the transfer of 1.0 N HC1
acid
into the sample vessel.
5. The pH meter was calibrated to accurately measure pH between 1 and 10 and
it was
verified that the electronic storage device was ready to collect pH and/or
temperature
data at a pre-defined rate.
6. When necessary, the sample was crushed into a fine powder using a mortar
and pestle
and then transferred to a suitable container and weighed.
7. The pH probe was placed into the glass sample vessel containing 50 mL of
0.1 N HC1
at 37 C ( 2 C).
8. The timer and pH data collection was then started. The sample was then
transferred
into the vessel and the exact time that the sample was introduced into the
acid was
recorded. The sample container was then re-weighed to determine the exact
weight
added.
9. The sample was then stirred for approximately 6 minutes and the flow of the
1.0 N
HC1 at a rate of 0.5 mL/min was started. The exact start time of the acid flow
was
recorded.
10. For samples with not more than (<) 30 mEq ANC the sample continued to stir
and the
pH was monitored for 1 hour in 15 second intervals.
11. The duration of the test was recorded and the total volume of 0.1 N HC1
added was
calculated based on the flow rate.
Various buffer combinations were screened using this modified Fuchs in-vitro
dynamic stomach model, described above, and it was discovered that the
correlation of the
theoretical ANC of a given buffer to the actual neutralization capacity and
the speed
depended on several factors such as solubility, particle size, presence and
level of binders
and/or disintegrants. For example, it was determined that the smaller the
particle size of the
buffer the closer the theoretical value was to the actual ANC of a given
buffer. This particle
size effect was especially noticeable for the insoluble or sparingly soluble
antacids such as
calcium carbonate or magnesium hydroxide. Contrastingly, the larger the
particles size of the
antacids, the lower the actual ANC was (e.g., sub-100 US mesh size, sub-80 US
mesh size,
and sub-60 mesh size of Magnesium Hydroxide).
It was also determined that spray dried magnesium hydroxide with 5% starch
such as
MS-90 from SPI Pharma performed better than the USP grade manufactured by
precipitation (USP grade Magnesium Hydroxide) in the on set speed of
neutralization. In
similar pattern, It spray dried calcium carbonate with 5% starch such as
Destab Calcium
carbonate-95S from Particle Dynamics performed better than the USP grade
calcium
carbonate manufactured by precipitation in the on set speed of neutralization
as well as the
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actual neutralization capacity measured by the area under curve (AUC) of the
dynamic pH
profile.
Example 2: Disintegrant Optimization Trials: Mixed Buffer System
Most proton pump inhibitors are sparingly soluble in water. These sparingly
soluble
drugs have a strong correlation of disintegration time to bioavailability, and
it is important to
optimize the disintegration time, which enhances in vivo dissolution of the
drug. This trial
used a sub-80 mesh US mesh size magnesium hydroxide based formulation as shown
in table
2A and tested levels between 3% and 11 % levels of disintegrant
(Croscarmellose Sodium,
Ac-di-Sol) for the capsule dosage form performance. Disintegration test
outlined by USP
(United State Pharmacopia) was chosen as the test method to determine the
optimal level of
disintegrant. All capsule products containing between 5% to 11 % Ac-Di-Sol
performed
similarly in terms of their physical characteristic, flow properties, and
encapsulation
characteristics. Disintegration testing of samples with mixed buffer systems
indicated that
capsule disintegration time is reduced when the level of disintegrant is
increased from 3% to
5%. Increasing the level of disintegrant beyond 5% did not lower the
disintegration time
significantly.
Table 2.A.1 Disinte rg ant_Optimization Trials
SAN-10D1 SAN-10D2 SAN-10D3 SAN-10D~
Ingredients 3% 5% 8% 11 %
Disintegrant Disintegrant Disinte rant Disinte rai
Mg/cap % Mg/cap % Mg/cap % Mg/cap 0,
OMEPRAZOLE USP 40.8 4.1 40.8 4.1 40.8 3.9 40.8 3.
Sodium Bicarbonate #2 USP 420 43.4 420 42.6 420 41.2 420 39
Magnesium Hydroxide 470 48.6 470 47.7 470 46.2 470 44
(sieved) sub 80 mesh
Croscarmellose Sodium NF 30 3.1 49 5.0 81 8.0 116 11
Magnesium Stearate NF 7 0.7 7 0.7 7 0.7 7 0.
Totals: 967 100.0 986 100.0 1018 100.0 1053 101
Table 2.A.2. Disinte rg ant Optimization Trials
Disintegration
Trial Number/ Times Comments/Observations
Description First Last
SAN-10D1 (3% Ac-Di-Sol) 9'10" 11'20" Virtually all disintegrated
at 9 mins.
SAN-10D2 (5% Ac-Di-Sol) 7'30" 12' Virtually all disintegrated
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at 7 mins 30 sees.
SAN-10D3 (8% Ac-Di-Sol) 8' 11' Virtually all disintegrated
at 7 mins.
SAN-10D4 (11% Ac-Di-Sol) 7'30" 10'30" Virtually all disintegrated
at 7 mins.
Example 2B: Disintegrant Optimization Trials - Sodium Bicarbonate Buffer
Sodium bicarbonate has effervescent characteristic when mixed with acid such
as
gastric fluid. This facilitates the disintegration time of a capsule product,
and the
disintegration requirement would be less than that of the mixed buffer system
when sodium
bicarbonate is used as a single buffer. This trial used a USP#2 grade sodium
bicarbonate
based formulation as shown in table 2.B. 1. and tested levels between 1% and
5% levels of
disintegrant (Croscarmerllose Sodium, Ac-di-Sol) for the capsule dosage form
performance.
Disintegration test outlined by USP (United State Pharmacopia) was chosen as
the test
method to determine the optimal level of disintegrant. All capsule products
containing
between 1% to 5% Ac-Di-Sol performed similarly in terms of their physical
characteristic,
flow properties, and encapsulation characteristics. However, disintegration
testing of
samples indicated that capsule disintegration time is reduced when the level
of disintegrant is
increased from 1% to 2%. Increasing the level of disintegrant beyond 3% did
not lower the
disintegration time significantly.
