U.S. patent application number 17/489939 was filed with the patent office on 2022-05-05 for pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them.
This patent application is currently assigned to Santarus, Inc.. The applicant listed for this patent is Santarus, Inc.. Invention is credited to Warren Hall, Kay Olmstead, Gerald T. Proehl.
Application Number | 20220133778 17/489939 |
Document ID | / |
Family ID | |
Filed Date | 2022-05-05 |
United States Patent
Application |
20220133778 |
Kind Code |
A1 |
Olmstead; Kay ; et
al. |
May 5, 2022 |
PHARMACEUTICAL FORMULATIONS USEFUL FOR INHIBITING ACID SECRETION
AND METHODS FOR MAKING AND USING THEM
Abstract
The present invention relates to pharmaceutical formulations
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. 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.
Inventors: |
Olmstead; Kay; (San Diego,
CA) ; Hall; Warren; (Del Mar, CA) ; Proehl;
Gerald T.; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Santarus, Inc. |
Bridgewater |
NJ |
US |
|
|
Assignee: |
Santarus, Inc.
Bridgewater
NJ
|
Appl. No.: |
17/489939 |
Filed: |
September 30, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16138859 |
Sep 21, 2018 |
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17489939 |
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14467741 |
Aug 25, 2014 |
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16138859 |
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11287888 |
Nov 28, 2005 |
8815916 |
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14467741 |
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11138763 |
May 25, 2005 |
8906940 |
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11287888 |
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60574663 |
May 25, 2004 |
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60574646 |
May 25, 2004 |
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International
Class: |
A61K 33/00 20060101
A61K033/00; A61K 9/00 20060101 A61K009/00; A61K 9/20 20060101
A61K009/20; A61K 9/48 20060101 A61K009/48; A61K 31/4439 20060101
A61K031/4439; A61K 33/08 20060101 A61K033/08 |
Claims
1. (canceled)
2. A pharmaceutical formulation comprising about 20 mg of
omeprazole or a salt thereof, an antacid consisting of about 1100
mg of sodium bicarbonate, a disintegrant consisting of
croscarmellose sodium, and a lubricant consisting of magnesium
stearate, wherein the pharmaceutical formulation does not comprise
a binder.
3. The pharmaceutical formulation of claim 2, wherein upon oral
administration of the capsule to a fasted human subject, a
T.sub.max of the omeprazole or salt thereof is obtained within 60
minutes after administration on day 1.
4. The pharmaceutical formulation of claim 2, wherein an initial
serum concentration of the omeprazole or salt thereof is greater
than 300 ng/ml within 45 minutes after administration.
5. The pharmaceutical formulation of claim 2, further comprising
polysorbate-80.
6. The pharmaceutical formulation of claim 2, wherein the
croscarmellose sodium is provided in an amount of about 2 wt-% to
about 8 wt-%.
7. The pharmaceutical formulation of claim 2, wherein the magnesium
stearate is provided in an amount of about 0.5 wt-% to about 3
wt-%.
8. A capsule comprising the pharmaceutical formulation of claim
2.
9. The capsule of claim 8, wherein the capsule comprises gelatin.
Description
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 11/138,763, filed on May 25, 2005, which in
turn claims benefit under 35 U.S.C. .sctn. 119(e) of U.S.
Provisional Application No. 60/574,646, filed May 25, 2004 and U.S.
Provisional Application No. 60/574,663, filed May 25, 2004, the
contents of each of which are incorporated herein by reference in
their entirety.
FIELD OF THE INVENTION
[0002] 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 5 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.
[0003] 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
[0004] 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-subject variability are all major set backs of
using enteric-coated systems for the controlled release of a
drug.
[0005] 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. Pat.
Nos. 5,840,737 and 6,489,346.
[0006] 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.RTM.), lansoprazole (Prevacid.RTM.),
esomeprazole (Nexium.RTM.), rabeprazole (Aciphex.RTM.),
pantoprazole (Protonix.RTM.), pariprazole, tenatoprazole, and
leminoprazole. The drugs of this class suppress gastrointestinal
acid secretion by the specific inhibition of the
H.sup.+/K.sup.+-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.
[0007] 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. Pat. 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.
[0008] 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.
[0009] It is believed that omeprazole, lansoprazole and other
proton pump inhibiting agents reduce gastrointestinal acid
production by inhibiting H.sup.+/K.sup.+-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.sup.+/K.sup.+-ATPase,
Nature, 290: 159-161 (1981); Wallmark et al., The Relationship
Between Gastrointestinal Acid Secretion and Gastrointestinal
H.sup.+/K.sup.+-ATPase Activity, J. Biol. Chem., 260: 13681-13684
(1985); and Fryklund et al., Function and Structure of Parietal
Cells After H.sup.+/K.sup.+-ATPase Blockade, Am. J. Physiol., 254
(1988).
[0010] 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.sup.+/K.sup.+-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.sup.+/K.sup.+-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
[0011] 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 T.sub.max of the proton pump inhibitor is obtained
within about 75 minutes after administration. In alternative
embodiments, T.sub.max 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.
[0012] 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.sub.max 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,
T.sub.max 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.
[0013] 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 T.sub.max 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 5 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.
[0014] 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 11% of a disintegrant, wherein upon oral
administration to a patient a therapeutically effective amount of
the proton pump inhibitor is delivered and T.sub.max 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, T.sub.max 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.
[0015] 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
T.sub.max 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, T.sub.max of the
proton pump inhibitor is obtained within about 60 minutes, or
within about 45 minutes, or within about 30 minutes after
administration.
[0016] 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 T.sub.max 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 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, T.sub.max 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.
[0017] 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 T.sub.max of the proton pump inhibitor
is obtained within about 75 minutes. In other embodiments,
T.sub.max of the proton pump inhibitor is obtained within about 60
minutes, or within about 45 minutes, or within about 30 minutes
after administration.
[0018] 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-%.
[0019] 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.
[0020] 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%.
[0021] 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.
[0022] 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.
[0023] 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.
[0024] 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
embodiments, the pharmaceutical formulation is bioequivalent to
Priolosec.RTM., Nexium.RTM., Prevacid.RTM., Protonic.RTM., and
Aciphex.RTM.. In other embodiments, the maximum concentration of
the proton pump inhibitor for the phamaceutical 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.
[0025] 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.
[0026] 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.
[0027] 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 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.
[0028] 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.
[0029] 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.
[0030] 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.
[0031] 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.
[0032] 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.
[0033] 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.
[0034] 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 inhibitor occurs
within about 1 hour after administration of a single dose of the
composition to the subject.
[0035] 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.
[0036] 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.
[0037] 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.
[0038] 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.
[0039] 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 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.RTM. (a mixture of sodium bicarbonate and sodium
carbonate) and mixtures thereof. In yet other embodiments, the
antacid can be sodium bicarbonate, sodium carbonate,
Effersoda.RTM., 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.
[0040] 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 pharmaceutical formulation comprises
about 5 mEq to about 30 mEq, or about 8 mEq to about 20 mEq, or
about mEq to about 15 mEq of antacid. In further embodiments, the
pharmaceutical formulations comprise about 13 mEq of antacid.
[0041] 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 formulation 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.
[0042] 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;
hydroxyethylcclluloses; 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.
[0043] 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 agents, disintegration agents,
filling agents, surfactants, solubilizers, stabilizers, lubricants,
wetting agents, diluents, anti-adherents, and antifoaming
agents.
DESCRIPTION OF THE FIGURES
[0044] FIG. 1 shows a comparison of buffer systems comprising
various mixtures of NaHCO.sub.3 and Mg(OH).sub.2.
[0045] FIG. 2 shows a comparison of buffer systems comprising
various mixtures of NaHCO.sub.3 and Mg(OH).sub.2.
[0046] FIG. 3 shows the particle size effect of magnesium hydroxide
on in-vitro/m-vivo neutralization for immediate release capsule
formulations SAN-10A, SAN-10B and SAN-10D.
[0047] FIG. 4 shows the particle size effect of magnesium hydroxide
on the pharmacokinetics of various formulations.
[0048] FIG. 5 shows the binder effect on various pharmaceutical
formulations.
[0049] FIG. 6 shows the capsule dissolution effect with 5% binder
as compared to a powder for suspension.
[0050] FIG. 7 shows the pH study results of high/low Ac-Di-Sol
(disintegrant).
[0051] FIG. 8 shows the pharmacokinetic study results of high/low
Ac-Di-Sol (disintegrant) as compared to Prilosec.
[0052] FIG. 9 shows the pharmacokinetic profiles for six different
pharmaceutical formulations.
[0053] FIG. 10 is a summary of exemplary formulations with the ANC
present in the individual pharmaceutical formulations.
[0054] FIG. 11 is a summary of the pharmacokinetics of various
formulations.
[0055] FIG. 12 shows the capsule stability of SAN-10E, SAN-10BB,
and SAN-10B.
[0056] FIG. 13 compares the concentration/time curve for
Prilosec.RTM. to the concentration/time curve of SAN-10K (10.5 mEq
of Sodium Bicarbonate and 40 mg omeprazole).
[0057] FIG. 14 is a graph comparing the average pharmacokinetic
release profiles of immediate release omeprazole chewable tablets
(SAN-15A, SAN-15B and SAN-15C), capsules (SAN-10A, SAN-10B,
SAN-10C, SAN-10E, SAN-10H, SAN-10BB), and a caplets (SAN-15D and
SAN-15E) according to the present invention as compared to
Priolosec.RTM. enteric coated omeprazole 40 mg. The compositions
according to the present invention are all set forth in Table 13A,
below.
[0058] FIG. 15 is a graph comparing the average pharmacokinetic
release profiles of SAN-10BB (P9), SAN-10H (P8) and SAN-10B (P4)
omeprazole capsules, 40 mg per dose. The formulations are described
in detail in Example 13.
[0059] FIG. 16 is a graph comparing the Cmax and Tmax values for
immediate release omeprazole powder, capsule, chew tab and caplet
formulations according to the present invention with those of
Prilosec.RTM. brand enteric coated omeprazole. The omeprazole
powder is immediate release omeprazole powder for suspension, 20 or
40 mg micronized omeprazole and 1680 mg (20 mEq) of sodium
bicarbonate, described in Example 16; the chewable tablets are 20
or 40 mg SAN-38 chewable tablets, as described herein; the capsules
are SAN-7E (40 mg) or SAN-7F (20 mg) capsules as described in
Examples 7, 14 and 15, below.
[0060] FIG. 17 is a graph comparing the average pharmacokinetic
release profiles of immediate release omeprazole suspension (20
mg)(Example 16), chewable tablets (20 mg), capsule (20 mg)(Example
7F), and Prilosec.RTM. brand enteric coated omeprazole (20) mg from
the human clinical trial described in Example 14B, Day 1.
[0061] FIG. 18 is a graph comparing the average pharmacokinetic
release profiles of immediate release omeprazole suspension (40 mg)
(Example 16), chewable tablets (40 mg), capsule (40 mg)(Example
7E), and Prilosec.RTM. enteric coated omeprazole (40 mg) from the
human clinical trial described in Example 15B, Day 1.
[0062] FIG. 19 is a graph comparing the mean peak plasma
concentration (Cmax) verses the time at which Cmax is observed
(Tmax) for 20 mg and 40 mg immediate release chewable tablets,
capsules (SAN-7F, SAN-7E, respectively), and immediate release
omeprazole suspension according to the present invention and 20 and
40 mg Prilosec.RTM. enteric coated omeprazole. The data are from
the human clinical trial in Examples 14B and 15 B, Day 1.
[0063] FIG. 20 is a graph comparing the average pharmacokinetic
release profiles of immediate release omeprazole suspension (20
mg), chewable tablets (20 mg), capsule (20 mg)(SAN-7F) according to
the present invention with Prilosec.RTM. (20 mg) from the human
clinical trial in Example 14B, Day 7.
[0064] FIG. 21 is a graph comparing the average pharmacokinetic
release profiles of immediate release omeprazole suspension (40
mg), chewable tablets (40 mg), capsule (40 mg)(SAN-7E) according to
the present invention with Prilosec.RTM. brand enteric coated
omeprazole (40 mg) from the human clinical trial in Example 15B,
Day 7.
[0065] FIG. 22 is a graph comparing the mean peak plasma
concentration (Cmax) verses the time at which Cmax is observed
(Tmax) for immediate release omeprazole chewable tablets, capsules,
and suspension according to the present invention (20 and 40 mg)
and Prilosec.RTM. brand enteric coated omeprazole (20 and 40 mg)
from the human clinical trial set forth in 143, 15B Day 7.
[0066] FIG. 23 is a graph comparing the Cmax versus Tmax of
immediate release omeprazole chewable tablets, capsules, and
suspension according to the present invention and Prilosec.RTM.
brand enteric coated omeprazole. The data for both 20 mg and 40 mg
doses are from the clinical trial set forth in Examples 14B, 15B,
Days 1 and 7.
[0067] FIG. 24 is a flow chart depicting Manufacturing Process of
immediate release capsules according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0068] 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.
[0069] 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.
[0070] 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.
[0071] Glossary
[0072] As used herein, the terms "comprising," "including," and
"such as" are used in their open, non-limiting sense.
[0073] 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 outside the cited values,
i.e., plus or minus 0.1% to 10%, which are also effective and
safe.
[0074] The phrase "acid-labile pharmaceutical agent" refers to any
pharmacologically active drug subject to acid catalyzed
degradation.
[0075] "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.RTM.;
tribasic calcium phosphate, talc, corn starch, DL-leucine, sodium
lauryl sulfate, magnesium stearate, calcium stearate, sodium
stearate, kaolin, and micronized amorphous silicon dioxide
(Syloid.RTM.) and the like.
[0076] "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.
[0077] "Antioxidants" include, e.g., butylated hydroxytoluene
(BHT), sodium ascorbate, and tocopherol.
[0078] "Binders" impart cohesive qualities and include, e.g.,
alginic acid and salts thereof; cellulose derivatives such as
carboxymethylcellulose, methylcellulose (e.g., Methocel.RTM.),
hydroxypropylmethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose (e.g., Klucel.RTM.), ethylcellulose (e.g.,
Ethocel.RTM.), and microcrystalline cellulose (e.g., Avicel.RTM.);
microcrystalline dextrose; amylose; magnesium aluminum silicate;
polysaccharide acids; bentonites; gelatin;
polyvinylpyrrolidonelvinyl acetate copolymer; crospovidone;
povidone; starch; pregelatinized starch; tragacanth, dextrin, a
sugar, such as sucrose (e.g., Dipac.RTM.), glucose, dextrose,
molasses, mannitol, sorbitol, xylitol (e.g., Xylitab.RTM.), and
lactose; a natural or synthetic gum such as acacia, tragacanth,
ghatti gum, mucilage of isapol husks, polyvinylpyrrolidone (e.g.,
Polyvidone.RTM. CL, Kollidon.RTM. CL, Polyplasdone.RTM. XL-10),
larch arabogalactan, Veegum.RTM., polyethylene glycol, waxes,
sodium alginate, and the like.
[0079] "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.
[0080] "Bioequivalence" or "bioequivalent" means that the area
under the serum concentration time curve (AUC) and the peak serum
concentration (C.sub.max) are each within 80% and 120%.
[0081] "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 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,
Pa. 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 & Wilkins 1999).
[0082] "Character notes" include, e.g., aromatics, basis tastes,
and feeling factors. The intensity ofthe character note can be
scaled from 0--none, 1--slight, 2--moderate, or 3--strong.
[0083] 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.
[0084] "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.RTM. 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.
[0085] "Diluents" increase bulk of the composition to facilitate
compression. Such compounds include e.g., lactose; starch;
mannitol; sorbitol; dextrose; microcrystalline cellulose such as
Avicel.RTM.; dibasic calcium phosphate; dicalcium phosphate
dihydrate; tricalcium phosphate; calcium phosphate; anhydrous
lactose; spray-dried lactose; pregelatinzed starch; compressible
sugar, such as Di-Pac.RTM. (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.
[0086] The term "disintegrate" includes both the dissolution and
dispersion of the dosage form when contacted with gastrointestinal
fluid.
[0087] "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.RTM., or sodium starch glycolate such as Promogel.RTM. or
Explotab.RTM.; a cellulose such as a wood product,
methylcrystalline cellulose, e.g., Avicel.RTM., Avicel.RTM. PH101,
Avicel.RTM. PH102, Avicel.RTM. PH105, Elcema.RTM. P100,
Emcocel.RTM., Vivacel.RTM., Ming Tia.RTM., and Solka-Floc.RTM.,
methylcellulose, croscarmellose, or a cross-linked cellulose, such
as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol.RTM.),
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.RTM. 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.
[0088] "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.
[0089] 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.
[0090] 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.
[0091] "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.
[0092] "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.
[0093] "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.RTM.), maltol, mannitol, maple,
marshmallow, menthol, mint cream, mixed berry, neohesperidine DC,
neotame, orange, pear, peach, peppermint, peppermint cream,
Prosweet.RTM. 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.
[0094] "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 1% sodium dodecyl sulfate solution or 0.1N HCl solution
in water.
[0095] "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.
[0096] "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.RTM.);
higher fatty acids and their alkali-metal and alkaline earth metal
salts, such as aluminum, calcium, magnesium, zinc, stearic acid,
sodium stearates, glycerol, talc, waxes, Stearowet.RTM., boric
acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a
polyethylene glycol or a methoxypolyethylene glycol such as
Carbowax.TM., sodium oleate, glyceryl behenate, polyethylene
glycol, magnesium or sodium lauryl sulfate, colloidal silica such
as Syloid.TM., Carb-O-Sil.RTM., a starch such as corn starch,
silicone oil, a surfactant, and the like.
[0097] A "measurable serum concentration" or "measurable plasma
concentration" describes the blood serum or blood plasma
concentration, typically measured in mg, .mu.g, or ng of
therapeutic agent per ml, dl, or l 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).
[0098] "Parietal cell activators" or "activators" stimulate the
parietal cells and enhance the pharmaceutical activity of the
proton pump inhibitor. Parictal 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.
[0099] "Pharmacodynamics" refers to the factors which determine the
biologic response observed relative to the concentration of drug at
a site of action.
[0100] "Pharmacokinetics" refers to the factors which determine the
attainment and maintenance of the appropriate concentration of drug
at a site of action.
[0101] "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
(C.sub.max) or time to reach maximum serum concentration
(T.sub.max), 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 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.