Table 2.B.1. Disintegrant Optimization Trials
SAN-10BB1 SAN-10BB2 SAN-10BB3 SAN-10BB4
Ingredients 1 % 2% 3% 5%
Disintegrant Disintegrant Disintegrant Disintegrani
Mg/cap % Mg/cap % Mg/cap % Mg/cap %
OMEPRAZOLE USP 40 3.5 40 3.4 40 3.4 40 3.3
Sodium Bicarbonate #2 USP 1100 94.9 1100 94.0 1100 93.1 1100 91.
Croscarmellose Sodium NF 12 1.0 23 20. 35 3.0 60 5.C
Magnesium Stearate NF 7 0.6 7 0.6 7 0.6 7 0.E
Totals: 967 100.0 986 100.0 1018 100.0 1053 100,
Table 2.B.2. Disintegrant Optimization Trials: Sodium Bicarbonate Buffer
Disintegration
Trial Number/ Times Comments/Observations
Description First Last
SAN-10BB1 (1% Ac-Di-Sol) 6'40" 8'20" Virtually all disintegrated
at 7 mins.
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SAN-1 OBB2 (2% Ac-Di-Sol) 4'30" 6' Virtually all disintegrated
at 5 miss 30 secs.
SAN-10B]33 (3% Ac-Di-Sol) 4' 5'30" Virtually all disintegrated
at 5 mins.
SAN-10BB4 (5% Ac-Di-Sol) 4' 5'30" Virtually all disintegrated
at 5 rains.
Example 3: Binder Optimization Trials
A low level of binder 3-8% is commonly used in capsule product manufacturing
to
make a plug before encapsulation. The use of the binder such as Klucel -EXP
(hydroxypropyl cellulose) or microcrystalline cellulose (Avicel PH-102, PH-
200) was
evaluated with the presence of 0-5% of disintegrant in the powder for the
performance using
the dynamic stomach model (modified Fuchs model). In general use of the binder
had a
negative impact on the actual ANC and the speed of neutralization in the pH
profiling tests,
unless used in combination with a disintegrant.
Table 3.A.1. Binder Optimization Trials
SAN-1OF1 SAN-10F2 SAN-10F3 SAN-10F4 SAN-10F5
Ingredients Mg/cap % Mg/cap % Mg/cap % Mg/cap % Mg/cap %
Om razole USP 40.0 4.5 40.0 4.0 40.0 3.8 40.0 3.6 40.0 3.6
Sodium Bicarbonate #2
USP 250 27.9 250 25.1 350 33.4 350 31.9 350 31.9
Magnesium Hydroxide 600.0 66.9 600.0 60.2 600.0 57.3 600.0 54.7 600.0 54.7
Klucel-EXP 0 0.0 100 10.0 0 0 100 9.1 50 4.6
Croscarmellose Sodium
NF 0 0.0 0 0.0 0 0.0 0 0.0 50 4.6
Magnesium Stearate
NF 7 0.8 7 0.7- 1 7 0.7 7 0.6 7 0.6
Totals: 897.0 100.0 997.0 100.0 997.0 100.0 1,097.0 100.0 1,097.0 100.0
Table 3.A.2. Binder Optimization Trials
Ingredients TR2001 TR2002 TR2003 TR2004 TR2005
Mg/cap % Mg/cap % Mg/cap % Mg/cap % Mg/cap %
Omeprazole USP 40 4.5 40 4.0 40 4.0 40 3.6 40 3.6
Sodium
Bicarbonate #2 45.
USP 450 50.2 450 45.1 450 1 450 41.0 450 41.0
Magnesium 50.
Hydroxide 500 55.7 500 50.2 500 2 500 45.6 500 45.6
Klucel-EXP 20 2.2 20 2.0 50 5.0 50 4.6 0 0.0
Croscarmellose 20 2.2 50 5.0 50 5.0 20 1.8 20 1.8
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Sodium NF
Magnesium
Stearate NF 7 0.8 7 0.7 7 0.7 7 0.6 7 0.6
Totals: 10 100.
897 100.0 997 100.0 997 0.0 1067.0 0 1017.0 100.0
The pH test results (table 3.A.1. and table 3.A.2.) shows that the capsules
with the .
binders at 5-10% level had a very slow neutralization speed while the capsule
with binder and
disintegrant had an adequate speed of neutralization. The capsules with no
binder and no
disintegrant showed a medium neutralization speed. Table 3BB showed the
similar findings
that the presence of binder slows down the neutralization speed while use of
disintegrant
mitigate the negative impact of binder in the formulation.
Table 3.B. 1 Neutralization Speed of Capsules with Various -Level of Binder
and
Disintegrant
Sample Binder Disintegrant Total Total Time Above pH (min)
Level Level (%) AN~C~ 3.5 5.0 6.0 6.5
(%) (
SAN-10F1 0 0 23.6 14.75 11.25 5.75 1.50
SAN-10F2 10 0 23.6 0 0 0 0
SAN-10F3 0 0 24.7 12.5 11.25 5.25 0
SAN-10F4 9.1 0 24.7 0 0 0 0
SAN-1OF5 4.6 4.6 24.7 34.25 30.00 22.50 15.25
Table 3.B.2 Neutralization Speed of Capsules with Various Level of Binder and
Disinteõgrant
Sample Binder Disintegrant Total Total Time Above pH (min)
Level Level (%) ANC 3.5 5.0 6.0 6.5
(%) (mEq)
TR2001 2.2 2.2 22.5 0 0 0 0
TR2002 2.0 5.0 22.5 7.25 6 0.25 0
TR2003 5.0 5.0 22.5 8.5 7 0.25 0
TR2004 4.6 1.8 22.5 0 0 0 0
TR2005 0.0 1.8 22.5 0 0 0 0
Example 4: Capsule Formulations
The following formulations were prepared by the following process: The sodium
bicarbonate and omeprazole were combined in a mixer and blended for 5 minutes.
To that
mixture, the magnesium hydroxide and croscarmellose sodium were added and
mixed for 5
minutes. The blend was then passes through a #20 mesh s/s screen and then
mixed for 10
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minutes. Magnesium stearate was then added to the mixture and blended for 3
minutes. The
material was then encapsulated into hard gelatinecapsule shells.
SAN-10A SAN-10B SAN-10BB SAN-10C
Ingredients Mg/caps Mg/caps Mg/caps Mg/caps
OMEPRAZOLE USP 40 40 40 20
Sodium Bicarbonate #2 USP 420 420 1100 800
Magnesium Hydroxide (sieved) 470 0 0 0
100 mesh
Magnesium Hydroxide (sieved) 60 0 470 0 0
mesh
Croscarmellose Sodium NF 30 30 20 20
Magnesium Stearate NF 10 10 10 8
Totals: 970 970 1170 848
SAN-1OD SAN-10E SAN-10F SAN-10G SAN-10H
Ingredients Mg/caps Mg/caps Mg/caps Mg/caps Mg/caps
OMEPRAZOLE USP 40 40 40 40 40
Sodium Bicarbonate #2 420 378 335 378 420
USP
Magnesium Hydroxide 470 0 0 0 0
(sieved) 80 mesh
Magnesium Hydroxide 0 0 375 0 375
(sieved) 60 mesh
Magnesium Hydroxide 95- 0 447.4 0 447.4 0
MS
Croscarmellose Sodium NF 30 27 24 56 82
Magnesium Stearate NF 7 6 5 6 5
Totals: 967 898.4 779.8 928 922
Example 5: Capsule Formulations with Sodium Bicarbonate and Less than 3%
Disintegrant
The following specific formulations are provided by way of reference only and
are
not intended to limit the scope of the invention. Each formulation contains
therapeutically
effective doses of PPI as well as sufficient buffering agent to prevent acid
degradation of at
least some of the PPI by raising the pH of gastric fluid. Amounts of buffer
are expressed in
weight as well as in molar equivalents (mEq). The capsules are prepared by
blending the PPI
with one or more buffering agents, and homogeneously blending with excipients.
The
appropriate weight of bulk blend composition is filled into a hard gelatine
capsule (e.g., size
00) using an automatic encapsulator. The PPI can be in a micronized form.
PPI Buffering Agent Excipient
40 mg omeprazole 11.3 mEq or 950 mg 50 mg Klucel
NaHCO3 30 mg Ac-di-Sol
mg magnesium stearate
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2.8% disintegrant
PPI Buffering Agent Excipient
40 mg omeprazole 10.5 mEq or 880 mg 30 mg Klucel
NaHCO3 20 mg Crospovidone
mg magnesium stearate
2.0% disintegrant
PPI Buffering Agent Excipient
60 mg omeprazole per 11.4 mEq or 960 mg 20 mg MCC
capsule NaHCO3 25 mg Ac-Di-Sol
10 mg magnesium stearate
1.9% disintegrant
Example 6: Capsule Formulations with Mixed Buffer Systems and 3-11%
disintegrant
The following specific formulations are provided by way of reference only and
are
not intended to limit the scope of the invention. Each formulation contains
therapeutically
effective doses of PPI as well as sufficient buffering agent to prevent acid
degradation of at
least some of the PPI by raising the pH of gastric fluid. Amounts of buffer
are expressed in
weight as well as in molar equivalents (mEq). The capsules are prepared by
blending the PPI
with one or more buffering agents, and homogeneously blending with excipients.
The
appropriate weight of bulk blend composition is filled into a hard
gelatinecapsule (e.g., size
00) using an automatic encapsulator. The PPI can be in a micronized form.
PPI Buffering A ent Excipient
40 mg omeprazole 20.6 mEq or 600 mg 20 mg MCC
Mg(OH)2 50 mg Ac-di-Sol
3 mEq or 250 mg NaHCO3 10 mg magnesium stearate
23.6 mEq or 950 mgs total 5.2% disintegrant
buffer
PPI Buffering Agent Excipient
40 mg omeprazole 20.6 mEq or 600 mg 100 mg MCC
Mg(OH)2 50 mg Ac-di-Sol
3 mEq or 250 mg NaHCO3 10 mg magnesium stearate
23.6 mE or 950 mgs total 4.8% disintegrant
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buffer
PPI Buffering Agent Excipient
40 mg omeprazole 20.6 mEq or 600 mg 30 mg MCC
Mg(OH)2 100 mg sodium starch
3 mEq or 250 mg NaHCO3 glycolate (Primojel(D)
mg magnesium stearate
23.6 mEq or 950 mgs total
buffer 9.7% disintegrant
PPI Buffering Agent Excipient
40 mg omeprazole 20.6 mEq or 600 mg 50 mg Klucel
Mg(OH)2 50 mg Ac-di-Sol
3 mEq or 250 mg NaHCO3 10 mg magnesium stearate
23.6 mEq or 850 mgs total 5.0 % disintegrant
buffer
PPI Buffering Agent Excipient
40 mg omeprazole 20.6 mEq or 600 mg 30 mg Klucel
Mg(OH)2 30 mg Ac-di-Sol
3 mEq or 250 mg NaHCO3 10 mg magnesium stearate
23.6 mEq or 850 mgs total 3.1% disintegrant
buffer
PPI Buffering Agent Excipient
mg omeprazole 20.6 mEq or 600 mg 100 mg Klucel
Mg(OH)2 30 mg Ac-di-Sol
3 mEq or 250 mg NaHCO3 10 mg magnesium stearate
23.6 mEq or 850 mgs total 3.0% disintegrant
buffer
PPI Buffering Agent Excipient
20 mg omeprazole 20.6 mEq or 600 mg 30 mg Klucel
Mg(OH)2 70 mg Crospovidone
3.0 mEq or 250 mg NaHCO3 10 mg magnesium stearate
23.6 mEq or 850 mgs total 7.1% disintegrant
buffer
PPI Buffering Agent Excipient
20 mg omeprazole per 20.6 mEq or 600 mg 50 mg Ac-Di-Sol
capsule Mg(OH)2 30 mg Klucel
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3.0 mEq or 250 mg NaHCO3 10 mg magnesium stearate
23.6 mEq or 850 mgs total 5.2% disintegrant
buffer
PPI Buffering Agent Excipient
20 mg omeprazole per 20.6 mEq or 600 mg 40 mg Ac-Di-Sol
capsule Mg(OH)2 35 mg Klucel