[0102] "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.
[0103] "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.
[0104] 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. J.
Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J.
Pharmaceutics, 47, 103 (1988); Sinkula et al., J. 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.
[0105] "Proton pump inhibitor product" refers to a product sold on
the market. Proton pump inhibitor products include, for example,
Priolosec.RTM., Ncxium.RTM., Prevacid.RTM., Protonic.RTM., and
Aciphex.RTM..
[0106] "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 (C.sub.max) or time to reach maximum serum
concentration (T.sub.max), 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.
[0107] "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.
[0108] "Stabilizers" include compounds such as any antioxidation
agents, buffers, acids, and the like.
[0109] "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.
[0110] "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.RTM. (BASF); and the like.
[0111] 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.
[0112] "Total intensity of aroma" is the overall immediate
impression of the strength of the aroma and includes both aromatics
and nose feel sensations.
[0113] "Total intensity of flavor" is the overall immediate
impression of the strength of the flavor including aromatics, basic
tastes and mouth feel sensations.
[0114] "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."
[0115] "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.
[0116] Proton Pump Inhibitors
[0117] 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.
[0118] 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).
[0119] Other proton pump inhibitors include but are not limited to:
soraprazan (Altana); ilaprazole (U.S. Pat. No. 5,703,097)
(Il-Yang); AZD-0865 (AstraZeneca); YH-1885 (PCT Publication WO
96/05177)(SB-641257)(2-pyrimidinamine,
4-(3,4-dihydro-1-methyl-2(1H)-isoquinolinyl)-N-(4-fluorophenyl)-5,6-dimet-
hyl-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); Pharmaprojects No. 3264 (EP
509974)(AstraZeneca); nepaprazole (Toa Eiyo); HN-11203 (Nycomed
Pharma); OPC-22575; purnilacidin 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.
[0120] Still other proton pump inhibitors contemplated by the
present invention include those described in the following U.S.
Pat. 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.
[0121] 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).
[0122] "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, .beta.-hydroxybutyric, galactaric
and galacturonic acids.
[0123] 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 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.
[0124] 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.
[0125] 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. Pat. 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 Ser. No.
02/019,8239 and U.S. Pat. No. 6,511,996. Other salts of
esomeprazole are described in U.S. Pat. Nos. 4,738,974 and
6,369,085. Salt forms of pantoprazole and lansoprazole are
discussed in U.S. Pat. Nos. 4,758,579 and 4,628,098,
respectively.
[0126] 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 RCOOR.sub.1 where R.sub.1 is a lower alkyl group. Esters
can be reconverted to the free acids, if desired, by using
conventional procedures such as hydrogenolysis or hydrolysis.
[0127] "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.
[0128] "Tautomers" of substituted bicyclic aryl-imidazoles include,
e.g., tautomers of omeprazole such as those described in U.S. Pat.
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.
[0129] 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),
C45, 1921-1923; U.S. Pat. No. 6,150,380; U.S. Patent Publication
No. 02/0156284; and PCT Publication No. WO02/085889.
[0130] Exemplary "polymorphs" include, but are not limited to,
those described in PCT Publication No. WO 92/08716, and U.S. Pat.
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.
[0131] Micronized Proton Pump Inhibitor
[0132] 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.
[0133] 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.
[0134] 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 .mu.m, or less than about 35 .mu.m,
or less than about 30 .mu.m, or less than about 25 .mu.m, or less
than about 20 .mu.m, or less than about 15 .mu.m, or less than
about 10. .mu.m. In other embodiments, at least 80% of the
micronized proton pump inhibitor has an average particle size of
less than about 40 .mu.m, or less than about 35 .mu.m, or less than
about 30 .mu.m, or less than about 25 .mu.m, or less than about 20
.mu.m, or less than about 15 .mu.m, or less than about 19 .mu.m. In
still other embodiments, at least 70% of the micronized proton pump
inhibitor has an average particle size of less than about 40 .mu.m,
or less than about 35 .mu.m, or less than about 30 .mu.m, or less
than about 25 .mu.m, or less than about 20 .mu.m, or less than
about 15 .mu.m, or less than about 19 .mu.m.
[0135] 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 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. 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 Ser. No.
10/893,092, filed Jul. 16, 2004, which claims priority to U.S.
Provisional Application No. 60/488,324 filed Jul. 18, 2003, both of
which are incorporated by reference in their entirety.
[0136] Particle Size of Ingredients
[0137] 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.
[0138] In various embodiments, the average particle size of the dry
powder (which can be administered directly, as a powder 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 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.
[0139] In another embodiment, the average particle size of the
insoluble excipients is between about 5 .mu.m to about 500 .mu.m,
or less than about 400 .mu.m, or less than about 300 m, or less
than about 200 .mu.m, or less than about 150 .mu.m, or less than
about 100 .mu.m, or less than about 90 .mu.m, or less than about 80
.mu.m, or less than about 70 .mu.m, or less than about 60 .mu.m, or
less than about 50 .mu.m, or less than about 40 .mu.m, or less than
about 30 .mu.m, or less than about 25 .mu.m, or less than about 20
.mu.m, or less than about 15 .mu.m, or less than about 10 .mu.m, or
less than about 5 .mu.m.
[0140] In other embodiments of the present invention, at least
about 80% of the particles have a particle size of less than about
300 .mu.m, or less than about 250 .mu.m, or less than about 200
.mu.m, or less than about 150 .mu.m, or less than about 100 .mu.m,
or less than about 500 .mu.m. In another embodiment, at least about
85% of the dry powder particles have a particle size of less than
about 300 .mu.m, or less than about 250 .mu.m, or less than about
200 .mu.m, or less than about 150 .mu.m, or less than about 100
.mu.m, or less than about 50 .mu.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 .mu.m, or
less than about 250 .mu.m, or less than about 200 .mu.m, or less
than about 150 .mu.m, or less than about 100 .mu.m, or less than
about 50 .mu.m. In yet another embodiment, at least about 95% of
the dry powder particles have a particle size of less than about
300 .mu.m, or less than about 250 .mu.m, or less than about 200
.mu.m, or less than about 150 .mu.m, or less than about 100 .mu.m,
or less than about 50 .mu.m.
[0141] In other embodiments, the average particle size of the
insoluble material is between about .mu.m to about 250 .mu.m in
diameter. In other embodiments, the average particle size of the
insoluble excipients is between about 5 .mu.m to about 100 .mu.m,
or between about 5 .mu.m to about 80 .mu.m, or between about 5
.mu.m to about 50 .mu.m in diameter.
[0142] 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 insoluble
excipients is chosen to be about the same as the particle size of
the proton pump inhibitor.
[0143] 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. "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.
[0144] 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.
[0145] Antacids
[0146] 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 HA metal); an aluminum antacid; a calcium antacid; or a
magnesium antacid.
[0147] 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 HA 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.
[0148] In various embodiments, an 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 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.RTM. (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.
[0149] 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.
[0150] In various embodiments, the antacid is selected from sodium
bicarbonate, sodium carbonate, calcium carbonate, magnesium oxide,
magnesium hydroxide, magnesium carbonate, and mixtures thereof.
[0151] 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.
[0152] In various embodiments, the antacid is selected from sodium
bicarbonate, sodium carbonate, calcium carbonate, magnesium oxide,
magnesium hydroxide, magnesium carbonate, aluminum hydroxide, and
mixtures thereof. In other embodiments, the antacid is present in
the pharmaceutical formulations of the present invention in an
amount greater than about 5 mEq of antacid. In other embodiments,
the antacid is present in the pharmaceutical formulations of the
present invention in an amount greater than about 7 mEq of antacid.
In other embodiments, the antacid is present in the pharmaceutical
formulations of the present invention in an amount greater than
about 10 mEq of antacid. In other embodiments, the antacid is
present in the pharmaceutical formulations of the present invention
in an amount greater than about 15 mEq of antacid. In other
embodiments, the antacid is present in the pharmaceutical
formulations of the present invention in an amount greater than
about 20 mEq of antacid.
[0153] In another embodiment, the antacid comprises sodium
bicarbonate in about 0.1 mEq/mg proton pump inhibitor to about 5
mEq/mg proton pump inhibitor. In yet another embodiment, the
antacid comprises a mixture of sodium bicarbonate and magnesium
hydroxide, wherein the sodium bicarbonate and magnesium hydroxide
are each present in about 0.1 mEq/mg proton pump inhibitor to about
5 mEq/mg proton pump inhibitor. In still another embodiment, the
antacid comprises a mixture of sodium bicarbonate, calcium
carbonate, and magnesium hydroxide, wherein the sodium bicarbonate,
calcium carbonate, and magnesium hydroxide are each present in
about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg of the
proton pump inhibitor.
[0154] In various other embodiments of the present invention, the
antacid is present in an amount of about 0.1 mEq/mg to about 5
mEq/mg of the proton pump inhibitor, or about 0.5 mEq/mg to about 3
mEq/mg of the proton pump inhibitor, or about 0.6 mEq/mg to about
2.5 mEq/mg of the proton pump inhibitor, or about 0.7 mEq/mg to
about 2.0 mEq/mg of the proton pump inhibitor, or about 0.8 mEq/mg
to about 1.8 mEq/mg of the proton pump inhibitor, or about 1.0
mEq/mg to about 1.5 mEq/mg of the proton pump inhibitor, or at
least 0.5 mEq/mg of the proton pump inhibitor.
[0155] In other embodiments, the antacid is present in the
pharmaceutical formulations of the present invention in an from
about 5 to about 50 mEq of antacid. In other embodiments, the
antacid is present in the pharmaceutical formulations of the
present invention in an amount from about 5 to about 40 mEq of
antacid. In other embodiments, the antacid is present in the
pharmaceutical formulations of the present invention in an amount
from about 10 to about 30 mEq of antacid. In other embodiments, the
antacid is present in the pharmaceutical formulations of the
present invention in an amount from about 10 to about 20 mEq of
antacid. In other embodiments, the antacid is present in the
pharmaceutical formulations of the present invention in an amount
from about 5 to about 15 mEq of antacid.
[0156] In another embodiment, the antacid is present in the
pharmaceutical formulations of the present invention in an amount
of about 0.1 mEq to about 15 mEq/ng of proton pump inhibitor, or
about 0.1 mEq/mg of proton pump inhibitor, or about 0.5 mEq/mg of
proton pump inhibitor, or about 1 mEq/mg of proton pump inhibitor,
or about 2 mEq/mg of proton pump inhibitor, or about 2.5 mEq/mg of
proton pump inhibitor, or about 3 mEqlmg of proton pump inhibitor,
or about 3.5 mEq/mg of proton pump inhibitor, or about 4 mEq/mg of
proton pump inhibitor, or about 4.5 mEq/mg of proton pump
inhibitor, or about 5 mEq/mg of proton pump inhibitor, or about 6
mEq/mg of proton pump inhibitor, or about 7 mEq/ng of proton pump
inhibitor, or about 8 mEq/mg of proton pump inhibitor, or about 9
mEq/mg of proton pump inhibitor, or about 10 mEq/mg of proton pump
inhibitor, or about 11 mEq/mg of proton pump inhibitor, or about 12
mEq/mg of proton pump inhibitor, or about 13 mEq/mg of proton pump
inhibitor, or about 14 mEq/mg of proton pump inhibitor, or about 15
mEq/mg of proton pump inhibitor.
[0157] In one embodiment, the antacid is present in the
pharmaceutical formulations of the present invention in an amount
of about 1 mEq to about 160 mEq per dose, or about 1 mEq, or about
5 mEq, or about 10 mEq, or about 15 mEq, or about 20 mEq, or about
25 mEq, or about 30 mEq, or about 35 mEq, or about 40 mEq, or about
45 mEq, or about 50 mEq, or about 60 mEq, or about 70 mEq, or about
80 mEq, or about 90 mEq, or about 100 mEq, or about 110 mEq, or
about 120 mEq, or about 130 mEq, or about 140 mEq, or about 150
mEq, or about 160 mEq per dose.
[0158] In another embodiment, the antacid is present in an amount
of more than about 5 times, or more than about 10 times, or more
than about 20 times, or more than about 30 times, or more than
about 40 times, or more than about 50 times, or more than about 60
times, or more than about 70 times, or more than about 80 times, or
more than about 90 times, or more than about 100 times the amount
of the proton pump inhibiting agent on a weight to weight basis in
the composition.
[0159] In another embodiment, the amount of antacid present in the
pharmaceutical formulation is between 200 and 3500 mg. In other
embodiments, the amount of antacid present in the pharmaceutical
formulation is about 200 mgs, or about 300 mgs, or about 400 mgs,
or about 500 mags, or about 600 mgs, or about 700 mgs, or about 800
mgs, or about 900 mgs, or about 1000 mgs, or about 1100 mgs, or
about 1200 mgs, or about 1300 mgs, or about 1400 mgs, or about 1500
mgs, or about 1600 mgs, or about 1700 mgs, or about 1800 mgs, or
about 1900 mgs, or about 2000 mgs, or about 2100 mgs, or about 2200
mgs, or about 2300 mgs, or about 2400 mgs, or about 2500 mgs, or
about 2600 mgs, or about 2700 mgs, or about 2800 mgs, or about 2900
mgs, or about 3000 mgs, or about 3200 mgs, or about 3500 mgs.
[0160] In some embodiments, if the at least one buffering agent is
a combination of two or more buffering agents, the combination
comprises at least two non-amino acid buffering agents, wherein the
combination of at least two non-amino acid buffering agents
comprises substantially no aluminum hydroxide-sodium bicarbonate
co-precipitate. In other embodiments, if the pharmaceutical
composition comprises an amino acid buffering agent, the total
amount of buffering agent present in the pharmaceutical composition
is less than about 5 mEq, or less than about 4 mEq, or less than
about 3 mEq. The phrase "amino acid buffering agent" as used herein
includes amino acids, amino acid salts, and amino acid alkali
salts. including: glycine, alanine, threonine, isoleucine, valine,
phenylalanine, glutamic acid, asparagininic acid, lysine, aluminum
glycinate and/or lysine glutamic acid salt, glycine hydrochloride,
L-alanine, DL-alanine, L-threonine, DL-threonine, L-isoleucine,
L-valine, L-phenylalanine, L-glutamic acid, L-glutamic acid
hydrochloride, L-glutamic acid sodium salt, L-asparaginic acid,
L-asparaginic acid sodium salt, L-lysine and L-lysine-L-glutamic
acid salt. The term "non-amino acid buffering agent" herein
includes buffering agents as defined hereinabove but does not
include amino acid buffering agents.
[0161] In other embodiments, the pharmaceutical composition
comprises substantially no or no poly[phosphoryl/sulfon]-ated
carbohydrate and is in the form of a solid dosage unit. In still
another related embodiment, if such a composition comprises a
poly[phosphoryl/sulfon]-ated carbohydrate (e.g. sucralfate or
sucrose octasulfate), the weight ratio of
poly[phosphoryl/sulfon]-ated carbohydrate to buffering agent is
less than 1:5 (0.2), less than 1:10 (0.1) or less than 1:20 (0.05).
Alternatively, the poly[phosphoryl/sulfon]-ated carbohydrate is
present in the composition, if at all, in an amount less than 50
mg, less than 25 mg, less than 10 mg or less than 5 mg.
[0162] Also provided herein are pharmaceutical formulations
comprising at least one soluble antacid. For example, in one
embodiment, the antacid is sodium bicarbonate and is present in
about 0.1 mEq/mg proton pump inhibitor to about 5 mEq/mg proton
pump inhibitor. In another embodiment, the antacid is a mixture of
sodium bicarbonate and magnesium hydroxide, wherein the sodium
bicarbonate and magnesium hydroxide are each present in about 0.1
mEq/mg proton pump inhibitor to about 5 mEq/mg proton pump
inhibitor. The term "soluble antacid" as used herein refers to an
antacid that has a solubility of at least 500 mg/mL, or 300 mg/mL,
or 200 mg/mL, or 100 mg/mL in the gastrointestinal fluid.
[0163] In some embodiments of the present invention, the antacid is
a specific particle size. For example, the average particle size of
the antacid may be no greater than 20 .mu.m, or no greater than 30
.mu.m, or no greater than 40 .mu.m, or no greater than 50 .mu.m, or
no greater than 60 .mu.m, or no greater than 70 .mu.m, or no
greater than 80 .mu.m, or no greater than 90 .mu.m or no greater
than 100 .mu.m in diameter. In various embodiments, at least about
70% of the antacid is no greater than 20 .mu.m, or no greater than
30 .mu.m, or no greater than 40 .mu.m, or no greater than 50 .mu.m,
or no greater than 60 .mu.m, or no greater than 70 .mu.m, or no
greater than 80 .mu.m, or no greater than 90 .mu.m or no greater
than 100 .mu.m in diameter. In other embodiments, at least about
85% of the antacid is no greater than 20 .mu.m, or no greater than
30 .mu.m, or no greater than 40 .mu.m, or no greater than 50 .mu.m,
or no greater than 60 .mu.m, or no greater than 70 .mu.m, or no
greater than 80 .mu.m, or no greater than 90 .mu.m or no greater
than 100 .mu.m in diameter.
[0164] 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 commercial scale due to their poor flow
and difficulties in processing (i.e., compression and
encapsulation).
[0165] In various embodiments of the present invention, the antacid
is micronized. In some embodiments, particle size of at least 90%
of antacid (D.sub.90) is less than about 300 .mu.m, or less than
about 250 .mu.m, or less than about 200 .mu.m, or less than about
150 .mu.m, or less than about 100 .mu.m. In other embodiments, at
least 75% of the antacid (D.sub.75) has particle size of less than
about 300 .mu.m, or less than about 250 .mu.m, or less than about
200 .mu.m, or less than about 150 .mu.m, or less than about 100
.mu.m. In still other embodiments, at least 50% of the antacid
(D.sub.50) has particle size of less than about 300 .mu.m, or less
than about 250 .mu.m, or less than about 200 .mu.m, or less than
about 150 .mu.m, or less than about 100 .mu.m.
[0166] 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.
[0167] Kinetic Stomach Model
[0168] 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 1, Aluminium Hydroxide-Magnesium
Carbonate Dried Gels, J. Am. Pharm. Assoc., 49, 191 (1960). For
example, a 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.
[0169] 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.
[0170] 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.
[0171] Disintegrants
[0172] Most PPs are sparingly soluble in water and therefore
exhibit a 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, p 862). Super disintegrants such as Ac-di-Sol or
Crospovidones are effective at lower levels (2-4%).
[0173] 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.
[0174] 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.
[0175] Solid Oral Dosage Forms
[0176] In some embodiments of the present invention, the
pharmaceutical 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-% or between about 1 wt-% to about 8 wt-%, or about 1 wt-% to
about 6 wt-%, or about 1 wt-% to about 4 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.RTM. or Explotab.RTM.. In still other embodiments, the
pharmaceutical formulations have between about 2 wt-% to about 8
wt-% disintegrant, or between about 2 wt-% to about 6 wt-%, or
between about 2 wt-% to about 4 wt-%. In yet other embodiments, the
pharmaceutical formulations have greater than about 2 wt-%
disintegrant.
[0177] Because sodium bicarbonate has effervescent characteristic
when mixed with acid such as gastric fluid, some embodiments of 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 embodiments, the sodium bicarbonate helps
facilitate the disintegration of the capsule product.
[0178] Because sodium bicarbonate has effervescent characteristic
when mixed with acid such as gastric fluid, some embodiments of the
pharmaceutical formulations of the present invention can comprise
at least about 200 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 embodiments, the sodium bicarbonate helps
facilitate the disintegration of the capsule product.
[0179] 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 to achieve
the desired bioavailability of the proton pump inhibitor.
[0180] Binders
[0181] 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.
[0182] 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 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 an amount of about 3 wt-%.
[0183] Microencapsulation
[0184] 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 Ser. No. 10/893,203, filed Jul.
16, 2004, which claims priority to U.S. Provisional Application No.
60/488,321 filed Jul. 18, 2003, both of which are incorporated by
reference in their entirety.
[0185] 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.
[0186] Exemplary microencapsulation 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.RTM. or Nisso HPC;
low-substituted hydroxypropyl cellulose ethers (L-HPC);
hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC,
Pharmacoat.RTM., Metolose SR, Methocel.RTM.-E, Opadry YS, PrimaFlo,
Benecel MP824, and Benecel MP843; methylcellulose polymers such as
Methocel.RTM.-A and Metolose.RTM.; Ethylcelluloses (EC) and
mixtures thereof such as E461, Ethocel.RTM., Aqualon.RTM.-EC,
Surelease.RTM.; Polyvinyl alcohol (PVA) such as Opadry AMB;
hydroxyethylcelluloses such as Natrosol.RTM.;
carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC)
such as Aqualon.RTM.-CMC; polyvinyl alcohol and polyethylene glycol
co-polymers such as Kollicoat IR.RTM.; monoglycerides (Myverol),
triglycerides (KLX), polyethylene glycols, modified food starch,
acrylic polymers and mixtures of acrylic polymers with cellulose
ethers such as Eudragit.RTM. EPO, Eudragit.RTM. RD100, and
Eudragit.RTM. E100; cellulose acetate phthalate; sepifilms such as
mixtures of HPMC and stearic acid, cyclodextrins; and mixtures of
these materials.
[0187] 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, 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.
[0188] 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.
[0189] 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.
[0190] 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
ar 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.
[0191] "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.RTM.), maltol, mannitol, maple,
marshmallow, menthol, mint cream, mixed berry, neohesperidine DC,
neotame, orange, pear, peach, peppermint, peppermint cream,
Prosweet.RTM. 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).
[0192] Methods of Microencapsulation
[0193] 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.
[0194] 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.
[0195] 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 .mu.m droplets are obtained. Once a 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.
[0196] In some embodiments of the present invention, the
microspheres have irregular geometries. In other embodiments, the
microspheres are aggregates of smaller particles.
[0197] 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.
[0198] Stability
[0199] 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.
[0200] 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.
[0201] 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.
[0202] Dosage
[0203] 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 described by Phillips et
al. in U.S. Pat. Nos. 5,840,737, 6,489,346, 6,699,885 and 6,645,988
are incorporated herein by reference.
[0204] 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.
Pat. 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.
[0205] 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 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.
[0206] 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.
[0207] 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.
[0208] 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.
[0209] 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.
[0210] 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 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.
[0211] 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
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/m from about 30 minutes to about 1
hour after administration of the composition.
[0212] 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.
[0213] In another embodiment of the present invention, the
composition is administered to the subject in an amount sufficient
to achieve a maximum serum concentration (Cmax) at a time (Tmax)
that is within about 90, 70, 60, 50, 40, 30 or 20 minutes after
administration of the composition according to the present
invention.
[0214] In still another embodiment of the invention, the
composition is administered to the subject in an amount sufficient
to achieve a maximum serum concentration (Cmax) at a time (Tmax)
that is between about 10 and about 90 minutes, between about 10 to
about 60 minutes, between about 15 to about 60 minutes or between
about 20 to about 60 minutes after administration of the
composition according to the present invention. In some specific
embodiments, the values of Cmax and Tmax are averages over a test
population. In other specific embodiments, the values of Cmax and
Tmax are the values for an individual.
[0215] In still another embodiment, the composition is administered
in an amount sufficient to achieve a maximum serum concentration
(Cmax) of from about 400 to about 2000 ng/mL, from about 400 to
about 1500 ng/mL, from about 1000 to about 1500 ng/mL, from about
400 to about 1000 ng/mL or from about 400 to about 700 ng/mL. In
some specific embodiments, the values of Cmax and Tmax are averages
over a test population. In other specific embodiments, the values
of Cmax and Tmax are the values for an individual.
[0216] In a further embodiment, the composition is administered in
an amount sufficient to achieve a maximum serum concentration
(Cmax) of greater than 400 ng/mL, greater than 600 ng/mL, greater
than 1000 ng/mL. In some specific embodiments, the values of Cmax
and Tmax are averages over a test population. In other specific
embodiments, the values of Cmax and Tmax are the values for an
individual.
[0217] 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.
[0218] 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 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%.
[0219] 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.RTM., Nexium.RTM.,
Prevacid.RTM., Protonic.RTM., or Aciphex.RTM.. 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.RTM., Nexium.RTM.,
Prevacid.RTM., Protonic.RTM., or Aciphex.RTM.. In still other
embodiments, the pharmaceutical composition comprises between about
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.RTM., Nexium.RTM., Prevacid.RTM.,
Protonic.RTM., or Aciphex.RTM.. "Bioequivalent" is intended to mean
that the area under the serum concentration time curve (AUC) and
the peak serum concentration (C.sub.max) are each within 80% and
120%.
[0220] 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.RTM., Nexium.RTM.,
Prevacid.RTM., Protonic.RTM., or Aciphex.RTM.. 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.RTM., Nexium.RTM.,
Prevacid.RTM., Protonic.RTM., or Aciphex.RTM.. In still other
embodiments, the pharmaceutical composition comprises between about
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.RTM., Nexium.RTM., Prevacid.RTM.,
Protonic.RTM., or Aciphex.RTM..
[0221] 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 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.
[0222] 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.
[0223] 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.
[0224] Dosage Forms
[0225] 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 lozenge, a sachet, a troche,
pellets, granules, or an aerosol. The pharmaceutical compositions
of the present invention can be manufactured by conventional
pharmacological techniques.
[0226] 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.
[0227] 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.
[0228] 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 coated prior 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.
[0229] 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.
[0230] 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 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.
[0231] Exemplary Solid Oral Dosage Compositions
[0232] 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.
[0233] 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.
[0234] 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.
[0235] 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 pharmaceutical
composition has disintegrated, the compressed mass has
substantially disintegrated.
[0236] 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.
[0237] Exemplary Powder Compositions
[0238] 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.
[0239] 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.
[0240] 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 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.
[0241] 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.
[0242] Powder for Suspension
[0243] 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 Ser.
No. 10/893,092, filed Jul. 16, 2004, which claims priority to U.S.
Provisional Application No. 60/488,324 filed Jul. 18, 2003, both of
which are herein incorporated by reference in their entirety.
[0244] 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.
[0245] 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.
[0246] 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 average particle
size of the insoluble material is less than about 200 .mu.m. In
some embodiments, the average particle size of the insoluble
material is less than about 100 .mu.m. In other embodiments, the
average particle size of the insoluble material is less than about
50 .mu.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.
[0247] 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.
[0248] Combination Therapy
[0249] 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.
[0250] 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 within
the knowledge of the skilled physician after evaluation of the
disease being treated and the condition of the patient.
[0251] 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.
[0252] 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.
[0253] 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 H.sub.2-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.
[0254] 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, etofenamate, flufenamic acid, isonixin, meclofenamic acid,
mefenamic acid, niflumic acid, talniflumate, terofenamate, and
tolfenamic acid; arylacetic acid derivatives such as aceclofenac,
acemetacin, alclofenac, 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-II 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,
az-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,
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.
[0255] For the sake of brevity, all patents and other references
cited herein are incorporated by reference in their entirety.
EXAMPLES
[0256] 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.
[0257] 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
[0258] 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-Up:
[0259] 1. A glass sample vessel (-150 mL capacity) containing 50 mL
of a standardized solution of 0.1 N HCl was placed into a water
bath set at 37.degree. C. (.+-.2.degree. C.). [0260] 2. A second
glass vessel containing >70 mL of a standardized solution of 1.0
N HCl was placed into the same water bath. [0261] 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.
[0262] 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 HC was
0.5 mL/min and the temperature was 37.degree. C. (.+-.2.degree.
C.). The pump and tubing were then set-up to allow the transfer of
1.0 N HCl acid into the sample vessel. [0263] 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. [0264] 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. [0265] 7. The pH probe was placed into the glass sample
vessel containing 50 mL of 0.1 N HCl at 37.degree. C.
(.+-.2.degree. C.). [0266] 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. [0267] 9. The sample was then stirred for
approximately 6 minutes and the flow of the 1.0 N HCl at a rate of
0.5 mL/min was started. The exact start time of the acid flow was
recorded. [0268] 10. For samples with not more than (.ltoreq.) 30
mEq ANC the sample continued to stir and the pH was monitored for 1
hour in 15 second intervals. [0269] 11. The duration of the test
was recorded and the total volume of 0.1 N HCl added was calculated
based on the flow rate.
[0270] 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).
[0271] It was also determined that spray dried magnesium hydroxide
with 5% starch such as MS-90.RTM. 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.RTM. 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 actual neutralization capacity measured by the area under curve
(AUC) of the dynamic pH profile.
Example 2: Disintegrant Optimization Trials: Mixed Buffer
System
[0272] 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 2.A.1 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.
[0273] Capsules were filled on a Pharm Op Zansi.RTM. LZ-64 dosator
encapsulator using the compositions set forth in Table 2.A.1,
below. The results of the disintegration study are shown in Table
2.A.2, below.
TABLE-US-00001 TABLE 2.A.1 Disintegram Optimization Trials SAN-10D1
SAN-10D2 SAN10D3 SAN10D4 3% Disintegrant 5% Disintegrant 8%
Disintegrant 11% Disintegrant Ingredients Mg/cap % Mg/cap % Mg/cap
% Mg/cap % OMEPRAZOLE USP 40.8 4.1 40.8 4.1 40.8 3.9 40.8 3.8
Sodium Bicarbonate #2 USP 420 43.4 420 42.6 420 41.2 420 39.9
Magnesium Hydroxide 470 48.6 470 47.7 470 46.2 470 44.6 (sieved)
sub 80 mesh Crosearmellose Sodium NF 30 3.1 49 5.0 81 8.0 116 11.0
Magnesium Stearate NF 7 0.7 7 0.7 7 0.7 7 0.7 Totals: 967 100.0 986
100.0 1018 100.0 1053 100.0
TABLE-US-00002 TABLE 2.A.2 Disintegrant Optimization Trials
Disintegration Trial Number/ Times Description First Last
Comments/Observations SAN-10D1 9'10'' 11'20'' Virtually all
disintegrated (3% Ac-Di-Sol) at 9 mins. SAN-10D2 7'30'' 12'
Virtually all disintegrated (5% Ac-Di-Sol) at 7 mins 30 secs.
SAN-10D3 8' 11' Virtually all disintegrated (8% Ac-Di-Sol) at 7
mins. SAN-10D4 7'30'' 10'30'' Virtually all disintegrated (11%
Ac-Di-Sol) at 7 mins.
Example 2B: Disintegrant Optimization Trials--Sodium Bicarbonate
Buffer
[0274] 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% A 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-US-00003 TABLE 2.B.1 Disintegram Optimization Trials
SAN-10BB1 SAN-10BB2 SANBB3 SAN10BB4 1% Disintegrant 2% Disintegrant
3% Disintegrant 5% Disintegrant Ingredients 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 91.1
Crosearmellose Sodium NF 12 1.0 23 20. 35 3.0 60 5.0 Magnesium
Stearate NF 7 0.6 7 0.6 7 0.6 7 0.6 Totals: 967 100.0 986 100.0
1018 100.0 1053 100.0
TABLE-US-00004 TABLE 2.B.2 Disintegrant Optimization Trials: Sodium
Bicarbonate Buffer Disintegration Trial Number/ Times Description
First Last Comments/Observations SAN-10BB1 6'40'' 8'20'' Virtually
all disintegrated (1% Ac-Di-Sol) at 7 mins. SAN-10BB2 4'30'' 6'
Virtually all disintegrated (2% Ac-Di-Sol) at 5 mins 30 secs.
SAN-10BB3 4' 5'30'' Virtually all disintegrated (3% Ac-Di-Sol) at 5
mins. SAN-10BB4 4' 5'30'' Virtually all disintegrated (5%
Ac-Di-Sol) at 5 mins.
Example 3: Binder Optimization Trials
[0275] 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.RTM.-EXP (hydroxypropyl cellulose) or
microcrystalline cellulose (Avicel.RTM. 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-US-00005 TABLE 3.A.1 Binder Optimization Trials SAN-10F1
SAN-10F2 SAN-10F3 SAN-10F4 SAN-10F5 Ingredients Mg/cap % Mg/cap %
Mg/cap % Mg/cap % Mg/cap % OMEPRAZOLE 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 50
4.8 100 9.1 50 4.6 Crosearmellose 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 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-US-00006 TABLE 3.A.2 Binder Optimization Trials TR2001 TR2002
TR2003 TR2004 TR2005 Ingredients 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
450 50.2 450 45.1 450 45.1 450 41.0 450 41.0 Bicarbonate #2 USP
Magnesium 500 55.7 500 50.2 500 50.2 500 45.6 500 45.6 Hydroxide
Klucel-EXP 20 2.2 20 2.0 50 5.0 50 4.6 0 0.0 Croscamellose 20 2.2
50 5.0 50 5.0 20 1.8 20 1.8 Sodium NF Magnesium 7 0.8 7 0.7 7 0.7 7
0.6 7 0.6 Stearate NF Totals: 897 100.0 997 100.0 997 100.0 1,097.0
100.0 1,097.0 100.0
[0276] The pH test results (table 3.A.1. and table 3.A.2.) shows
that hand-filled 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-US-00007 TABLE 3.B.1 Neutralization Speed of Capsules with
Various Level of Binder and Disintegrant Binder Level Disintegrant
Total ANC Total Time Above pH (min) Sample (%) Level (%) (mEq) 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 4.8 24.7 19.5 18.25 12.2 6.50 SAN-10F4 9.1
4.8 24.7 15.45 11.30 9.50 7.45 SAN-10F5 4.6 4.6 24.7 34.25 30.00
22.50 15.25
TABLE-US-00008 TABLE 3.B.2 Neutralization Speed of Capsules with
Various Level of Binder and Disintegant Binder Total Total Time
Above Level Disintegrant ANC pH min) Sample (%) Level (%) (mEq) 3.5
5.0 6.0 6.5 TR2001 2.2 2.2 22.5 8.5 7.00 0.25 0 TR2002 2.0 5.0 22.5
0.25 0 0 0 TR2003 5.0 5.0 22.5 7.25 6.00 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
[0277] 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 (if any) and croscarmellose sodium were added and mixed
for minutes. The blend was then passed through a #20 mesh s/s
screen and then mixed for 10 minutes. Magnesium stearate was then
added to the mixture and blended for 3 minutes. The material was
then encapsulated into hard gelatin capsule shells using a
Profill.RTM. manual capsule filler.
TABLE-US-00009 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 420 420 1100 800 #2 USP Magnesium Hydroxide 470 0 0 0
(sieved) 100 mesh Magnesium Hydroxide 0 470 0 0 (sieved) 60 mesh
Croscarmellose 30 30 20 20 Sodium NF Magnesium Stearate NF 10 10 10
8 Totals: 970 970 1170 848
TABLE-US-00010 SAN-10D 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 USF 420 378 335 378 420 Magnesium
Hydroxide 470 0 0 0 0 (sieved) 80 mesh Magnesium Hydroxide 0 0 375
0 375 (sieved) 60 mesh Magnesium Hydroxide 95-MS 0 447.4 0 447.4 0
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 2% Disintegrant
[0278] 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 appropate 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.
TABLE-US-00011 PPI Buffering Agent Excipient 40 mg omeprazole 11.3
mEq or 50 mg Klucel 950 mg NaHCO.sub.3 30 mg Ac-di-Sol 10 mg
magnesium stearate 2.8% disintegrant
TABLE-US-00012 PPI Buffering Agent Excipient 40 mg omeprazole 10.5
mEq or 30 mg Klucel 880 mg NaHCO.sub.3 20 mg Crospovidone 10 mg
magnesium stearate 2.0% disintegrant
TABLE-US-00013 PPI Buffering Agent Excipient 60 mg omeprazole 11.4
mEq or 960 mg NaHCO.sub.3 20 mg MCC per capsule 25 mg Ac-Di-Sol 10
mg magnesium stearate 1.9% disintegrant
Example 6: Capsule Formulations with Mixed Buffer Systems and 3-11%
disintegrant
[0279] 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.