4.2 mEq or 350 mg NaHCO3 10 mg magnesium stearate
24.7 mEq or 950 mg total 4.1% disintegrant
buffer
PPI Buffering Agent Excipient
15 mg microencapsulated 17.1 mEq or 500 mg 50 mg Ac-Di-Sol
lansoprazole per capsule Mg(OH)2 15 mg Klucel
3.0 mEq or 250 mg NaHCO3 7 mg magnesium stearate
20.7 1 mEq or 750 mg total 6.0% disintegrant
buffer
PPI Buffering Agent Excipient
30 mg lansoprazole per 17.1 mEq or 500 mg 40 mg Ac-Di-Sol
capsule Mg(OH)2 30 mg Klucel
4.2 mEq or 350 mg NaHCO3 10 mg magnesium stearate
21.3 mEq or 850 mg total 4.2% disintegrant
buffer
PPI Buffering Agent Excipient
60 mg ompeprazole per 17.1 mEq or 500 mg 30 mg Crospovidone
capsule Mg(OH)2 15 mg Klucel
3.0 mEq or 250 mg NaHCO3 7 mg magnesium stearate
20.1 mEq or 750 mg total 3.5% disintegrant
buffer
PPI Buffering Agent Excipient
mg ompeprazole per 17.1 mEq or 500 mg 30 mg sodium starch
capsule Mg(OH)2 glycolate (Explotab )
3.0 mEq or 250 mg NaHCO3 15 mg Klucel
7 mg magnesium stearate
20.1 mEq or 750 mg total
buffer 3.7% disintegrant
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PPI Buffering Agent Excipient
20 mg microencapsulated 20.6 mEq or 600 mg Mg(OH)2 50 mg Ac-Di-Sol
omeprazole per capsule 3.0 mEq or 250 mg NaHCO3 50 mg Klucel
mg magnesium stearate
23.6 mEq or 850 mg total
buffer 5.1 % disintegrant
PPI Buffering Agent Excipient
40 mg omeprazole per 17.1 mEq or 500 mg Mg(OH)2 40 mg Ac-Di-Sol
capsule 4.2 mEq or 350 mg NaHCO3 45 mg Klucel
10 mg magnesium stearate
21.3 mEq or 850 mg total
buffer 4.1% disintegrant
PPI Buffering Agent Excipient
mg lansoprazole per 17.1 mEq or 500 mg 30 mg Crospovidone
capsule Mg(OH)2 15 mg Klucel
3.0 mEq or 250 mg NaHCO3 7 mg magnesium stearate
20.1 mEq or 750 mg total 3.7% disintegrant
buffer
PPI Buffering Agent Excipient
mg omeprazole per 17.1 mEq or 500 mg 50 mg Ac-Di-Sol
capsule Mg(OH)2 30 mg Klucel
3.0 mEq or 250 mg NaHCO3 10 mg magnesium stearate
20.1 mEq or 750 mg total 5.8% disintegrant
buffer
PPI Buffering Agent Excipient
40 mg omeprazole per 20.6 mEq or 600 mg 40 mg Ac-Di-Sol
capsule Mg(OH)2 35 mg Klucel
4.2 mEq or 350 mg NaHCO3 10 mg magnesium stearate
24.8 mEq or 950 mg total 3.7% disintegrant
buffer
PPI Buffering Agent Excipient
15 mg microencapsulated 17.1 mEq or 500 mg 60 mg Ac-Di-Sol
lansoprazole per capsule Mg(OH)2 15 mg Klucel
3.0 mEq or 250 mg NaHCO3 7 mg magnesium stearate
20.1 mEq or 750 mg total 7.1% disintegrant
buffer
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PPI Buffering Agent Excipient
60 mg ompeprazole per 17.1 mEq or 500 mg 30 mg Ac-Di-Sol
capsule Mg(OH)2 15 mg Klucel
3.0 mEq or 250 mg NaHCO3 7 mg magnesium stearate
20.1 mEq or 750 mg total 3.5% disintegrant
buffer
PPI Buffering Agent Excipient
20 mg omeprazole per 6.9 mEq or 200 mg Mg(OH)2 30 mg Ac-Di-Sol
capsule 3.9 mEq or 330 mg NaHCO3 35 mg Klucel
6 mg magnesium stearate
Size 0 capsule 10.8 mEq or 530 mg total
buffer 4.8% disintegrant
PPI Buffering Agent Excipient
15 mg microencapsulated 6.9 mEq or 200 mg Mg(OH)2 35 mg Ac-Di-Sol
lansoprazole per capsule 2.6 mEq or 220 mg NaHCO3 20 mg Klucel
6 mg magnesium stearate
Size 1 capsule 8.5 mEq or 420 mg total
buffer 7.1% disintegrant
PPI Buffering Agent Excipient
30 mg lansoprazole per 3.4 mEq or 100 mg Mg(OH)2 20 mg Ac-Di-Sol
capsule 3.8 mEq or 315 mg NaHCO3 30 mg Klucel
mg magnesium stearate
Size 1 capsule 7.2 mEq or 415 mg total
buffer 4.0% disintegrant
PPI Buffering Agent Excipient
60 mg ompeprazole per 5.1mEq or 150 mg Mg(OH)2 20 mg Ac-Di-Sol
capsule 3.0 mEq or 250 mg NaHCO3 10 mg Klucel
4 mg magnesium stearate
Size 2 capsule 8.1 mEq or 400 mg total
buffer 4.1% disintegrant
PPI Buffering Agent Excipient
120 mg ompeprazole per 8.6 mEq or 250 mg Mg(OH)2 30 mg Ac-Di-Sol
capsule 2.4 mEq or 200 mg NaHCO3 30 mg Klucel
8 mg magnesium stearate
Size 1 capsule 11.0 mEq or 450 mg total
buffer 4.7% disintegrant
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PPI Buffering Agent Excipient
mg ompeprazole per 3.4 mEq or 100 mg Mg(OH)2 18 mg Ac-Di-Sol
capsule 3.0 mEq or 250 mg NaHCO3 15 mg Klucel
7 mg magnesium stearate
Size 2 capsule 6.4 mEq or 350 mg total
buffer 4.5% disintegrant
Example 7: Capsule Formulations withithout Binder
The following specific formulations are provided by way of reference only and
are
not intended to limit the scope of the invention. Each formulation contains
therapeutically
effective doses of PPI as well as sufficient buffering agent to prevent acid
degradation of at
least some of the PPI by raising the pH of gastric fluid. Amounts of buffer
are expressed in
weight as well as in molar equivalents (mEq). The capsules are prepared by
blending the PPI
with one or more buffering agents, and homogeneously blending with excipients.