TABLE-US-00014 PPI Buffering Agent Excipient 40 mg omeprazole 20.6
mEq or 600 mg Mg(OH).sub.2 20 mg MCC 3 mEq or 250 mg NaHCO.sub.3 50
mg Ac-di-Sol 23.6 mEq or 950 mgs total 10 mg magnesium stearate
buffer 5.2% disintegrant
TABLE-US-00015 PPI Buffering Agent Exeipient 40 mg omeprazole 20.6
mEq or 600 mg Mg(OH).sub.2 100 mg MCC 3 mEq or 250 mg NaHCO.sub.3
50 mg Ac-di-Sol 23.6 mEq or 950 mgs total 10 mg magnesium stearate
buffer 4.8% disintegrant
TABLE-US-00016 PPI Buffering Agent Excipient 40 mg omeprazole 20.6
mEq or 600 mg Mg(OH).sub.2 30 mg MCC 3 mEq or 250 mg NaHCO.sub.3
100 mg sodium starch 23.6 mEq or 950 mgs total glycolate (Primojel
.RTM.) buffer 10 mg magnesium stearate 9.7% disintegrant
TABLE-US-00017 PPI Buffering Agent Excipient 40 mg omeprazole 20.6
mEq or 600 mg Mg(OH).sub.2 50 mg Klucel 3 mEq or 250 mg NaHCO.sub.3
50 mg Ac-di-Sol 23.6 mEq or 850 mgs total 10 mg magnesium stearate
buffer 5.0% disintegrant
TABLE-US-00018 PPI Buffering Agent Excipient 40 mg omeprazole 20.6
mEq or 600 mg Mg(OH).sub.2 30 mg Klucel 3 mEq or 250 mg NaHCO.sub.3
30 mg Ac-di-Sol 23.6 mEq or 850 mgs total 10 mg magnesium stearate
buffer 3.1% disintegrant
TABLE-US-00019 PPI Buffering Agent Excipient 20 mg omeprazole 20.6
mEq or 600 mg Mg(OH).sub.2 100 mg Klucel 3 mEq or 250 mg
NaHCO.sub.3 30 mg Ac-di-Sol 23.6 mEq or 850 mgs total 10 mg
magnesium stearate buffer 3.0% disintegrant
TABLE-US-00020 PPI Buffering Agent Excipient 20 mg omeprazole 20.6
mEq or 600 mg Mg(OH).sub.2 30 mg Klucel 3.0 mEq or 250 mg
NaHCO.sub.3 70 mg Crospovidone 23.6 mEq or 850 mgs total 10 mg
magnesium stearate buffer 7.1% disintegrant
TABLE-US-00021 PPI Buffering Agent Excipient 20 mg omeprazole 20.6
mEq or 600 mg Mg(OH).sub.2 50 mg Ac-Di-Sol per capsule 3.0 mEq or
250 mg NaHCO.sub.3 30 mg Klucel 23.6 mEq or 850 mgs total 10 mg
magnesium stearate buffer 5.2% disintegrant
TABLE-US-00022 PPI Buffering Agent Excipient 20 mg omeprazole 20.6
mEq or 600 mg Mg(OH).sub.2 40 mg Ac-Di-Sol per capsule 4.2 mEq or
350 mg NaHCO.sub.3 35 mg Klucel 24.7 mEq or 950 mg total 10 mg
magnesium stearate buffer 4.1% disintegrant
TABLE-US-00023 PPI Buffering Agent Excipient 15 mg 17.1 mEq or 500
mg Mg(OH).sub.2 50 mg Ac-Di-Sol microencapsulated 3.0 mEq or 250 mg
NaHCO.sub.3 15 mg Klucel lansoprazole 20.7 1 mEq or 750 mg total 7
mg magnesium stearate per capsule buffer 6.0% disintegrant
TABLE-US-00024 PPI Buffering Agent Excipient 30 mg lansoprazole
17.1 mEq or 500 mg Mg(OH).sub.2 40 mg Ac-Di-Sol per capsule 4.2 mEq
or 350 mg NaHCO.sub.3 30 mg Klucel 21.3 mEq or 850 mg total 10 mg
magnesium stearate buffer 4.2% disintegrant
TABLE-US-00025 PPI Buffering Agent Excipient 60 mg ompeprazole 17.1
mEq or 500 mg Mg(OH).sub.2 30 mg Crospovidone per capsule 3.0 mEq
or 250 mg NaHCO.sub.3 15 mg Klucel 20.1 mEq or 750 mg total 7 mg
magnesium stearate buffer 3.5% disintegrant
TABLE-US-00026 PPI Buffering Agent Excipient 10 mg ompeprazole 17.1
mEq or 500 mg Mg(OH).sub.2 30 mg sodium starch per capsule 3.0 mEq
or 250 mg NaHCO.sub.3 glycolate (Explotab .RTM.) 20.1 mEq or 750 mg
total 15 mg Klucel buffer 7 mg magnesium stearate 3.7%
disintegrant
TABLE-US-00027 PPI Buffering Agent Excipient 20 mg 20.6 mEq or 600
mg Mg(OH).sub.2 50 mg Ac-Di-Sol microencapsulated 3.0 mEq or 250 mg
NaHCO.sub.3 50 mg Klucel omeprazole 23.6 mEq or 850 mg total 10 mg
magnesium stearate per capsule buffer 5.1% disintegrant
TABLE-US-00028 PPI Buffering Agent Excipient 40 mg omeprazole 17.1
mEq or 500 mg Mg(OH).sub.2 40 mg Ac-Di-Sol per capsule 4.2 mEq or
350 mg NaHCO.sub.3 45 mg Klucel 21.3 mEq or 850 mg total 10 mg
magnesium stearate buffer 4.1% disintegrant
TABLE-US-00029 PPI Buffering Agent Excipient 15 mg lansoprazole
17.1 mEq or 500 mg Mg(OH).sub.2 30 mg Crospovidone per capsule 3.0
mEq or 250 mg NaHCO.sub.3 15 mg Klucel 20.1 mEq or 750 mg total 7
mg magnesium stearate buffer 3.7% disintegant
TABLE-US-00030 PPI Buffering Agent Excipient 20 mg omeprazole 17.1
mEq or 500 mg Mg(OH).sub.2 50 mg Ac-Di-Sol per capsule 3.0 mEq or
250 mg NaHCO.sub.3 30 mg Klucel 20.1 mEq or 750 mg total 10 mg
magnesium stearate buffer 5.8% disintegrant
TABLE-US-00031 PPI Buffering Agent Excipient 40 mg omeprazole 20.6
mEq or 600 mg Mg(OH).sub.2 40 mg Ac-Di-Sol per capsule 4.2 mEq or
350 mg NaHCO.sub.3 35 mg Klucel 24.8 mEq or 950 mg total 10 mg
magnesium stearate buffer 3.7% disintegrant
TABLE-US-00032 PPI Buffering Agent Excipient 15 mg 17.1 mEq or 500
mg Mg(OH).sub.2 60 mg Ac-Di-Sol microencapsulated 3.0 mEq or 250 mg
NaHCO.sub.3 15 mg Klucel lansoprazole 20.1 mEq or 750 mg total 7 mg
magnesium stearate per capsule buffer 7.1% disintegrant
TABLE-US-00033 PPI Buffering Agent Excipient 60 mg ompeprazole 17.1
mEq or 500 mg Mg(OH).sub.2 30 mg Ac-Di-Sol per capsule 3.0 mEq or
250 mg NaHCO.sub.3 15 mg Klucel 20.1 mEq or 750 mg total 7 mg
magnesium stearate buffer 3.5% disintegrant
TABLE-US-00034 PPI Buffering Agent Excipient 20 mg omeprazole 6.9
mEq or 200 mg Mg(OH).sub.2 30 mg Ac-Di-Sol per capsule 3.9 mEq or
330 mg NaHCO.sub.3 35 mg Klucel Size 0 capsule 10.8 mEq or 530 mg
total 6 mg magnesium stearate buffer 4.8% disintegrant
TABLE-US-00035 PPI Buffering Agent Excipient 15 mg 6.9 mEq or 200
mg Mg(OH).sub.2 35 mg Ac-Di-So microencapsulated 2.6 mEq or 220 mg
NaHCO.sub.3 20 mg Klucel lansoprazole 8.5 mEq or 420 mg total 6 mg
magnesium stearate per capsule buffer 7.1% disintegrant Size 1
capsule
TABLE-US-00036 PPI Buffering Agent Excipient 30 mg lansoprazole 14
mEq or 100 mg Mg(OH).sub.2 20 mg Ac-Di-Sol per capsule 18 mEq or
315 mg NaHCO.sub.3 30 mg Klucel Size 1 capsule 7.2 mEq or 415 mg
total 5 mg magnesium stearate buffer 4.0% disintegrant
TABLE-US-00037 PPI Buffering Agent Excipient 60 mg ompeprazole 5.1
mEq or 150 mg Mg(OH).sub.2 20 mg Ac-Di-Sol per capsule 3.0 mEq or
250 mg NaHCO.sub.3 10 mg Klucel Size 2 capsule 8.1 mEq or 400 mg
total 4 mg magnesium stearate buffer 4.1% disintegrant
TABLE-US-00038 PPI Buffering Agent Excipient 120 mg ompeprazole 8.6
mEq or 250 mg Mg(OH).sub.2 30 mg Ac-Di-Sol per capsule 2.4 mEq or
200 mg NaHCO.sub.3 30 mg Klucel Size 1 capsule 11.0 mEq or 450 mg
total 8 mg magnesium stearate buffer 4.7% disintegrant
TABLE-US-00039 PPI Buffering Agent Excipient 10 mg ompeprazole 3.4
mEq or 100 mg Mg(OH).sub.2 18 mg Ac-Di-Sol per capsule 3.0 mEq or
250 mg NaHCO.sub.3 15 mg Klucel Size 2 capsule 6.4 mEq or 350 mg
total 7 mg magnesium stearate buffer 4.5% disintegrant
Example 7A: Capsule Formulations without Binder
[0280] 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.
TABLE-US-00040 TABLE 7A PPI Buffering Agent Excipient 40 mg
omeprazole 20.6 mEq or 600 mg Mg(OH).sub.2 50 mg Ac-di-Sol 3.0 mEq
or 250 mg NaHCO.sub.3 10 mg magnesium stearate 23.6 mEq or 950 mgs
total buffer
TABLE-US-00041 TABLE 7B PPI Buffering Agent Excipient 40 mg 15.4 v
or 450 mg Mg(OH).sub.2 30 mg Ac-Di-Sol microencapsulated 2.4 mEq or
200 mg NaHCO.sub.3 7 mg magnesium stearate ompeprazole 17.8 mEq or
650 mg total per capsule buffer
TABLE-US-00042 TABLE 7C PPI Buffering Agent Excipient 40 mg
omeprazole 10.5 mEq or 880 mg NaHCO.sub.3 20 mg Ac-Di-Sol per
capsule 10.5 mEq or 880 mg total 9 mg magnesium stearate buffer
Size 0 Elongated capsule
TABLE-US-00043 TABLE 7D PPI Buffering Agent Excipient 40 mg
microencap- 3.4 mEq or 100 mg Mg(OH).sub.2 20 mg Ac-Di-Sol sulated
ompeprazole 2.4 mEq or 200 mg NaHCO.sub.3 5 mg magnesium per
capsule 5.8 mEq or 300 mg total stearate buffer Size 2 capsule
Example 7B: 40 mg Omeprazole (SAN-7E)
[0281] The following specific formulations are provided by way of
illustrating the present invention and are not intended to be
limiting. The capsules were prepared by blending the indicated
amount of micronized omeprazole USP (purchased from Union Quimico
Farmaceutica, "UQUIFA") about half the indicated amount of sodium
bicarbonate USP #2. After blending the omeprazole and sodium
bicarbonate, the remaining sodium bicarbonate USP #2 was added
along with the indicated amount of croscarmellose sodium and
magnesium stearate. Once the omeprazole was homogeneously blended
with the excipients, the appropriate weight of composition was
filled into hard gelatin capsules, size 00, using a dosing
disc/tampling pin-type automatic encapsulator.
[0282] In particular, a 110 kg blend for manufacturing 40
mg/capsule omeprazole immediate release capsules according to the
present invention was manufactured by the following procedure:
First, about half of the sodium bicarbonate was blended with
omeprazole in a 5 cubic foot V-blender. First, about one quarter of
the total sodium bicarbonate (i.e. about 25% of 102.47 kg (the
total amount of sodium bicarbonate USP #2) was passed through a
16/20 mesh screen and charged into the V-blender. Next, 3.80 kg of
omeprazole USP were passed through a 16/20 mesh screen and charged
into the V-blender. Then, about one quarter of the total sodium
bicarbonate were passed through the 16/20 mesh screen and charged
into the V-blender. Once the sodium bicarbonate (about half the
total) and omeprazole were charged into the V-blender, they were
mixed for 5 minutes to form a pre-blend.
[0283] Next, about half of the sodium bicarbonate and the
crocarmellose was added to the pre-blend. Approximately one quarter
of the of the total sodium bicarbonate was passed through a 16/20
mesh screen and charged into the V-blender. Then 2.79 kg of
crocarmellose sodium NF, EP was passed through the 16/20 mesh
screen and charged into the V-blender. Finally, the remaining one
quarter of the sodium bicarbonate was passed through the screen and
charged into the V-blender. The resulting mixture was 5 minutes,
sampled for BU, mixed again for 5 minutes, sampled for BU, mixed
again for 5 minutes, and sampled again for BU.
[0284] Last, magnesium stearate was added to the mixture. The
magnesium stearate, 0.93 Kg, was passed through a 30 mesh screen
and charged into the V-blender. The mixture was mixed for 3 minutes
then discharged into a drum. The mixture was then sampled for BU
and then encapsulated in size 00 hard gelatin capsules on a H&K
tamping pin encapsulator.
[0285] The amounts of omeprazole and excipients used in this
example are set forth in the following table:
TABLE-US-00044 TABLE 7E Amount Required Acid Neutralizing Content
Ingredient % mg/capsule for 110 Kg: (meq per capsule) Omeprazole
USP 3.5% 40.8 mg/caps 3.80 Kg -- Sodium Bicarbonate USP #2 93.2
1100 102.47 13.1 meq Croscarmellose Sodium NF, EP 2.5 30 2.79 --
Magnesium Stearate 0.8 10 0.93 -- Total: 100.0 1180.8 110.00 13.1
An overage of 2% of omeprazole was used to ensure at least 100%
indicated omeprazole per capsule.
Example 7C: 20 mg Omeprazole (SAN-7F)
[0286] In another particular example, a 1300 Kg blend of 20 mg
omeprazole per capsule was manufactured by the following
procedure:
[0287] First, about half of the sodium bicarbonate was blended with
omeprazole in a 60 cubic foot V-blender. About one quarter of the
total sodium bicarbonate (i.e. about 25% of 1232.33 kg (the total
amount of sodium bicarbonate USP #2) was passed through a 16/20
mesh screen and charged into the V-blender. Next, 22.85 Kg of
omeprazole USP were passed through the 16/20 mesh screen and
charged into the V-blender. Then, about one quarter of the total
sodium bicarbonate were passed through the 16/20 mesh screen and
charged into the V-blender. Once the sodium bicarbonate (about half
the total) and omeprazole were charged into the V-blender, they
were mixed for 5 minutes to form a pre-blend.
[0288] Next, about half of the sodium bicarbonate and the
croscarmellose was added to the pre-blend. Approximately one
quarter of the of the total sodium bicarbonate was passed through a
16/20 mesh screen and charged into the V-blender. Then 33.61 Kg of
Croscannellose sodium NF, EP was passed through the 16/20 mesh
screen and charged into the V-blender. Finally, the remaining one
quarter of the sodium bicarbonate was passed through the screen and
charged into the V-blender. The resulting mixture was mixed 5
minutes, sampled for batch uniformity (BU), mixed again for 5
minutes, sampled for BU, mixed again for 5 minutes, and sampled
again for BU.
[0289] Last, magnesium stearate was added to the mixture. The
magnesium stearate, 11.20 Kg, was passed through a 30 mesh screen
and charged into the V-blender. The mixture was mixed for 3 minutes
then discharged into a drum. The mixture was then sampled for BU
and encapsulated in size 00 hard gelatin capsules on a H&K
tamping pin encapsulator.
[0290] The amounts of omeprazole and excipients used in this
example are set forth in the following table:
TABLE-US-00045 TABLE 7F Amount Acid Neutralizing Required Content
Ingredient % mg/capsule for 110 Kg: (meq per capsule) Omeprazole
USP 1.8% 20.4* 22.85 Kg -- mg/capsule Sodium Bicarbonate 94.8
1100.0 1232.33 13.1 meq USP #2 Croscarmellose 2.6 30.0 33.61 --
Sodium NF, EP Magnesium Stearate 0.9 10.0 11.20 -- Total: 100.1
1160.4 1300.00 13.1 *An overage of 2% omeprazole was used to ensure
that each capsule contained at least 100% of the indicated dose of
20 mg/capsule.
Example 8: Capsule Formulations
[0291] 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 encapsulator (H & K
1500 or MG2 G60). The PPI can be in a micronized form.
TABLE-US-00046 TABLE 8.A Omeprazole (20 mg) Capsule PPI Antacid
Excipient 20 mg omeprazole 6.9 mEq or 200 mg Mg(OH).sub.2 30 mg
Ac-Di-Sol per capsule 3.9 mEq or 330 mg NaHCO.sub.3 35 mg Klucel
10.8 mEq or 530 mg total 6 mg magnesium antacid stearate Size 0
capsule
TABLE-US-00047 TABLE 8.B Omeprazole (40 mg) Capsule PPI Antacid
Excipient 40 mg omeprazole 10.5 mEq or 880 mg NaHCO.sub.3 40 mg
Ac-Di-Sol per capsule 10.5 mEq or 880 mg total 9 mg magnesium
antacid stearate Size 0 Elongated capsule
TABLE-US-00048 TABLE 8.C Lansoprazole (15 mg) Capsule PPI Antacid
Excipient 15 mg microencap- 6.9 mEq or 200 mg Mg(OH).sub.2 35 mg
Ac-Di-Sol sulated lansoprazole 2.6 mEq or 220 mg NaHCO.sub.3 20 mg
Klucel per capsule 9.5 mEq or 420 mg total 6 mg magnesium antacid
stearate Size 1 capsule
TABLE-US-00049 TABLE 8.D Lansoprazole (30 mg) Capsule PPI Antacid
Excipient 30 mg lansoprazole 3.4 mEq or 100 mg Mg(OH).sub.2 20 mg
Ac-Di-Sol per capsule 3.8 mEq or 315 mg NaHCO.sub.3 30 mg Klucel
7.2 mEq or 415 mg total 5 mg magnesium antacid stearate Size 1
capsule
TABLE-US-00050 TABLE 8.E Omeprazole (60 mg) Capsule PPI Antacid
Excipient 60 mg omeprazole 5.1 mEq or 150 mg Mg(OH).sub.2 20 mg
Ac-Di-Sol per capsule 3.0 mEq or 250 mg NaHCO.sub.3 10 mg Klucel
8.1 mEq or 400 mg total 4 mg magnesium antacid stearate Size 2
capsule
TABLE-US-00051 TABLE 8.F Omeprazole (60 mg) Capsule PPI Antacid
Excipient 120 mg omeprazole 8.6 mEq or 250 mg Mg(OH).sub.2 30 mg
Ac-Di-Sol per capsule 2.4 mEq or 200 mg NaHCO.sub.3 30 mg Klucel
11.0 mEq or 450 mg total 8 mg magnesium antacid stearate Size 1
capsule
TABLE-US-00052 TABLE 8.G Omeprazole (10 mg) Capsule PPI Antacid
Excipient 10 mg micro- 3.4 mEq or 100 mg Mg(OH).sub.2 18 mg
Ac-Di-Sol encapsulated 3.0 mEq or 250 mg NaHCO.sub.3 15 mg
Microcrystalline omeprazole 6.4 mEq or 350 mg total Cellulose (MCC,
PH102) per capsule antacid 7 mg magnesium stearate Size 2
capsule
TABLE-US-00053 TABLE 8.H Omeprazole (40 mg) Capsule PPI Antacid
Excipient 40 mg micro- 3.4 mEq or 100 mg Mg(OH).sub.2 20 mg
Ac-Di-Sol encapsulated 2.4 mEq or 200 mg NaHCO.sub.3 5 mg magnesium
omeprazole 5.8 mEq or 300 mg total stearate per capsule antacid
Size 2 capsule
Example 9: Tablet Formulations
[0292] 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 leat some of the PPI by raising the pH of gastric fluid. Amounts
of antacid are expressed in weight as well as in molar equivalents
(mE). 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-US-00054 TABLE 9.A Omeprazole (20 mg) Tablet PPI Antacid
Excipient 20 mg omepra- 5.1 mEq or 150 mg Mg(OH).sub.2 30 mg
Ac-Di-Sol zole per tablet 4.8 mEq or 400 mg NaHCO.sub.3 65 mg
Klucel 9.9 mEq or 550 mg total 10 mg magnesium antacid stearate
TABLE-US-00055 TABLE 9.B Omeprazole (40 g) Tablet PPI Antacid
Excipient 40 mg micro- 5.1 mEq or 150 mg Mg(OH).sub.2 20 mg
Ac-Di-Sol encapsulated 3.0 mEq or 250 mg NaHCO.sub.3 40 mg
Microcrystalline omeprazole 8.1 mEq or 350 mg total cellulose (MCC,
PH102) per tablet antacid 7 mg magnesium stearate
TABLE-US-00056 TABLE 9.C Lansoprazole (15 mg) Tablet PPI Antacid
Excipient 15 mg micro- 8.6 mEq or 250 mg Mg(OH).sub.2 30 mg
Ac-Di-Sol encapsulated 2.4 mEq or 200 mg NaHCO.sub.3 55 mg Plasdone
lansoprazole 11.0 mEq or 450 mg total 8 mg magnesium per tablet
antacid stearate
TABLE-US-00057 TABLE 9.D Lansoprazole (30 mg) Tablet PPI Antacid
Excipient 30 mg lansopraz- 6.2 mEq or 180 mg Mg(OH).sub.2 25 mg
Ac-Di-Sol ole per tablet 4.2 mEq or 350 mg NaHCO.sub.3 55 mg Klucel
10.4 mEq or 430 mg total 8 mg magnesium antacid stearate
TABLE-US-00058 TABLE 9.E Omeprazole (60 mg) Tablet PPI Antacid
Excipient 60 mg 7.5 mEq or 220 mg Mg(OH).sub.2 20 mg Ac-Di-Sol
omeprazole 3.0 mEq or 250 mg NaHCO.sub.3 60 mg Klucel per tablet
10.5 mEq or 470 mg total 10 mg magnesium antacid stearate
TABLE-US-00059 TABLE 9.F Omeprazole (20 mg) Tablet PPI Antacid
Excipient 20 mg 7.5 mEq or 220 mg Mg(OH).sub.2 20 mg Ac-Di-Sol
omeprazole 2.4 mEq or 200 mg NaHCO.sub.3 60 mg Klucel per tablet
9.9 mEq or 420 mg total 8 mg magnesium antacid stearate
TABLE-US-00060 TABLE 9.G Omeprazole (10 mg) Tablet PPI Antacid
Excipient 10 mg 3.4 mEq or 100 mg Mg(OH).sub.2 15 mg Ac-Di-Sol
microencapsulated 3.0 mEq or 250 mg NaHCO.sub.3 40 mg Klucel
omeprazole per 6.4 mEq or 350 mg total 6 mg magnesium tablet
antacid stearate
TABLE-US-00061 TABLE 9.H Omeprazole (40 mg) Tablet PPI Antacid
Excipient 40 mg 5.1 mEq or 150 mg 20 mg Ac-Di-Sol microeneapsulated
Mg(OH).sub.2 50 mg Microcrystalline omeprazole per 3.8 mEq or 315
mg Cellulose (MCC, PH102) tablet NaHCO.sub.3 10 mg magnesium 8.9
mEq or 465 mg total stearate antacid
Example 10: Chewable Tablet Formulations
[0293] 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 a prepared by blending the PPI and
antacids, and homogeneously blending with excipients as shown in
Tables 10.A to 10H. below. The appropriate weight of bulk blended
composition is compressed using 17 mm 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-US-00062 TABLE 10.A Omeprazole (20 mg) Chewable Tablet PPI
Antacid Excipient 20 mg 5.1 mEq or 150 mg 100 mg Xylitab
microencapsulated Mg(OH).sub.2 30 mg Ac-Di-Sol omeprazole 3.8 mEq
or 315 mg 80 mg Klucel per tablet NaHCO.sub.3 20 mg Sucralose 8.9
mEq or 465 mg total 10 mg cherry flavor antacid 10 mg magnesium
stearate 1 mg Red #40 Lake
TABLE-US-00063 TABLE 10.B Omeprazole (40 mg) Chewable Tablet PPI
Antacid Excipient 40 mg 7.5 mEq or 220 mg 100 mg Dipac sugar
microencapsulated Mg(OH).sub.2 20 mg Ac-Di-Sol omeprazole per 2.4
mEq or 200 mg 80 mg Klucel tablet NaHCO.sub.3 17 mg grape flavor
9.9 mEq or 420 mg total 11 mg magnesium antacid stearate 1 mg Red
#40 Lake 1 mg Blue #2 Lake
TABLE-US-00064 TABLE 10.C Lansoprazole (15 mg) Chewable Tablet PPI
Antacid Excipient 15 mg 5.1 mEq or 150 mg Mg(OH).sub.2 80 mg
Xylitab lansoprazole 2.4 mEq or 200 mg NaHCO.sub.3 25 mg Ac-Di-Sol
per tablet 7.5 mEq or 350 mg total 70 mg Microcrystalline antacid
Cellulose 50 mg Asulfatne-K 15 mg grape flavor 10 mg magnesium
stearate 1 mg red #40 lake 1 mg blue #2 lake
TABLE-US-00065 TABLE 10.D Lansoprazole (30 mg) Chewable Tablet PPI
Antacid Excipient 30 mg 5.1 mEq or 150 mg 70 mg Destab Sugar
microencapsulated Mg(OH).sub.2 30 mg Ac-Di-Sol lansoprazole per 3.8
mEq or 315 mg 100 mg Klucel tablet NaHCO.sub.3 20 mg Asulfame-K 8.9
mEq or 465 mg total 15 mg cherry flavor antacid 9 mg magnesium
stearate 1 mg Red #40 Lake
TABLE-US-00066 TABLE 10.E Omeprazole (60 mg) Chewable Tablet PPI
Antacid Excipient 60 mg 4.4 mEq or 220 mg 80 mg Xylitab
microencapsulated Ca(OH).sub.2 30 mg Ac-Di-Sol omeprazole per 16
mEq or 300 mg 100 mg Klucel tablet NaHCO.sub.3 35 mg Sucralose 8.0
mEq or 520 mg total 10 mg cherry flavor antacid 9 mg magnesium
stearate 2 mg Red #40 Lake
TABLE-US-00067 TABLE 10.F Omeprazole (60 mg) Chewable Tablet PPI
Antacid Excipient 60 mg 3.0 mEq or 150 mg 70 mg Xylitab omeprazole
per Ca(OH).sub.2 25 mg Ac-Di-Sol tablet 3.0 mEq or 250 mg 90 mg
Microcrystalline NaHCO.sub.3 Cellulose (PH 102) 6.0 mEq or 400 mg
total 8 mg mint flavor antacid 10 mg magnesium stearate
TABLE-US-00068 TABLE 10.G Omeprazole (10 mg) Chewable Tablet PPI
Antacid Excipient 10 mg 8.0 mEq or 400 mg Ca(OH).sub.2 110 mg Ditab
Sugar omeprazole per 3.6 mEq or 300 mg NaHCO.sub.3 30 mg Ae-Di-Sol
tablet 11.6 mEq or 700 mg total 20 mg Sucralose antacid 100 mg
Klucel 15 mg mint flavor 15 mg magnesium stearate
TABLE-US-00069 TABLE 10.H Omeprazole (40 mg) Chewable Tablet PPI
Antacid Excipient 40 mg 7.5 mEq or 350 mg Ca(OH).sub.2 70 mg
Xylitab microencapsulated 3.0 mEq or 250 mg NHCO.sub.3 30 mg
Ac-Di-Sol omeprazole per 10.5 mEq or 600 mg total 10 mg Sucralose
tablet antacid 80 mg Klucel 10 mg mint flavor 8 mg magnesium
stearate
Example 11: Bite-Disintegration Chewable Tablet Formulations
[0294] 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 10 mm FFBE toolings in a
rotary press (Manesty Express) to achieve a hardness of 5-9 kPa.
The PPI can be in a micronized form.
TABLE-US-00070 TABLE 11.A Omeprazole (20 mg) Bite-Disintegration
Chewable Tablet PPI Antacid Excipient 20 mg per 7.5 mEq or 350 mg
Ca(OH).sub.2 20 mg sucralose tablet 3.0 mEq or 250 mg NaHCO.sub.3
40 mg Ac-Di-Sol 10.5 mEq or 600 mg total 30 mg pregelatinized
antacid starch 30 mg Kind 15 mg cherry flavor 8 mg magnesium
stearate 1 mg Red #40 Lake
TABLE-US-00071 TABLE 11.B Omeprazole (40 mg) Bite-Disintegration
Chewable Tablet PPI Antacid Excipient 40 mg 8.0 mEq or 400 mg
Ca(OH).sub.2 20 mg sucralose microencapsulated 3.6 mEq or 300 mg
NaHCO.sub.3 40 mg Ac-Di-Sol omeprazole 11.6 mEq or 700 mg total 35
mg pregelatinized per tablet starch 25 mg Klucel 15 mg cherry
flavor 8 mg magnesium stearate 1 mg Red #Lake
TABLE-US-00072 TABLE 11.C Lansoprazole (15 mg) Bite-Disintegration
Chewable Tablet PPI Antacid Excipient 15 mg 7.9 mEq or 230 mg
Mg(OH).sub.2 20 mg sucralose lansoprazole 3.6 mEq or 300 mg
NaHCO.sub.3 35 mg Ac-Di-Sol per tablet 11.5 mEq or 530 mg total 35
mg pregelatinized starch 25 mg Klueel 17 mg grape flavor 8 mg
magnesium stearate 1 mg Red #40 Lake 1 mg Blue #2 lake
TABLE-US-00073 TABLE 11.D Lansoprazole (30 mg) Bite-Disintegration
Chewable Tablet PPI Antacid Excipient 30 mg microen- 5.1 mEq or 150
mg Mg(OH).sub.2 27 mg sucralose capsulated 3.8 mEq or 315 mg
NaHCO.sub.3 40 mg Ac-Di-Sol lansoprazole 8.9 mEq or 465 mg total 35
mg pregelatinized per tablet antacid starch 30 mg Microcrystalline
Cellulose (PH101) 20 mg cherry flavor 10 mg magnesium stearate 2 mg
Red #40 Lake
TABLE-US-00074 TABLE 11.E Omeprazole (60 mg) Bite-Disintegration
Chewable Tablet PPI Antacid Excipient 60 mg microen- 7.9 mEq or 230
mg Mg(OH).sub.2 34 mg sucralose capsulated 3.0 mEq or 250 mg
NaHCO.sub.3 30 mg Ac-Di-Sol omeprazole 10.9 mEq or 480 mg total 35
mg pregelatinized per tablet antacid starch 30 mg Klucel 25 mg
cherry flavor 10 mg magnesium stearate 2 mg Red #40 Lake
TABLE-US-00075 TABLE 11.F Omeprazole (60 mg) Bite-Disintegration
Chewable Tablet PPI Antacid Excipient 60 mg omep- 7.0 mEq or 350 mg
Ca(OH).sub.2 30 mg sucralose razole 3.0 mEq or 250 mg NaHCO.sub.3
40 mg Ac-Di-Sol per tablet 10.0 mEq or 600 mg total 30 mg
pregelatinized antacid starch 30 mg Klucel 40 mg Xylitab 7 mg mint
flavor 10 mg magnesium stearate
TABLE-US-00076 TABLE 11.G Omeprazole (10 mg) Bite-Disintegration
Chewable Tablet PPI Antacid Excipient 10 mg omepra- 5.0 mEq or 250
mg Ca(OH).sub.2 20 mg sucralose zole per tablet 2.9 mEq or 240 mg
NaHCO.sub.3 40 mg Ac-Di-Sol 7.9 mEq or 490 mg total 30 mg
pregelatinized antacid starch 30 mg Klucel 15 mg cherry flavor 8 mg
magnesium stearate 1 mg Red #40 Lake
TABLE-US-00077 TABLE 11.H Omeprazole (40 mg) Bite-Disintegration
Chewable Tablet PPI Antacid Excipient 40 mg microen- 8.0 mEq or 400
mg Ca(OH).sub.2 30 mg sucralose capsulated 2.9 mEq or 240 mg
NaHCO.sub.3 40 mg Ac-Di-Sol omeprazole 10.9 mEq or 1590 mg total 30
mg pregelatinized per tablet antacid starch 30 mg Klucel 40 mg
Xylitab 7 mg mint flavor 10 mg magnesium stearate
Example 12: Powder for Suspension Formulations
[0295] 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-US-00078 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 Xylitol 300 (sweetener) 1000 1000 1000
1000 1000 1000 1000 1000 1000 1000 Sucrose-powder 1000 1000 1000
1000 1000 1000 1000 1000 1000 1000 (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 2880 Total ANC 11.0 8.4 8.7 10.2
9.7 10.5 9.4 10.5 5.2 10.5
TABLE-US-00079 TABLE 12.B Omeprazole (20 mg) Powder for Suspension
1 2 3 4 5 6 7 8 9 10 Omeprazole 20 20 20 20 20 20 20 20 20 20
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 Xylitol 300 (sweetener) 1000
1000 1000 1000 1000 1000 1000 1000 1000 1000 Sucrose-powder
(sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000
Sueralose (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 2625 2685 2730 2775 2760 2510 2780 Total ANC 11.0 8.4 8.7
10.2 9.7 10.5 9.4 10.5 5.2 10.5
TABLE-US-00080 TABLE 12.C Omeprazole (40 mg) Powder for Suspension
1 2 3 4 5 6 7 8 9 10 Omeprazole 40 40 40 40 40 40 40 40 40 40
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 Xylitol 300 (sweetener) 1000
1000 1000 1000 1000 1000 1000 1000 1000 1000 Sucrose-powder
(sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000
Sucralose (sweetener) 60 100 150 75 100 70 80 130 125 80 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 50 Total Weight
2606 2610 2775 2645 2705 2750 2795 2780 2530 2800 Total ANC 11.0
8.4 8.7 10.2 9.7 10.5 9.4 10.5 5.2 10.5
TABLE-US-00081 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 60
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 Xylitol 300 (sweetener) 1000
1000 1000 1000 1000 1000 1000 1000 1000 1000 Sucrose-powder
(sweetener) 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000
Sucralose (sweetener) 60 100 150 75 100 70 80 130 125 80 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 50 Total Weight
2626 2630 2795 2665 2725 2770 2815 2800 2550 2820 Total ANC 11.0
8.4 8.7 10.2 9.7 10.5 9.4 10.5 5.2 10.5
Example 13: Naked or Microencapsulated Omeprazole 40 mg Chewable
Tablets, Cansules, and Caplets are Pharmacokinetically
Bioequivalent to Prilosec.RTM. Delayed-Release Capsules 40 mg with
Respect to Area Under the Curve (AUC)
[0296] This trail was conducted as an open-label, single-dose,
crossover trial, with each subject receiving up to twelve different
oral omeprazole formulations, one in each of the twelve treatment
periods. Each dose was followed by a minumum 7-day washout.
Omeprazole was administered at a dose of 40 mg. The amount of
antacid used in the formulations varied as set forth in Table 13A.
All formulations were administered with about 120 ml (4 oz) of
water after an overnight fast and 1 hour prior to a standardized,
high-fat breakfast. Within a given treatment period, the same
treatment was administered to all subjects.
[0297] The omeprazole was delivered as either Prilosec.RTM. or as
an immediate-release formulation according to the invention (i.e.
without an enteric coating). Omeprazole was formulated as uncoated
or microencapsulated granules a powder in capsule, a caplet or in a
compressed chewable tablet.
[0298] Selection of the exact formulation for each treatment period
is set forth in Table 13A, below.