The
appropriate weight of bulk blend composition is filled into a hard gelatine
capsule (e.g., size
00) using an automatic encapsualtor. The PPI can be in a micronized form.
PPI Buffering Agent Excipient
40 mg omeprazole 20.6 mEq or 600 mg 50 mg Ac-di-Sol
Mg(OH)2 10 mg magnesium stearate
3.0 mEq or 250 mg NaHCO3
23.6 mEq or 950 mgs total
buffer
PPI Buffering Agent Excipient
40 mg microencapsulated 15.4 mEq or 450 mg Mg(OH)2 30 mg Ac-Di-Sol
ompeprazole per capsule 2.4 mEq or 200 mg NaHCO3 7 mg magnesium stearate
17.8 mEq or 650 mg total
buffer
PPI Buffering Agent Excipient
40 mg omeprazole per 10.5 mEq or 880 mg 20 mg Ac-Di-Sol
capsule NaHCO3 9 mg magnesium stearate
10.5 mEq or 880 mg total Size 0 Elongated capsule
buffer
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PPI Buffering Agent Excipient
40 mg microencapsulated 3.4 mEq or 100 mg Mg(OH)2 20 mg Ac-Di-Sol
ompeprazole per capsule 2.4 mEq or 200 mg NaHCO3 5 mg magnesium stearate
5.8 mEq or 300 mg total Size 2 capsule
buffer
PPI Buffering Agent Excipient
40 mg omeprazole per 13.1 mEq or 1100 mg USP 30 mg croscarmellose
capsule #2 NaHCO3 sodium, NF
mg magnesium stearate,
NF
Size 00 ca sule
PPI Buffering Agent Excipient
mg omeprazole per 13.1 mEq or 1100 mg USP 30 mg croscarmellose
capsule #2 NaHCO3 sodium, NF
10 mg magnesium stearate,
NF
Size 00 capsule
Example 8: Capsule Formulations
The following specific formulations are provided by way of reference only and
are
not intended to limit the scope of the invention. Each formulation contains
therapeutically
effective doses of PPI as well as sufficient antacid to prevent acid
degradation of at least
some of the PPI by raising the pH of gastric fluid. Amounts of antacid are
expressed in
weight as well as in molar equivalents (mEq). The capsules are prepared by
blending the PPI
with antacids, and homogeneously blending with excipients as shown in Tables
8.A. to 8.H.
below. The appropriate weight of bulk blend composition is filled into a hard
gelatine
capsule (e.g., size 00) using an automatic encapsualtor (H & K 1500 or MG2
G60). The PPI
can be in a micronized form.
Table 8.A. Omeprazole (20 mg) Capsule
PPI Antacid Excipient
20 mg omeprazole per 6.9 mEq or 200 mg Mg(OH)2 30 mg Ac-Di-Sol
capsule 3.9 mEq or 330 mg NaHCO3 35 mg Klucel
6 mg magnesium stearate
10.8 mEq or 530 mg total Size 0 capsule
antacid
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Table 8.B. Omeprazole (40 mg) Capsule
PPI Antacid Excipient
40 mg omeprazole per 10.5 mEq or 880 mg 40 mg Ac-Di-Sol
capsule NaHCO3 9 mg magnesium stearate
Size 0 Elongated capsule
10.5 mEq or 880 mg total
antacid
Table 8.C. Lansoprazole (15 mg) Capsule
PPI Antacid Excipient
15 mg microencapsulated 6.9 mEq or 200 mg Mg(OH)2 35 mg Ac-Di-Sol
lansoprazole per capsule 2.6 mEq or 220 mg NaHCO3 20 mg Klucel
6 mg magnesium stearate
9.5 mEq or 420 mg total Size 1 capsule
antacid
Table 8.D. Lansoprazole (30 mg) Capsule
PPI Antacid Excipient
30 mg lansoprazole per 3.4 mEq or 100 mg Mg(OH)2 20 mg Ac-Di-Sol
capsule 3.8 mEq or 315 mg NaHCO3 30 mg Klucel
mg magnesium stearate
7.2 mEq or 415 mg total Size 1 capsule
antacid
Table 8.E. Omeprazole (60 mg) Capsule
PPI Antacid Excipient
60 mg omeprazole per 5.1mEq or 150 mg Mg(OH)2 20 mg Ac-Di-Sol
capsule 3.0 mEq or 250 mg NaHCO3 10 mg Klucel
4 mg magnesium stearate
8.1 mEq or 400 mg total Size 2 capsule
antacid
Table 8.F. Omeprazole (60 mg) Capsule
PPI Antacid Excipient
120 mg omeprazole per 8.6 mEq or 250 mg Mg(OH)2 30 mg Ac-Di-Sol
capsule 2.4 mEq or 200 mg NaHCO3 30 mg Klucel
8 mg magnesium stearate
11.0 mEq or 450 mg total Size 1 capsule
antacid
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Table 8.G. Omeprazole (10 mg) Capsule
PPI Antacid Excipient
mg microencapsulated 3.4 mEq or 100 mg Mg(OH)2 18 mg Ac-Di-Sol
omeprazole per capsule 3.0 mEq or 250 mg NaHCO3 15 mg Microcrystalline
Cellulose (MCC, PH 102)
6.4 mEq or 350 mg total 7 mg magnesium stearate
antacid Size 2 ca sule
Table 8.H. Omeprazole (40 mg) Capsule
PPI Antacid Excipient
40 mg microencapsulated 3.4 mEq or 100 mg Mg(OH)2 20 mg Ac-Di-Sol
omeprazole per capsule 2.4 mEq or 200 mg NaHCO3 5 mg magnesium stearate
5.8 mEq or 300 mg total Size 2 capsule
antacid
Example 9: Tablet Formulations
The following specific formulations are provided by way of reference only and
are
not intended to limit the scope of the invention. Each formulation contains
therapeutically
effective doses of PPI and sufficient antacid to prevent acid degradation of
at least some of
the PPI by raising the pH of gastric fluid. Amounts of antacid are expressed
in weight as well
as in molar equivalents (mEq). The tablets are prepared by blending the PPI
and antacids,
and homogeneously blending with excipients as shown in Tables 9.A. to 9.H.