TABLE-US-00082 TABLE 13A The pharmacokinetic release trial periods
1-12 with the tested omeprazole dosage forms. (All dosage forms
contained 40 mg omeprazole as follows: Prilosec .RTM. 40 mg, or a
capsule, tablet, or caplet form, 40 mg). Period Study Material 1
(Prilosec .RTM.) Prilosec .RTM. (40 mg omeprazole) 2 (SAN-10A)
SAN-10A Capsule, 21.1 mEq (420 mg SB & 470 mg MH) Utilizes <
100 mesh MH 3 (SAN-15A) Period 3 Tablet, 30.7 mEq (850 mg SB &
600 mg MH) "Naked" OME & MS95 MH 4 (SAN-10B) SAN-10B Capsule,
21.1 mEq (420 mg SB & 470 mg MH) Utilizes < 60 mesh MH
5(SAN-15B) Period 5 Tablet, 30.7 mEq (850 mg SB & 600 mg MH)
with Klucel eAPI & MS95 MH 6 (SAN-10J) SAN-10J Capsule, 19.1
mEq (378 mg SB & 425 mg MH) Utilizes MS95 MH 7 (SAN-15C) Period
7 Tablet, 30.7 mEq (850 mg SB & 600 mg MH) with Methocel eAPI
& MS95 MH 8 (SAN-10H) SAN-10H Capsule, 17.9 mEq (420 mg SB
& 375 mg MH) Utilizes < 60 mesh MH 9 (SAN - 10BB) SAN-10BB
Capsule, 13.1 mEq (1100 mg SB) 10 (SAN-15D) Period 10 Caplet, 18.8
mEq (280 mg SB & 450 mg MH) eAPI, MS95 MH & 4.9%
disintegrant 11 (SAN-10C) SAN-10C Capsule, 10.5 mEq (880 mg SB) 12
(SAN-15E) Period 12 Caplet, 18.8 mEq (280 mg SB & 450 mg MH)
eAPI, MS95 MH & 7.9% disintegrant
[0299] Volunteers were screened for up to 14 days before baseline
measurements of blood plasma levels of omeprazole. In each period,
a standardized high-fat breakfast was given in the clinic 1 hour
after dosing of omeprazole. Blood samples for determination of
plasma omeprazole concentrations were collected for 12 hours post
treatment.
Duration of Treatment
[0300] Including screening, subjects participated in this trial for
up to 170 days.
Design Rationale
[0301] This trial was designed to assess the pharmacokinetics of
immediate-release omeprazole chewable tablets, oral capsule and
caplets versus the Prilosec.RTM. 40 mg delayed-release formulation.
The duration of the trial for each subject was approximately 24
weeks, including up to 14 days for screening and a minimum 7 day
wash-out period between omeprazole doses.
[0302] Data from 12 healthy male subjects were expected to provide
adequate power to assess pharmacokinetics and safety using
descriptive statistics. The descriptive statistics were assessed
using the pharmacokinetic parameters: Tmax, Cmax, AUC(0-t),
AUC(0-inf), T1/2 and kel. Safety evaluations were based on the
occurrence (vel non) of adverse events, blood chemistry and
hematology, use of concomitant medications and change from baseline
in physical examination findings and vital signs.
[0303] As the study employed a single dose of omeprazole for each
period of dosing, the analysis focused on Day 1 of dosing.
[0304] The time of drug administration (after an overnight fast and
1 hour prior to a meal) meets the regulatory guidance for
bioequivalence (fasting) and anticipates actual use.
Treatments Administered:
[0305] The treatments administered to subjects in this trial are
listed in Table 13A, above. In general, the treatment protocol
entailed a 14 day assessment period, followed by a first period
(Period 1) in which Prilosec.RTM. 40 mg delayed release capsule was
administered to the subjects, after an overnight fast, and 1 hour
prior to a standardized high-fat breakfast. Plasma sampling was
conducted for 6 hour post-dose. Period 1 was followed by a 7-14 day
washout period, during which the plasma levels of omeprazole were
expected to decrease to a steady baseline. The second through
twelfth periods (Periods 2-12) were conducted in a similar manner
to Period 1, in each period substituting a dosage form according to
the invention for the delayed-release formulation used in Period 1.
The specific dosage forms used in the study are set forth in Table
13A, above. Each of the 12 healthy male volunteers received the
same course of treatment without randomization.
Pharmacokinetic Sampling, Analytical Methods, and Parameters
[0306] Blood samples (3 mL) were obtained by venipuncture within 30
minutes before each dose and at 0, 5, 10, 15, 20, 30, 45, 60, 90,
120, 180, 240, 300, 360 minutes (6 hours) after delivery of each
dose during each trial period. Zero time was the time that the
subject swallowed a capsule, caplet or chewable tablet of trial
drug.
[0307] Plasma omeprazole concentrations were measured using a
previously validated liquid chromatography mass spectrometry
(LC-MSIMS) assay (MDS Pharma Services, Lincoln, Nebr.).
The linear assay range was 5.0 to 750 ng/mL. The following
pharmacokinetic parameters were measured for each subject: [0308]
Plasma omeprazole concentration at each sampling time [0309] Peak
omeprazole plasma concentration (Cmax) and the time at which Cmax
is observed (Tmax) obtained directly from the data without
interpolation [0310] Terminal elimination rate constant (Kel)
determined from a log-linear regression analysis of the terminal
plasma omeprazole concentrations [0311] Half-life of drug
elimination (T %) calculated as 0.693/Kel [0312] Area under the
plasma drug time-concentration curve calculated from 0 time to last
time point evaluated [AUC(0-t)] calculated using the trapezoidal
rule with the plasma concentration at time t being the last
measurable concentration [0313] Area under the plasma drug
time-concentration curve calculated from 0 time and extrapolated to
infinity [AUC(0-int)] calculated as AUC(0-t)+Ct/Kel, where Ct is
the last measurable plasma concentration (at time t) and Kel is the
terminal elimination rate constant defined above
Primary Endpoint
[0314] The primary pharmacokinetic endpoint was the bioavailability
of omeprazole [AUC(0-inf)].
Pharmacokinetic Analysis
[0315] For the analysis of data collected on Day 1 of each period
(pre-meal dosing), an analysis of variance (ANOVA) model was used
to test the bioequivalence of each of the tested drug formulations.
The model included the following factors: treatment, period,
sequence, and subject nested within sequence. Ninety percent
confidence intervals (CIs) for treatment differences were
calculated; the endpoints of these CIs were then reverse
transformed to represent CIs about the percent mean ratios on the
original scale. With respect to AUC(0-inf) and Cmax, equivalence
was declared for each parameter if the bounds of the 90% CIs for
the percent mean ratio, comparing a composition according to the
invention (Periods 2-12) with Prilosec, were between 80% and
125%.
Determination of Sample Size
[0316] A sample size of 12 initial healthy male subjects was
considered sufficient to ensure that at least 5 subjects finished
the entire trial.
Pharmacokinetic Results
[0317] Pharmacokinetic results are presented in Table 13 B. and
FIGS. 14-16, 18, 19, 21, 22, 23.
TABLE-US-00083 TABLE 13.B Pharmacokinetic Release Profiles of
Formulated OME and Prilosec 40 mg Study of Periods 1-12 Intervals
(Minutes) ng/mL Period/Test Dosage Day 0 5 10 15 20 30 45 60 90
Mean Prilosec (P1) 1 0 0 0 0 2 20 205 485 991 Min Prilosec (P1) 1 0
0 0 0 0 0 37 104 241 Max Prilosec (P1) 1 0 0 0 0 15 80 543 1474
2994 Mean Capsule (P2) (SAN-10A) 1 0 0 29 176 647 1043 1022 929 733
Min Capsule (P2) (SAN-10A) 1 0 0 0 0 11 26 152 158 96 Max Capsule
(P2) (SAN-10A) 1 0 0 340 888 1600 2351 2696 2295 2133 Mean Chew Tab
(P3) (SAN-15A) 1 0 80 642 921 1001 1092 939 800 597 Min Chew Tab
(P3) (SAN-15A) 1 0 0 73 149 188 177 145 132 71 Max Chew Tab (P3)
(SAN-15A) 1 0 352 1321 1779 2073 2705 2571 2311 2133 Mean Capsule
(P4) (SAN-10B) 1 0 0 36 192 413 623 698 682 799 Min Capsule (P4)
(SAN-10B) 1 0 0 0 8 19 94 128 175 120 Max Capsule (P4) (SAN-10B) 1
0 0 373 966 1403 1727 1801 1792 2358 Mean Chew Tab (P5) (SAN-15B) 1
0 53 473 820 956 958 897 856 633 Min Chew Tab (P5) (SAN-15B) 1 0 0
36 330 428 379 227 167 70 Max Chew Tab (P5) (SAN-15B) 1 0 150 1073
1770 2110 2327 2848 3097 2586 Mean Capsule (P6) (SAN-10E) 1 0 0 1
65 502 1007 969 818 648 Min Capsule (P6) (SAN-10E) 1 0 0 0 0 14 47
156 170 92 Max Capsule (P6) (SAN-10E) 1 0 0 10 173 1126 2323 2721
2474 2415 Mean Chew Tab (P7) (SAN-15C) 1 0 65 706 1396 1386 1230
1048 852 610 Min Chew Tab (P7) (SAN-15C) 1 0 0 191 473 711 515 321
226 67 Max Chew Tab (P7) (SAN-15C) 1 0 382 1172 2807 2306 2580 2358
2117 2244 Mean Capsule (P8) (SAN-10H) 1 0 0 136 293 586 893 848 823
724 Min Capsule (P8) (SAN-10H) 1 0 0 0 11 57 266 196 197 87 Max
Capsule (P8) (SAN-10H) 1 0 0 451 1100 1428 1697 1627 1871 2196 Mean
Capsule (P9) (SAN-10BB) 1 0 0 37 286 867 1198 1111 936 652 Min
Capsule (P9) (SAN-10BB) 1 0 0 0 24 120 299 275 204 120 Max Capsule
(P9) (SAN-10BB) 1 0 0 172 809 1624 2305 1957 2222 1806 Mean Caplet
(P10) (SAN-15D) 1 0 56 184 269 199 213 235 322 699 Min Caplet (P10)
(SAN-15D) 1 0 0 5 23 28 49 48 56 143 Max Caplet (P10) (SAN-15D) 1 0
440 1256 1518 744 595 469 101 1440 Mean Capsule (P11) (SAN-10C) 1 0
1 33 292 1027 1026 868 767 591 Min Capsule (P11) (SAN-10C) 1 0 0 0
26 52 267 337 237 74 Max Capsule (P11) (SAN-10C) 1 0 7 196 827 2024
2056 1729 1992 1842 Mean Caplet (P12) (SAN-15E) 1 0 5 43 81 116 327
540 583 909 Intervals (Minutes) Cmax Tmax ng/mL Period/Test Dosage
Day 120 180 240 300 360 N (ng/mL) (hr) Mean Prilosec (P1) 1 679 417
265 203 143 12 1061 1.38 Min Prilosec (P1) 1 127 37 8 8 0 12 273
1.00 Max Prilosec (P1) 1 2146 1596 1093 1081 707 12 2994 1.50 Mean
Capsule (P2) (SAN-10A) 1 504 309 226 149 107 12 1155 0.76 Min
Capsule (P2) (SAN-10A) 1 51 19 6 0 0 12 285 0.63 Max Capsule (P2)
(SAN-10A) 1 1670 1362 1215 835 676 12 2696 1.50 Mean Chew Tab (P3)
(SAN-15A) 1 441 280 193 129 95 12 1201 0.54 Min Chew Tab (P3)
(SAN-15A) 1 42 9 0 0 0 12 196 0.50 Max Chew Tab (P3) (SAN-15A) 1
1701 1322 999 709 587 12 2705 1.50 Mean Capsule (P4) (SAN-10B) 1
616 371 274 182 147 12 990 1.22 Min Capsule (P4) (SAN-10B) 1 44 9 0
0 0 12 222 0.33 Max Capsule (P4) (SAN-10B) 1 2168 1691 1491 983 900
12 2358 2.00 Mean Chew Tab (P3) (SAN-15C) 1 467 305 226 148 122 12
1192 0.50 Min Chew Tab (P3) (SAN-15C) 1 29 14 7 0 0 12 428 0.17 Max
Chew Tab (P3) (SAN-15C) 1 2058 1532 1279 788 744 12 3097 1.00 Mean
Capsule (P6) (SAN-10E) 1 436 284 175 137 89 12 1130 0.78 Min
Capsule (P6) (SAN-10E) 1 51 20 0 0 0 12 399 0.33 Max Capsule (P6)
(SAN-10E) 1 1879 1323 994 858 590 12 2721 1.50 Mean Chew Tab (P7) 1
436 295 217 161 112 11 1550 0.33 Min Chew Tab (P7) 1 31 7 0 0 0 11
711 0.25 Max Chew Tab (P7) 1 1538 1279 1069 760 596 11 2807 0.50
Mean Capsule (P8) (SAN-10H) 1 516 323 192 135 102 8 1128 0.78 Min
Capsule (P8) (SAN-10H) 1 48 14 0 0 0 8 362 0.25 Max Capsule (P8)
(SAN-10H) 1 1848 1426 882 685 556 8 2196 1.50 Mean Capsule (P9)
(SAN-10BB) 1 519 323 234 161 118 8 1364 0.55 Min Capsule (P9)
(SAN-10BB) 1 82 20 0 0 0 8 535 033 Max Capsule (P9) (SAN-10BB) 1
1755 1269 1074 824 637 8 2305 0.75 Mean Caplet (P10) 1 598 430 271
178 136 8 111 1.59 Min Caplet (P10) 1 97 42 21 10 6 8 531 0.25 Max
Caplet (P10) 1 1850 1404 1036 749 633 8 1850 3.00 Mean Capsule
(P11) (SAN-10C) 1 473 286 204 133 111 7 1378 0.57 Min Capsule (P11)
(SAN-10C) 1 41 16 0 0 0 7 414 0.33 Max Capsule (P11) (SAN-10C) 1
1826 1214 1004 657 592 7 2056 1.00 Mean Caplet (P12) 1 531 320 196
143 110 8 1083 1.59
Formulations in Tables 13A and 13B were prepared according to the
following protocols:
Preparation of Capsules
[0318] SAN-10A, SAN-10B, SAN-10BB and SAN-10K capsules were
prepared on a 1.5 kg batch size in a 6 quart planetary mixer. The
grade of each ingredient is shown in Table 13C below. Omeprazole
USP is micronized omeprazole obtained from UQUIFA, holder of the
Type II DMF for micronized omeprazole.
[0319] About half the sodium bicarbonate (#2 USP) was blend
together with omeprazole and then with the other half of the sodium
bicarbonate. Magnesium hydroxide was screened through a 100 or 60
US mesh screen and then charged into the planetary mixer. Then the
entire blend was passed through a #20 mesh s/s screen and
reintroduced into the Planetary Mixer and mixed for 10 minutes.
Magnesium stearate was screened through a #40 mesh s/s screen
directly into the Planetary Mixer and blended for 3 minutes. The
mixture was then encapsulated in hard gelatin capsules, size #00,
using a Profill.RTM. manual encapsulator. The amount of each
ingredient used in SAN-10A, SAN-10B, SAN-10BB and SAN-10K capsules
is set forth in Table 13C.
TABLE-US-00084 TABLE 13C SAN-10A SAN-10B SAN-10BB SAN-10K
Ingredients mg/caps % mg/cap % mg/caps % mg/caps % Omeprazole USP
40.8 4.2 40.8 4.2 40.8 3.5 40.8 4.3 Sodium Bicarbonate #2 420 43.3
420 43.3 1100 94.0 882 93 USP Magnesium Hydroxide 470 48.4 0 0 0 0
0 0 (screened) 100 mesh Magnesium Hydroxide 0 0 470 48.4 0 0 0 0
(screened) 60 mesh Croscarmellose Sodium 30 3.1 30 3.1 20 1.7 20
2.1 NF Magnesium Stearate NF 10 1.0 10 1.0 10 0.9 10 1.0 Totals
970.8 100.0 970.8 100 mg/caps % mg/caps %
[0320] SAN10E and SAN-10H were prepared in a manner similar to that
described for SAN-10A, etc., above, except that SAN-10E used a
special grade of magnesium hydroxide (MS-95), which is a
spray-dried magnesium hydroxide containing 95% magnesium hydroxide
and 5% pro-gelatinized starch. SAN-10H is a blend fortified with
croscarmellose sodium, which was developed for encapsulation on a
Zinasi LZ64 dosator-type encapsulator. The amount of each
ingredient is set forth in Table 13C. Both SAN-10E and SAN-10H were
encapsulated in hard gelatin capsules size #00. SAN-10E capsules
were encapsulated using the Profill.RTM. hand encapsulator. SAN-10H
capsules were encapsulated using the Zansi LZ64 dosator type
encapsulator. The amount of each ingredient per capsule is set
forth in Table 13C below.
TABLE-US-00085 TABLE 13D SAN-10E SAN-10H Ingredients mg/caps %
mg/caps % Omeprazole USP 40.8 4.5 40.8 4.4 Sodium 378 42.0 420 45.6
Bicarbonate #2 USP Magnesium 0 0 0 0 Hydroxide (screened) 100 mesh
Magnesium 0 0 375 40.6 Hydroxide (screened) 60 mesh Magnesium 447.4
49.8 0 0 Hydroxide MS-95 Croscarmellose 27 3.0 82 8.9 Sodium NF
Magnesium 6 0.7 5 0.5 Stearate NF Totals 899.2 100.0 922.8
100.0
Preparation of Chewable Tablets
[0321] Micronized omeprazole USP (UQUIFA) was microencapsulated
with hydroxypropylcellulose (HPC) using a spray drying process. The
grade of HPC was Klucel.RTM., EF. The amount of each excipient used
is set forth in Table 13E.
TABLE-US-00086 TABLE 13E Weight Weigh (%) Feed (%) Dry Excipient
Suspension Product Function Omeprazole USP 6.00% 37.00% API HPC
Klucel .RTM. EF, NF 10.0 61.6 Coating Material Sodium Bicarbonate,
USP 0.23 1.4 pH Adjuster Purified Water, USP 83.8 N/A Suspension
Medium Totals 100.00% 100.00%
[0322] HPC was added slowly to purified water and mixed until
dissolved. Sodium bicarbonate and omeprazole were then added slowly
to prevent agglomeration. The spray composition was then screened
prior to introducing it into the spray drier. The spray composition
was then spray dried using a Niro.RTM. spray drier, which is
equipped with a rotary spray atomizer. The final omeprazole content
of the microencapsulated formulation is 37%.
[0323] Microencapsulated omeprazole was combined with about half
the antacid excipient were blended to homogeneity to form an
omeprazole pre-blend. The flavor components were next mixed with
one another to form a flavor pre-blend. The omeprazole pre-blend
and the flavor pre-blend were combined to form a main blend.
Finally, a lubricant, magnesium stearate was added to the main
blend to form the final blend. Tablets were formed on a commercial
Fette press. The amount of the active ingredient and excipients
used are set forth in Table 13A, above.