below. The
appropriate weight of bulk blended composition is compressed using oval shaped
toolings in
a rotary press (Manesty Express) to achieve a hardness of 15-20 kPa. The PPI
can be in a
micronized form.
Table 9.A. Omeprazole (20 mg) Tablet
PPI Antacid Excipient
mg omeprazole per tablet 5.1 mEq or 150 mg Mg(OH)2 30 mg Ac-Di-Sol
4.8 mEq or 400 mg NaHCO3 65 mg Klucel
10 mg magnesium stearate
9.9 mEq or 550 mg total
antacid
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Table 9.B. Omeprazole (40 mg) Tablet
PPI Antacid Excipient
40 mg microencapsulated 5.1 mEq or 150 mg Mg(OH)2 20 mg Ac-Di-Sol
omeprazole per tablet 3.0 mEq or 250 mg NaHCO3 40 mg Microcrystalline
cellulose (MCC, PHI 02)
8.1 mEq or 350 mg total 7 mg magnesium stearate
antacid
Table 9.C. Lansoprazole (15 mg) Tablet
PPI Antacid Excipient
15 mg microencapsulated 8.6 mEq or 250 mg Mg(OH)2 30 mg Ac-Di-Sol
lansoprazole per tablet 2.4 mEq or 200 mg NaHCO3 55 mg Plasdone
8 mg magnesium stearate
11.0 mEq or 450 mg total
antacid
Table 9.D. Lansoprazole (30 mg) Tablet
PPI Antacid Excipient
30 mg lansoprazole per tablet 6.2 mEq or 180 mg Mg(OH)2 25 mg Ac-Di-Sol
4.2 mEq or 350 mg NaHCO3 55 mg Klucel
8 mg magnesium stearate
10.4 mEq or 430 mg total
antacid
Table 9.E. Omeprazole (60 mg) Tablet
PPI Antacid Excipient
60 mg omeprazole per tablet 7.5 mEq or 220 mg Mg(OH)2 20 mg Ac-Di-Sol
3.0 mEq or 250 mg NaHCO3 60 mg Klucel
mg magnesium stearate
10.5 mEq or 470 mg total
antacid
Table 9.F. Omeprazole (20 mg) Tablet
PPI Antacid Excipient
mg omeprazole per tablet 7.5 mEq or 220 mg Mg(OH)2 20 mg Ac-Di-Sol
2.4 mEq or 200 mg NaHCO3 60 mg Klucel
8 mg magnesium stearate
9.9 mEq or 420 mg total
antacid
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Table 9.G. Omeprazole (10 mg) Tablet
PPI Antacid Excipient
mg microencapsulated 3.4 mEq or 100 mg Mg(OH)2 15 mg Ac-Di-Sol
omeprazole per tablet 3.0 mEq or 250 mg NaHCO3 40 mg Klucel
6 mg magnesium stearate
6.4 mEq or 350 mg total
antacid
Table 9.H. Omeprazole (40 mg) Tablet
PPI Antacid Excipient
40 mg microencapsulated 5.1 mEq or 150 mg Mg(OH)2 20 mg Ac-Di-Sol
omeprazole per tablet 3.8 mEq or 315 mg NaHCO3 50 mg Microcrystalline
Cellulose (MCC, PH102)
8.9 mEq or 465 mg total 10 mg magnesium stearate
antacid
Example 10: Chewable Tablet Formulations
The following specific formulations are provided by way of reference only and
are
not intended to limit the scope of the invention. Each formulation contains
therapeutically
effective doses of PPI and sufficient antacid to prevent acid degradation of
at least some of
the PPI by raising the pH of gastric fluid. Amounts of antacid are expressed
in weight as well
as in molar equivalents (mEq). The tablets are prepared by blending the PPI
and antacids,
and homogeneously blending with excipients as shown in Tables 10.A to 10.H.
below. The
appropriate weight of bulk blended composition is compressed using 17mm FFBE
toolings in
a rotary press (Manesty Express) to achieve a hardness of 10-14 kPa. The PPI
can be in a
micronized form.