CONCLUSION
[0324] Naked or microencapsulated omeprazole 40 mg in Tablet,
Capsule and Caplet forms (Periods 2-12) were bioequivalent to
Prilosec.RTM. Capsules 40 mg with regard to AUC(0-inf). See FIGS.
14 and 15. The two treatments were not equivalent with regard to
peak plasma concentration, Cmax. This difference in Cmax had no
apparent effect on the pharmacodynamics or safety of the 40 mg
formulation in this trial. The two treatments were also not
equivalent with regard to pharmacokinetic release profiles.
Example 14A: Formulation of SAN-7F (20 mOmeprazole Capsules)
[0325] A 1300 kg lot of 20 mg omeprazole capsules was manufactured
under cGMP conditions. The formulation is set forth in Table 14A,
below:
TABLE-US-00087 TABLE 14A % Amount Required for Ingredient Weight
mg/Capsule 1300 kg Batch (kg) Omeprazole, USP 1.8% 20.4 22.9 kg
mg/cap Sodium Bicarbonate, 94.8 1100 1232 USP #2 Croscarmellose
Sodium, NF 2.6 30 33.6 Magnesium Stearate, NF 0.9 10 11.2 Totals
100 1160.4 1300
[0326] The following ingredients were added to a tote (tote #1) in
the following order: Sodium bicarbonate (about 25% of total),
omeprazole USP, sodium bicarbonate (about 25% of total). The
contents of tote #1 were then charged into a 60 ft.sup.3 V-blender
through a Comil.RTM. powder mill equipped with a 16 mesh equivalent
screen, operating the powder screen at a speed setting of high (800
rpm). The contents were mixed for 5 minutes at 8 rpm. About 25% of
the total amount of sodium bicarbonate was then charged into a tote
(tote #2). Then the contents of the V-blender were charged into
tote #2. The contents of tote #2 were then passed through a
Comil.RTM. powder mill equipped with a 16 mesh equivalent screen at
a speed setting of high (800 rpm).
[0327] Next, croscarmellose sodium and the remaining amount of
sodium bicarbonate were charged into tote #1. The contents of tote
#1 were then passed through a Comil.RTM. powder mill equipped with
a 16 mesh equivalent screen at a speed setting of high (800 rpm)
and charged into the V-blender. The mixture was then blended for 15
minutes a 8 rpm. Then magnesium stearate was screened through a #30
mesh hand screen and charged into the V-blender. The resulting
mixture was then blended for 3 minutes at 8 rpm. The contents of
the V-blender were then discharged into labeled containers lined
with inner clear polyethylene bag overwrapped with an outer black
polyethylene bag. The resulting mixture was encapsulated on a
H&K 1200.RTM. dosing disc/tamping pin-type encapsulator using
hard gelatin capsules size #00.
Critical Encapsulation Process Parameters
[0328] Encapsulator powder bed depth [0329] Dosing disc size [0330]
Tamping pin settings The encapsulator powder bed depth, dosing disc
size, and tamping pin settings are all controlling factors in
achieving target capsule weights and maintaining the consistency of
those weights throughout the encapsulation process. The
encapsulator powder bed depth is maintained at a uniform level
above the dosing disc. The dosing disc size is fixed by the dosing
disc thickness, which is 24 mm for the SAN-7F Capsules 20 mg
process. Tamping pin settings are adjusted to achieve the desired
target weight and maintain consistent weight uniformity.
Example 14B: Clinical Trial with SAN-7F 20 mg Capsule
Trial Objectives
Primary Objective
[0331] The primary objective was to test the hypothesis that SAN-7F
Capsules 20 mg (omeprazole 20 mg/dose) are pharmacokinetically
bioequivalent to Prilosec 20 mg with respect to area under the
curve (AUC).
Secondary Objectives:
[0332] The secondary objectives were:
[0333] 1. To assess whether SAN-7F Capsules 20 mg are
pharmacodynamically bioequivalent to Prilosec 20 mg with respect to
percent decrease from Baseline in integrated gastric acidity;
and
[0334] 2. To compare the pharmacokinetics of SAN-7F Capsules 20 mg
administered post-meal to the pharmacokinetics of SAN-7F Capsules
20 mg administered pre-meal.
Deign:
[0335] This was an open-label, randomized, 2-period crossover trial
to evaluate the pharmacokinetics, pharmacodynamics, and safety of 7
consecutive daily doses of SAN-7F. Capsules containing 20 mg
omeprazole were compared to 7 consecutive daily doses of Prilosec
20 mg in healthy subjects. A comparison of pharmacokinetic
parameters for SAN-7F administered before versus after a meal was
conducted.
[0336] Volunteers were screened within 21 days before baseline
measurements (gastric pH, vital signs). Gastric pH was recorded for
24 hours before the first dose of trial drug. In Period 1, subjects
received SAN-7F 20 mg or Prilosec 20 mg, as randomized, 1 hour
before breakfast for 7 consecutive days. A standardized high-fat
breakfast was given in the clinic 1 hour after dosing on Days 1 and
7, or 1 hour after water for baseline assessment. Standardized
lunch and dinner were also given 5 and 10 hours post-dose at
baseline and on Days 1 and 7 in the clinic. Blood samples for
determination of plasma omeprazole concentrations were collected
for 12 hours, and gastric pH was measured for 24 hours after the
doses on Days 1 and 7. Subjects who had received SAN-7F 20 mg
(omeprazole) in Period 1 were given an eighth dose (Day 8) 1 hour
after the start of the standardized high-fat breakfast. Blood
samples were collected for 12 hours after the eighth dose (see
Section 9.8 regarding the Dose 8 deviation). After a 10- to 14-day
washout period, subjects returned for Period 2 and received an
alternate treatment from that received in Period 1. Procedures in
Period 2 were identical to those in Period 1, except that there was
no eighth dose of SAN-7F 20 mg.
Number of Subjects (Planned and Analyzed)
[0337] Thirty-six subjects were dosed and 30 subjects complete 7
days of dosing in each period of the trial. Thirty subjects were
included in the pharmacokinetic analysis and 25 subjects were
included in the pharmacodynamic analysis for Doses 1 and 7. Because
of an error in post-meal administration of SAN-7F Capsules 20 mg on
Day 8 (Period 1), pharmacokinetic analyses for post-meal
administration of SAN-7F Capsules 20 mg were not completed.
Duration of Treatment
[0338] Including screening, subjects participated in this trial for
up to 40 days.
Design Rationale:
[0339] A 2-period crossover design is consistent with FDA guidance
for the assessment of comparative pharmacokinetics in healthy
volunteers.
Data from 24 subjects were expected to provide adequate power to
show bioequivalence between the 2 formulations evaluated in this
trial, based on the intersubject variability with regard to the
pharmacokinetics [AUC(0-inf)] and pharmacodynamics of omeprazole in
previous trials.
[0340] The 20-mg dose was studied in support of using a SAN-7F
Capsules 20 mg omeprazole dose for short-term treatment of active
duodenal ulcer, treatment of heartburn and other symptoms
associated with gastroesophageal reflux disease (GERD), short-term
treatment of erosive esophagitis, and maintenance of healing of
erosive esophagitis.
[0341] The primary analysis focused on Day 7 of dosing, since the
pharmacokinetics of omeprazole are known to change with repeated
dosing and the pharmacodynamic effects are maximal by the seventh
day of consecutive daily dosing (steady state).
[0342] The time of drug administration (after an overnight fast and
1 hour prior to a meal) meets the regulatory guidance for
bioequivalence (fasting) and anticipates actual use.
[0343] In Period 1 at steady state (Day 8), the pharmacokinetics of
SAN-7F Capsules 20 mg given post-meal were compared to those of
SAN-7F 20 mg given pre-meal (Day 7). This comparison was conducted
to evaluate the effect of food on the bioavailability of SAN-7F
Capsules 20 mg. This portion of the protocol was not conducted
correctly during this period.
Treatments Administered:
[0344] The treatments administered to subjects in this trial are
listed in the table below.
TABLE-US-00088 TABLE 14 B Treatment Description Treatment Treatment
Description SAN-7F SAN-7F Capsules (omeprazole immediate- release
capsules) 20 mg administered orally with 120 mL water each morning
after an overnight fast, 1 hour before starting a standardized high
fat breakfast. Prilosec Prilosec Capsules (omeprazole
delayed-release capsules) 20 mg administered orally with 120 mL
water each morning after an overnight fast, 1 hour before starting
a standardized high-fat breakfast. SAN-7F Dose 8 SAN-7F Capsules
(omeprazole immediate- release capsules) 20 mg, administered orally
with 120 mL water on Day 8 in Period 1, 1 hour after starting a
standardized high-fat breakfast.
The description below represents the schedule of events:
Events:
[0345] 1. Period 1--SAN-7F Capsules 20 mg or Prilosec 20 mg (by
randomization).
[0346] Location of the lower esophageal sphincter (LES) on the day
the subject checked into the clinic (Day minus 2).
[0347] Seven consecutive single daily AM doses pre-meal (plus Dose
8 on Day 8 post-meal only for subjects receiving SAN-7F Capsules 20
mg). Twelve-hour PK sampling after Doses 1, 7, and 8 (SAN-7F
Capsules 20 mg only). Twenty-four-hour gastric pH monitoring during
Baseline starting on Day minus 1, and during treatment starting on
Day 1 (Dose 1) and Day 7 (Dose 7).
2. 10-14 Day Washout
[0348] 3. Period 2--SAN-7F Capsules 20 mg or Prilosec 20
mg--Alternative formulation to that in Period 1. Seven consecutive
single daily AM doses pre-meal. Twelve-hour PK sampling after Doses
1 and 7. Twenty-four-hour gastric pH monitoring during Baseline
starting on Day minus 1, and during treatment starting on Day 1
(Dose 1) and Day 7 (Dose 7). Pharmacokinetic Sampling. Analytical
Methods, and Parameters
[0349] Blood samples (3 mL) were obtained by venipuncture within 30
minutes before each dose and at 5, 10, 15, 20, 30, 45, 60, 90, 120,
150, 180, 210, 240, 300, 360, 420, 480, 540, 600, 660, and 720
minutes (12 hours) after each dose on Days 1 and 7 of both periods
and Day 8 of Period 1 (for SAN-7F Capsules 20 mg). Zero time was
the time that the subject swallowed a capsule of trial drug.
[0350] Plasma omeprazole concentrations were measured using a
validated liquid chromatography mass spectrometry (LC-MSIMS) assay
(MDS Pharma Services, Lincoln, Nebr.). The linear assay range was
5.0 to 750 ng/mL.
[0351] The following pharmacokinetic parameters were measured for
each subject: [0352] Plasma omeprazole concentration at each
sampling time [0353] Peak omeprazole plasma concentration (Cmax)
and the time at which Cmax is observed (Tmax) obtained directly
from the data without interpolation [0354] Terminal elimination
rate constant (Kel) determined from a log-linear regression
analysis of the terminal plasma omeprazole concentrations [0355]
Half-life of drug elimination (Tl) calculated as 0.693/Kel [0356]
Area under the plasma drug time-concentration curve calculated from
0 time to last time point evaluated [AUC(0-t)] calculated using the
trapezoidal rule with the plasma concentration at time t being the
last measurable concentration [0357] Area under the plasma drug
time-concentration curve calculated from 0 time and extrapolated to
infinity [AUC(0-inf)] calculated as AUC(0-t)+Ct/Kel, where Ct is
the last measurable plasma concentration and Kel is the terminal
elimination rate constant defined above
Measurement of Gastric pH
[0358] Subjects remained propped up in bed (about 45 degrees) from
the time of initial gastric pH recording, through 5 hours post
dose. Subjects were then allowed restricted physical activity until
bedtime, at which time they were again propped up in bed
(approximately 45 degrees) and remained in this position for the
remainder of the pH monitoring period. Gastric pH data were
collected every 4 seconds (this measured value was then imputed for
each of the following 3 seconds by the software) using an
ambulatory pH recording system (Digitrapper@ 400, Medtronic
Functional Diagnostics, Inc, Shoreview, Minn. USA) with a
disposable antimony electrode and an internal standard (Medtronic
Zinetics 24@Single-Use pH Catheter with or without the lower
esophageal [LES] locator). At the Period 1 check-in (Day minus 2),
the LES was located manometrically (Medtronic Polygram '98 for
Windows v. 2.20) and the distance from the upper border of the LES
to the nares was recorded on the CRF.
[0359] For all measurements of gastric pH, the electrode was placed
in the stomach 10 cm below the upper border of the LES using
measurements determined at Day minus 2 of Period 1. The probe was
inserted approximately 1 hour prior to dosing and the proximal end
was taped to the side of the face to prevent shifting of the probe.
Prior to insertion, the electrode was calibrated at room
temperature to pH 1 and 7 using standard commercial polyelectrolyte
solutions (Medtronic, Toronto). The software used to process the pH
data corrected for the difference between electrode calibration
temperature (approximately 25.degree. C.) and recording temperature
(37.degree. C.). Recordings continued from approximately 1 minute
before until 24 hours after dosing (trial drug or water during
Baseline). Times for the following events were indicated
electronically on the pH record using the following event markers:
beginning of pH recording, dosing of trial drugs, initiation of
each meal, and the end of the pH recording.
[0360] Readjustment of the gastric pH probe for any potential
migration of the pH probe out of the stomach during evening hours
was achieved using the following procedures: During baseline
periods before dosing, the Digitrappers were checked every hour
from 16 hours to 24 hours after administering 120 mL water. If a pH
value was >2.5 (1-minute observation), the subject was
repositioned and asked to take 1 or more sips of water (.ltoreq.60
mL total). If the pH did not decrease to .ltoreq.2.5 within 5
minutes, the probe was partially withdrawn and then advanced to 10
cm below the upper border of the LES (the administration of
.ltoreq.60 mL water per hour was permitted to facilitate this
procedure). If after repositioning the probe, the pH was not
.ltoreq.2.5, no further adjustments were made during that hour.
These procedures were repeated as necessary during the subsequent
hours to ensure that the probe was properly placed. The number of
times that the probe was adjusted (water administered or probe
repositioned) was recorded on the CRF.
[0361] For all dosing periods, the Digitrappers were checked every
hour from 16 hours to 24 hours after administering the dose. If the
pH was >5 (1-minute observation), the subject was repositioned.
If the pH did not decrease to .ltoreq.5 within the next 5 minutes,
the subject was administered .ltoreq.60 ml of water. If the pH did
not decrease to .ltoreq.5 within the next 1 minute, the probe was
partially withdrawn and then advanced to 10 cm below the upper
border of the LES (5 60 mL of water may have been administered to
facilitate this procedure). If after repositioning the probe, the
pH was still >5, no further adjustments were made during that
hour. These procedures were repeated, as needed, during the
subsequent hour(s) to assure that the probe was properly placed.
The hourly assessments and actions taken were recorded on the
CRF.
Pharmacodynamic Parameters and Methodology
[0362] The following pharmacodynamic parameters were measured for
each 24-hour period in 15-minute intervals: [0363] Integrated
gastric acidity (mmol*hr/L), calculated for each 15-minute interval
during the 24-hour recording period, as follows: [0364] Acid
concentration (mmol/L)=1000.times.10.sup.-pH [0365] Acidity
(mmol*hr/L)=(acid concentration at time "t"+acid concentration at
time "t.sub.1")/2 .times.(t-t.sub.1), where t and t.sub.1 are the
times of 2 consecutive pH measurements [0366] Integrated gastric
acidity (mmol*hr/L) calculated as the sum of acidity over each
15-minute interval [0367] Mean gastric acid concentration (mmol/t),
calculated as integrated gastric acidity for each 15-minute
interval/0.25 hour [0368] Median gastric pH, calculated for each
15-minute interval [0369] Percent time gastric pH was .ltoreq.4,
calculated for each 15-minute interval
[0370] Values for gastric pH were recorded once every 4 seconds.
The software used to process the record filled in the same value
for the following 3 seconds. Each record was divided into 15-minute
intervals beginning with zero time as the recording interval prior
to dosing. All pH values outside the acceptable range of 0.5 to
7.5, inclusive, were excluded prior to analysis.
[0371] Missing (or excluded) values for gastric pH were handled as
follows:
[0372] If pH values were missing in a 15-minute interval,
integrated gastric acidity and mean gastric acid concentration were
calculated by integrating across the missing data; however, only
the available values were used to calculate the percentage of time
gastric pH was .ltoreq.4 and the median gastric pH.
[0373] If all of the pH values were missing in an entire 15 minute
interval, integrated gastric acidity, mean gastric acid
concentration, and percentage of time gastric pH was 54 were
calculated as the mean of the values from the interval immediately
preceding and immediately following the interval for which all pH
values were missing. For an interval with all missing pH values,
the median of all values from the interval immediately preceding
and immediately following were assigned to the interval with all
missing values.
Primary Endpoint
[0374] The primary pharmacokinetic endpoint was the bioavailability
of omeprazole [AUC(0-inf)] after the seventh dose of each
omeprazole formulation.
Secondary Endpoints
[0375] The secondary endpoints were: [0376] Peak plasma
concentration (Cmax) after the seventh dose of each omeprazole
formulation. [0377] AUC(0-inf) and Cmax after the first dose of
each omeprazole formulation. [0378] All other pharmacokinetic
parameters after the first and seventh doses of each omeprazole
formulation: Tmax, Kel, Ti, AUC(0-t). [0379] All pharmacokinetic
parameters obtained with SAN-7F Capsules 20 mg administered
post-meal.
Pharmacokinetic Analysis
[0380] For the analysis of data collected on Days 1 and 7 of each
period (pre-meal dosing), an analysis of variance (ANOVA) model was
used to test the bioequivalence of SAN-7F Capsules 20 mg and
Prilosec, using the natural logarithmic transformation of
AUC(0-inf) and Cmax. The model included the following factors:
treatment, period, sequence, and subject nested within sequence.
Ninety percent confidence intervals (CIs) for treatment differences
were calculated; the endpoints of these CIs were then reverse
transformed to represent CIs about the percent mean ratios on the
original scale. With respect to AUC(0-inf) and Cmax, equivalence
was declared for each parameter, if the bounds of the 90% CIs for
the percent mean ratio, SAN-7F to Prilosec, were between 80% and
125%.
Pharmacodynamic Statistical and Analytical Plan
Pharmacodynamic Endpoints
Primary Endpoint
[0381] The primary pharmacodynamic endpoint was the percent
decrease from Baseline in integrated gastric acidity for the
24-hour interval after the seventh dose of each omeprazole
formulation.