Table 10.A. Omeprazole (20 mg) Chewable Tablet
PPI Antacid Excipient
mg microencapsulated 5.1 mEq or 150 mg Mg(OH)2 100 mg Xylitab
omeprazole per tablet 3.8 mEq or 315 mg NaHCO3 30 mg Ac-Di-Sol
80 mg Klucel
20mg Sucralose
8.9 mEq or 465 mg total 10 mg cherry flavor
antacid 10 mg magnesium stearate
1 mg Red #40 Lake
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Table 10.B. Omeprazole (40 mg) Chewable Tablet
PPI Antacid Excipient
40 mg microencapsulated 7.5 mEq or 220 mg Mg(OH)2 100 mg Dipac sugar
omeprazole per tablet 2.4 mEq or 200 mg NaHCO3 20 mg Ac-Di-Sol
80 mg Klucel
9.9 mEq or 420 mg total 17 mg grape flavor
antacid 11 mg magnesium stearate
1 mg Red #40 Lake
1 mg Blue #2 Lake
Table 10.C. Lansoprazole (15 mg) Chewable Tablet
PPI Antacid Excipient
15 mg lansoprazole per tablet 5.1 mEq or 150 mg Mg(OH)2 80 mg Xylitab
2.4 mEq or 200 mg NaHCO3 25 mg Ac-Di-Sol
70 mg Microcrystalline
7.5 mEq or 350 mg total Cellulose
antacid 50 mg Asulfame-K
15 mg grape flavor
mg magnesium stearate
1 mg red #40 lake
1 mg blue #2 lake
Table 10.D. Lansoprazole (30 mg) Chewable Tablet
PPI Antacid Excipient
30 mg microencapsulated 5.1 mEq or 150 mg Mg(OH)2 70 mg Destab Sugar
lansoprazole per tablet 3.8 mEq or 315 mg NaHCO3 30 mg Ac-Di-Sol
100 mg Klucel
8.9 mEq or 465 mg total 20mg Asulfame-K
antacid 15 mg cherry flavor
9 mg magnesium stearate
1 mg Red #40 Lake
Table 10.E. Omeprazole (60 mg) Chewable Tablet
PPI Antacid Excipient
60 mg microencapsulated 4.4 mEq or 220 mg Ca(OH)2 80 mg Xylitab
omeprazole per tablet 3.6 mEq or 300 mg NaHCO3 30 mg Ac-Di-Sol
100 mg Klucel
8.0 mEq or 520 mg total 35mg Sucralose
antacid 10 mg cherry flavor
9 mg magnesium stearate
2 mg Red #40 Lake
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Table 10.F. Omeprazole (60 mg) Chewable Tablet
PPI Antacid Excipient
60 mg omeprazole per tablet 3.0 mEq or 150 mg Ca(OH)2 70 mg Xylitab
3.0 mEq or 250 mg NaHCO3 25 mg Ac-Di-Sol
90 mg Microcrystalline
6.0 mEq or 400 mg total Cellulose (PH 102)
antacid 8 mg mint flavor
mg magnesium stearate
Table 10.G. Omeprazole (10 mg) Chewable Tablet
PPI Antacid Excipient
10 mg omeprazole per tablet 8.0 mEq or 400 mg Ca(OH)2 110 mg Ditab Sugar
3.6 mEq or 300 mg NaHC03 30 mg Ac-Di-Sol
20mg Sucralose
11.6 mEq or 700 mg total 100 mg Klucel
antacid 15 mg mint flavor
mg magnesium stearate
Table 10.H. Omeprazole (40 mg) Chewable Tablet
PPI Antacid Excipient
40 mg microencapsulated 7.5 mEq or 350 mg Ca(OH)2 70 mg Xylitab
omeprazole per tablet 3.0 mEq or 250 mg NaHCO3 30 mg Ac-Di-Sol
10 mg Sucralose
10.5 mEq or 600 mg total 80 mg Klucel
antacid 10 mg mint flavor
8 mg magnesium stearate
Example 11: Bite-Disintegration Chewable Tablet Formulations
The following specific formulations are provided by way of reference only and
are
not intended to limit the scope of the invention. Each formulation contains
therapeutically
effective doses of PPI and sufficient antacid to prevent acid degradation of
at least some of
the PPI by raising the pH of gastric fluid. Amounts of antacid are expressed
in weight as well
as in molar equivalents (mEq). The tablets are prepared by blending the PPI
with antacids,
and homogeneously blending with excipients as shown in Tables 11 .A to 11 .H.
below. The
appropriate weight of bulk blended composition is compressed using 10mm FFBE
toolings in
a rotary press (Manesty Express) to achieve a hardness of 5-9 kPa. The PPI can
be in a
micronized form.
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Table 11 .A. Omeprazole (20 mg) Bite-Disintegration Chewable Tablet
PPI Antacid Excipient
20 mg per tablet 7.5 mEq or 350 mg Ca(OH)2 20 mg sucralose
3.0 mEq or 250 mg NaHCO3 40 mg Ac-Di-Sol
30 mg pregelatinized starch
10.5 mEq or 600 mg total 30 mg Klucel
antacid 15 mg cherry flavor
8 mg magnesium stearate
1 mg Red #40 Lake
Table 11.B. Omeprazole (40 mg) Bite-Disintegration Chewable Tablet
PPI Antacid Excipient
40 mg microencapsulated 8.0 mEq or 400 mg Ca(OH)2 20 mg sucralose
omeprazole per tablet 3.6 mEq or 300 mg NaHCO3 40 mg Ac-Di-Sol
35 mg pregelatinized starch
11.6 mEq or 700 mg total 25 mg Klucel
15 mg cherry flavor
8 mg magnesium stearate
1 mg Red #40 Lake
Table 11.C. Lansoprazole (15 mg) Bite-Disintegration Chewable Tablet
PPI Antacid Excipient
15 mg lansoprazole per tablet 7.9 mEq or 230 mg Mg(OH)2 20 mg sucralose
3.6 mEq or 300 mg NaHCO3 35 mg Ac-Di-Sol
35 mg pregelatinized starch
11.5 mEq or 530 mg total 25 mg Klucel
17 mg grape flavor
8 mg magnesium stearate
1 mg Red #40 Lake
1 mg Blue #2 lake
Table 11.D. Lansoprazole (30 mg) Bite-Disintegration Chewable Tablet
PPI Antacid Excipient
30 mg microencapsulated 5.1 mEq or 150 mg Mg(OH)2 27 mg sucralose
lansoprazole per tablet 3.8 mEq or 315 mg NaHCO3 40 mg Ac-Di-Sol
35 mg pregelatinized starch
8.9 mEq or 465 mg total 30 mg Microcrystalline
antacid Cellulose (PH101)
20 mg cherry flavor
mg magnesium stearate
2 mg Red #40 Lake
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Table 11.E. Omeprazole (60 mg) Bite-Disintegration Chewable Tablet
PPI Antacid Excipient
60 mg microencapsulated 7.9 mEq or 230 mg Mg(OH)2 34 mg sucralose
omeprazole per tablet 3.0 mEq or 250 mg NaHCO3 30 mg Ac-Di-Sol
35 mg pregelatinized starch
10.9 mEq or 480 mg total 30 mg Klucel
antacid 25 mg cherry flavor
mg magnesium stearate
2mg Red #40 Lake
Table 11.F. Omeprazole (60 mg) Bite-Disintegration Chewable Tablet
PPI Antacid Excipient
60 mg omeprazole per tablet 7.0 mEq or 350 mg Ca(OH)2 30 mg sucralose
3.0 mEq or 250 mg NaHCO3 40 mg Ac-Di-Sol
30 mg pregelatinized starch
10.0 mEq or 600 mg total 30 mg Klucel
antacid 40mg Xylitab
7 mg mint flavor
10 mg magnesium stearate
Table 11.G. Omeprazole (10 mg) Bite-Disintegration Chewable Tablet
PPI Antacid Excipient
10 mg omeprazole per tablet 5.0 mEq or 250 mg Ca(OH)2 20 mg sucralose
2.9 mEq or 240 mg NaHCO3 40 mg Ac-Di-Sol
30 mg pregelatinized starch
7.9 mEq or 490 mg total 30 mg Klucel
antacid 15 mg cherry flavor
8 mg magnesium stearate
1 mg Red #40 Lake
Table 11.H. Omeprazole (40 mg) Bite-Disintegration Chewable Tablet
PPI Antacid Excipient
40 mg microencapsulated 8.0 mEq or 400 mg Ca(OH)2 30 mg sucralose
omeprazole per tablet 2.9 mEq or 240 mg NaHCO3 40 mg Ac-Di-Sol
30 mg pregelatinized starch
10.9 mEq or 1590 mg total 30 mg Klucel
antacid 40mg Xylitab
7 mg mint flavor
10 mg magnesium stearate
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Example 12: Powder for Suspension Formulations
The following specific formulations are provided by way of reference only and
are
not intended to limit the scope of the invention. Each formulation contains
therapeutically
effective doses of PPI and sufficient antacid to prevent acid degradation of
at least some of
the PPI by raising the pH of gastric fluid. The PPI can be in a micronized
form.
Table 12.A. Microencapsulated Omeprazole (20/40/60/120 mg) Powder for
Suspension
1 2 3 4 5 6 7 8 9 10
Microencapsulated 20 20 20 40 40 40 60 60 120 120
Omeprazole
Sodium Bicarbonate 200 220 300 140 160 200 300 280 150 200
Magnesium Hydroxide 250 170 150 250 170 150 170 150 100 150
Calcium Carbonate 0 0 0 0 100 150 0 100 0 150
X litol300 (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 100(
Sucrose-powder 1000 1000 1000 1000 1000 1000 1000 1000 1000 100(
(sweetener)
Sucralose (sweetener) 60 100 150 75 100 70 80 130 125 80
Xanthan Gum 10 55 31 80 39 48 72 25 64 68
Peach Flavor 33 15 75 32 60 50 77 38 35 62
Peppermint 13 10 29 28 36 42 56 17 16 50
Total Weight 2586 2590 2755 2645 2705 2750 2815 2800 2610 288(
Total ANC 11.0 8.4 8.7 10.2 9.7 10.5 9.4 10.5 5.2 10.5
Table 12.B. Omeprazole (20 mg) Powder for Suspension
1 2 3 4 5 6 7 8 9 1(
Omeprazole 20 20 20 20 20 20 20 20 20 2(
Sodium Bicarbonate 200 220 300 140 160 200 300 280 150 20,
Magnesium Hydroxide 250 170 150 250 170 150 170 150 100 15,
Calcium Carbonate 0 0 0 0 100 150 0 100 0 15,
X litol300 (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 10(
Sucrose-powder (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 10(
Sucralose (sweetener) 60 100 150 75 100 70 80 130 125 8(
Xanthan Gum 10 55 31 80 39 48 72 25 64 6E
Peach Flavor 33 15 75 32 60 50 77 38 35 6:
Peppermint 13 10 29 28 36 42 56 17 16 5(
Total Weight 2586 2590 2755 2625 2685 2730 2775 2760 2510 27F
Total ANC 11.0 8.4 8.7 10.2 9.7 10.5 9.4 10.5 5.2 10.
Table 12.C. Omeprazole (40 mg) Powder for Suspension
1 2 3 4 5 6 7 8 9 1(
Omeprazole 40 40 40 40 40 40 40 40 40 4(
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Sodium Bicarbonate 200 220 300 140 160 200 300 280 150 201
Magnesium Hydroxide 250 170 150 250 170 150 170 150 100 1.
Calcium Carbonate 0 0 0 0 100 150 0 100 0 151
Xylitol 300 (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 10C
Sucrose-p owder (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 10C
Sucralose (sweetener) 60 100 150 75 100 70 80 130 125 8C
Xanthan Gum 75 10 55 31 80 39 48 72 25 64 68
Peach Flavor 33 15 75 32 60 50 77 38 35 62
Peppermint 13 10 29 28 36 42 56 17 16 5C
Total Weight 2606 2610 2775 2645 2705 2750 2795 2780 2530 28C
Total ANC 11.0 8.4 8.7 10.2 9.7 10.5 9.4 10.5 5.2 10.
Table 12.D. Omeprazole (60 mg) Powder for Suspension
1 2 3 4 5 6 7 8 9 10
Omeprazole 60 60 60 60 60 60 60 60 60 6(
Sodium Bicarbonate 200 220 300 140 160 200 300 280 150 20,
Magnesium Hydroxide 250 170 150 250 170 150 170 150 100 15,
Calcium Carbonate 0 0 0 0 100 150 0 100 0 15,
X litol300 (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 10Ã
Sucrose-powder (sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 10Ã
Sucralose (sweetener) 60 100 150 75 100 70 80 130 125 8(
Xanthan Gum 75 10 55 31 80 39 48 72 25 64 6~
Peach Flavor 33 15 75 32 60 50 77 38 35 62
Peppermint 13 10 29 28 36 42 56 17 16 5C
Total Weight 2626 2630 2795 2665 2725 2770 2815 2800 2550 282
Total ANC 11.0 8.4 8.7 10.2 9.7 10.5 9.4 10.5 5.2 10.
Many modifications, equivalents, and variations of the present invention are
possible
in light of the above teachings, therefore, it is to be understood that within
the scope of the
appended claims, the invention may be practiced other than as specifically
described.
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