Secondary Endpoint
[0382] The secondary pharmacodynamic endpoint was the percent
decrease from Baseline in integrated gastric acidity for the
24-hour interval after the first dose of each omeprazole
formulation.
Other Pharmacodynamic Parameters (24-Hour Pst-Dose Intervals)
[0383] Mean gastric acid concentration (mM) [0384] Median gastric
pH [0385] Percent time gastric pH .ltoreq.4
Pharmacodynamic Analysis
[0386] The pharmacodynamic effects of SAN-7F Capsules 20 mg and
Prilosec 20 mg during the 24-hour post-dose recording period were
assessed after the first and seventh doses by evaluating the
following parameters: integrated gastric acidity, mean gastric acid
concentration, median gastric pH, and the percentage of time
gastric pH was .ltoreq.4 for the 24-hour period.
Evaluation of Period Effect
[0387] Prior to evaluating the pharmacodynamic effects of SAN-7F
Capsules and Prilosec with respect to integrated gastric acidity,
the possibility of a period effect was assessed using an ANOVA
model that included factors for period and subject, fit to the
24-hour baseline values for integrated gastric acidity for each of
the 2 periods. If no statistically significant difference was found
between the 2 baseline values, it was concluded that there was no
period effect. In this case, the mean of the 2 baseline values was
used as the baseline value for each subject. If a statistically
significant difference was found between the baseline values, it
would be concluded that there was a period effect. In this case,
integrated gastric acidity was adjusted for the period effect in
the statistical analysis by analyzing the percent decrease from the
corresponding baseline value for each subject.
Analysis of Pharmacodynamic Endpoints
[0388] The analysis of integrated gastric acidity for the 24-hour
period following dosing was conducted on the percent decrease from
Baseline on Days 1 and 7 calculated for each subject as
100.times.[Baseline-Day 1 (or Day 7)]/Baseline.
[0389] An ANOVA model was used to test the pharmacodynamic
equivalence of SAN-7F. Capsules and Prilosec, using the natural
logarithmic transformation of percent decrease from Baseline in
integrated gastric acidity. The model included the following
factors: treatment, period, sequence, and subject nested within
sequence. Ninety percent confidence intervals (CIs) for treatment
differences were calculated; the endpoints of these CIs were then
reverse transformed to represent CIs about the percent mean ratios
on the original scale. Pharmacodynamic equivalence was declared if
the bounds of the 90% CIs for the percent mean ratio of percent
decrease from Baseline in integrated gastric acidity, SAN-7F to
Prilosec, were between 80% and 125%.
Descriptive Analyses
[0390] The ratio of the percent decrease from Baseline for
integrated gastric acidity for the 24-hour period following the
first and seventh doses with SAN-7F Capsules and Prilosec was
calculated for each subject as: percent decrease from Baseline for
SAN-7F/percent decrease from Baseline for Prilosec using the
appropriate baseline value. The medians and boundaries of the
inter-quartile range (25th and 75th percentiles) of the ratios for
all subjects were tabulated.
Analyses of Other Pharmacodynamic Parameters
[0391] The ratio of the percent decrease from Baseline for mean
gastric acid concentration and for the percentage of time gastric
pH was .ltoreq.4 for the 24 hour period following dosing with
SAN-7F Capsules and Prilosec was calculated for each subject as:
percent decrease from Baseline for SAN-7F/percent decrease from
Baseline for Prilosec (using the appropriate baseline value). For
median gastric pH, the ratio of the increase from Baseline for
SAN-7F and Prilosec was calculated for each subject (using the
appropriate baseline value) as: increase from Baseline for
SAN-7F/increase from Baseline for Prilosec. The medians and
boundaries of the inter-quartile range (25th and 75th percentiles)
of the ratios for all subjects were tabulated.
Disposition of Subjects
[0392] Thirty-six subjects entered the trial and received at least
one dose of trial drug; 30 subjects completed the trial.
TABLE-US-00089 TABLE 14. C Summary of Subject Disposition n %
Subjects who received at least one dose of 36 100.0 either trial
drug Subjects who completed both 7-day treatment 30 83.3 periods
Subjects who received 8 doses of SAN-7F 20 mg* 22 61.1 Subjects who
withdrew 6 16.7 *Includes 15 subjects who received an eighth dose
of SAN-7F 20 mg on Day 9 but no dose on Day 8 in Period 1 and 7
other subjects who received 8 consecutive daily dose of SAN-7F 20
mg in Period 2.
Pharmacokinetic Results
[0393] Pharmacokinetic results are presented the in Table 14.D. and
FIGS. 16, 17, 19, 20, 22 and 23.
[0394] After one dose, SAN-7F Capsules 20 mg and Prilosec 20 mg
were bioequivalent with respect to AUC. The percent mean ratio of
SAN-7F 20 mg to Prilosec 20 mg was 105.31% for AUC(0-inf) with the
bounds of the 90% CI between 80% and 125% (98.94% and 112.09%). As
expected for the immediate-release product, the Cmax for SAN-7F 20
mg was higher than for Prilosec 20 mg (percent mean ratio of
148.49%, 90 CI of 129.16% to 170.72%). The Tmax for SAN-7F was
shorter than the Tmax for Prilosec (p<0.001; ANOVA).
Pharmacokinetic Conclusions
[0395] After the first dose and at steady state (Day 7), SAN-7F
Capsules 20 mg were equivalent to Prilosec 20 mg with respect to
[AUC(0-inf)] (the primary pharmacokinetic endpoint). The 2
treatments were not equivalent with respect to Cmax on Days 1 and 7
with the percent mean ratio of 148% on Day 1 and 145% on Day 7. The
Tmax was shorter for the immediate-release product on Days 1 and 7
(p<0.001).
Pharmacodynamic Conclusions
[0396] On Day 7 of dosing, SAN-7F Capsules 20 mg were found
equivalent to Prilosec 20 mg with regard to the primary
pharmacodynamic endpoint, percent decrease from Baseline in
integrated gastric acidity over 24 hours. SAN-7F 20 mg and Prilosec
20 mg both decreased integrated gastric acidity by approximately
70% from Baseline at Day 7.
Trial Conclusion
[0397] Since comparisons in this trial involved a delayed-release
formulation (Prilosec 20 mg) and an immediate-release formulation
(SAN-7F Capsules 20 mg), it was anticipated that the Tmax would
occur earlier and the Cmax would be higher for SAN-7F 20 mg than
for Prilosec 20 mg. It was also expected that the 2 products would
be equivalent with regard to AUC and, therefore, also with regard
to their pharmacodynamic effects.
[0398] As anticipated, SAN-7F 20 mg was found equivalent to
Prilosec 20 mg on Day 7 (and Day 1) of dosing with regard to AUC
(0-inf) and equivalent at Day 7 with regard to percent decrease
from Baseline in integrated gastric acidity over 24 hours. For
Cmax, the upper bound of the 90% confidence interval for the
percent mean ratio exceeded 125% on Days 1 and 7. The
pharmacodynamic data show that SAN-7F 20 mg and Prilosec 20 mg were
equally effective in decreasing integrated gastric acidity at
steady state (Day 7).
[0399] Both SAN-7F Capsules 20 mg and Prilosec 20 mg were well
tolerated during the 7-day to 9-day dosing periods in this trial.
No meaningful differences between the treatments were observed with
respect to safety.
TABLE-US-00090 TABLE 14 20 mg PK Summary for Day 1 and 7 (S7F =
SAN-7F; Pr = Prilosec .RTM.) Interval (minutes) Drug ng/mL Day 0 5
10 15 20 30 45 60 90 120 150 180 210 S7F Mean 1 0 0 11 111 202 388
320 274 177 83 55 35 22 S7F Min 1 0 0 0 0 0 0 0 94 36 0 9 0 0 S7F
Max 1 0 0 110 1090 927 1090 958 775 466 246 181 120 76 S7F Mean 7 0
4 23 125 231 418 417 384 391 245 169 123 90 S7F Min 7 0 0 0 0 0 0 0
7 22 53 28 15 10 S7F Max 7 0 120 257 721 1130 1530 1240 1080 1270
735 576 473 362 Pr Mean 1 0 0 0 0 1 17 87 171 309 160 96 68 44 Pr
Min 1 0 0 0 0 0 0 0 0 81 50 23 13 8 Pr Max 1 0 0 0 0 27 205 319 441
794 622 394 301 163 Pr Mean 7 0 0 0 1 8 76 222 292 380 277 194 145
104 Pr Min 7 0 0 0 0 0 0 0 0 0 62 43 25 14 Pr Max 7 12 8 8 12 88
333 994 988 1220 775 560 420 308 Interval (minutes) Cmax Tmax Drug
ng/mL Day 240 300 360 420 480 540 600 660 720 N (ng/mL) (hr) S7F
Mean 1 14 6 3 1 0 0 0 0 0 30 498 0.61 S7F Min 1 0 0 0 0 0 0 0 0 0
30 140 0.25 S7F Max 1 46 23 18 10 14 0 5 7 6 30 1090 1.50 S7F Mean
7 65 38 22 13 7 4 3 1 1 30 680 0.82 S7F Min 7 6 0 0 0 0 0 0 0 0 30
228 0.25 S7F Max 7 297 196 143 91 61 42 28 18 13 30 1530 1.50 Pr
Mean 1 28 12 6 3 1 0 0 0 0 30 328 1.41 Pr Min 1 0 0 0 0 0 0 0 0 0
30 101 0.75 Pr Max 1 105 51 25 13 8 0 0 6 5 30 794 3.00 Pr Mean 7
86 47 26 15 8 5 3 1 1 30 487 1.30 Pr Min 7 0 0 0 0 0 0 0 0 0 30 170
0.50 Pr Max 7 456 167 122 73 65 39 25 18 11 30 1220 2.50
Example 15A: Formulation of SAN-7E (40 mg Omeprazole Capsules)
[0400] A 1300 kg lot of 40 mg omeprazole capsules was manufactured
under ceGMP conditions. The formulation is set forth in Table 15A,
below:
TABLE-US-00091 TABLE 15A % Amount Required for Ingredient Weight
mg/Capsule 1300 kg Batch (kg) Omeprazole, USP 3.5% 40.8 45.7 kg
mg/cap Sodium Bicarbonate, USP 93.2 1100 1232 #2 Croscarmellose
Sodium, NF 1.5 30 33.6 Magnesium Stearate, NF 0.8 10 11.2 Totals
100 1160.4 1300
[0401] The following ingredients were added to a tote (tote #1) in
the following order. Sodium bicarbonate (about 25% of total),
omeprazole USP, sodium bicarbonate (about 25% of total). The
contents of tote #1 were then charged into a 60 ft.sup.3 V-blender
through a Comil.RTM. powder mill equipped with a 16 mesh equivalent
screen, operating the powder screen at a speed setting of high (800
rpm). The contents were mixed for 5 minutes at 8 rpm. About 25% of
the total amount of sodium bicarbonate was then charged into a tote
(tote #2). Then the contents of the V-blender were charged into
tote #2. The contents of tote #2 were then passed through a
Comil.RTM. powder mill equipped with a 16 mesh equivalent screen at
a speed setting of high (800 rpm).
[0402] Next, croscarmellose sodium and the remaining amount of
sodium bicarbonate were charged into tote #1. The contents of tote
#1 were then passed through a Comil.RTM. powder mill equipped with
a 16 mesh equivalent screen at a speed setting of high (800 rpm)
and charged into the V-blender. The mixture was then blended for 15
minutes a 8 rpm. Then magnesium stearate was screened through a #30
mesh hand screen and charged into the V-blender. The resulting
mixture was then blended for 3 minutes at 8 rpm. The contents of
the V-blender were then discharged into labeled containers lined
with inner clear polyethylene bag overwrapped with an outer black
polyethylene bag. The resulting mixture was encapsulated on a
H&K 1200.RTM. dosing disc/tamping pin-type encapsulator using
hard gelatin capsules size #00.
Example 15B: Clinical Trial
[0403] A clinical trial was conducted in order to compare the
pharmacokinetic profile of a 40 mg omeprazole capsule according to
the present invention with Prilosec.RTM. 40 mg delayed release
capsules. SAN-7E 40 mg capsules according to the invention were
formulated as in Example 7B, above. The results of these clinical
trials are discussed below and are depicted graphically in FIGS.
16, 18, 19, 21, 22 and 23.
[0404] Trial objectives, design, pharmacokinetic and
pharmacodynamic endpoints, design rationale, treatments
administered, schedule of events, pharmacokinetic sampling,
analytical methods and parameters, measurement of gastric pH,
pharmacodynamic parameters and methodology, pharmacokinetic
statistical and analytical plan are the same as in Example 14 above
with the exception of use with SAN-7E Capsules 40 mg and Prilosec
40 mg instead of 20 mg of each drug. The capsules are prepared by
blending the PPI and homogeneously blending with other components
shown in Table 15A.
Number of Subjects (Planned and Analyzed):
[0405] Thirty-six subjects were dosed and 30 subjects complete 7
days of dosing in each period of the trial. Thirty-five subjects
were included in the pharmacokinetic analysis and 34 subjects were
included in the pharmacodynamic analysis for Doses 1 and 7.
Eighteen subjects were included in the post-meal (Day 8) versus
pre-meal (Day 7) analysis.
Duration of Treatment:
[0406] Including screening, subjects participated in this trial for
up to 41 days.
Pharmacokinetic Results
[0407] Pharmacokinetic results are presented in the Table 15.B. and
FIGS. 16, 19, 1921, 22 and 23.
Phiarnacokinetic Conclusions
[0408] After the first dose and at steady state (Day 7), SAN-7E
Capsules 40 mg were equivalent to Prilosec 40 mg with respect to
[AUC(0-inf)] (the primary pharmacokinetic endpoint). The 2
treatments were not equivalent with respect to Cmax on Days 1 and 7
with the percent mean ratio of 149% hon Day 1 and 117% on Day 7.
The Tmax was shorter for the immediate-release producton Days and 7
(p<0.001).
Pharmacodynamic Conclusions
[0409] On Day 7 of dosing, SAN-7E Capsules 40 mg were found
equivalent to Prilosec 40 mg with regard to the primary
pharmacodynamic endpoint, percent decrease from baseline in
integrated gastric acidity over 24 hours. SAN-7E 40 mg and Prilosec
40 mg both decreased integrated gastric acidity by 74% and 80%,
respectively, from Baseline at Day 7.
TABLE-US-00092 TABLE 15.A SAN-7E Capsules Composition, 40 mg
Omeprazole Quantity Ingredient (40 mg) Omeprazole 40.8 mg* Sodium
Bicarbonate 1100 mg CROSCARMELLOSE SODIUM 30 mg Magnesium Stearate
10 mg Gelatin Capsule 1 shell Total Weight/Unit 1180 mg *Includes a
2% omeprazole overage in the blend manufacture that assures label
claim amount of omeprazole in the final product.
TABLE-US-00093 TABLE 15.B 40 mg PK Summary or Day 1 and 7. (Drug:
S7E = SAN-7E; Pr = Prilosec .RTM. 40 mg.) Interval (minutes) Drug
ng/mL Day 0 5 10 15 20 30 45 60 90 120 150 180 S7E Mean 1 0 0 46
237 535 842 840 709 545 338 248 193 S7E Min 1 0 0 0 0 0 24 116 127
0 19 14 7 S7E Max 1 0 12 703 1730 2310 2420 2420 2120 2000 1570
1450 1210 S7E Mean 7 3 3 63 202 398 949 1115 1104 1083 747 585 463
S7E Min 7 0 0 0 0 0 13 32 37 262 0 74 42 S7E Max 7 96 82 1900 3420
2960 3020 2420 2380 2350 1980 1850 1620 Pr Mean 1 0 0 0 0 3 71 195
408 793 546 369 259 Pr Min 1 0 0 0 0 0 0 0 0 111 59 23 10 Pr Max 1
0 0 0 0 58 1800 1140 1580 2650 2100 1650 1350 Pr Mean 7 1 1 1 2 20
171 456 639 1217 969 725 606 Pr Min 7 0 0 0 0 0 0 0 0 12 119 116 67
Pr Max 7 16 14 14 19 392 1420 2110 2230 2950 2370 1770 1620
Interval (minutes) Cmax Tmax Drug ng/mL Day 210 240 300 360 420 480
540 600 660 720 N (ng/mL) (hr) S7E Mean 1 152 125 86 60 41 30 22 16
12 9 35 1154 0.56 S7E Min 1 5 0 0 0 0 0 0 0 0 0 35 255 0.25 S7E Max
1 1140 1080 871 707 520 457 362 294 230 186 35 2420 1.50 S7E Mean 7
393 323 249 183 131 94 74 53 37 28 35 1526 0.97 S7E Min 7 27 14 0 0
0 0 0 0 0 0 35 437 0.25 S7E Max 7 1570 1570 1350 1190 1060 736 636
572 418 386 35 3420 3.50 Pr Mean 1 208 164 114 77 45 38 27 20 17 12
35 888 1.51 Pr Min 1 0 6 0 0 0 0 0 0 0 0 35 119 0.50 Pr Max 1 1250
1140 919 592 295 422 310 270 217 174 35 2650 2.50 Pr Mean 7 466 397
264 188 131 95 65 46 34 22 35 1344 1.51 Pr Min 7 30 20 7 0 0 00 0 0
0 0 35 234 0.50 Pr Max 7 1420 1260 1000 801 549 435 310 240 199 133
35 2950 2.50
The number of patients who completed the post-meal portion of the
study was 18. The following table summarizes the pharmacokinetic
parameters for the pre- and post-meal dosing of 40 mg omeprazole
immediate release capsules.
TABLE-US-00094 TABLE 15.C Summary of Post-meal (Day 8) and Pre-meal
(Day 7) Plasma Omeprazole Pharmacokinetic Parameters for Immediate
Release Capsules (SAN-7E) Plasma Omeprazole SAN-7E SAN-7E
(Post-meal) (Pre-meal) Parameter n Mean S.D. n Mean S.D. Cmax
(ng/mL) 18 1026 645.6 18 1646 771.4 Tmax (hr) 18 1.74 1.27 18 0.93
0.74 AUC (0-t)(ng*hr/mL) 18 3221 2349 18 3976 2592 AUC
(0-inf)(ng*hr/mL) 18 3221 2488 18 4071 2721 T1/2 (hr) 18 1.38 0.66
18 1.38 0.66 kel (1/hr) 18 0.61 0.26 18 0.61 0.27 In (Cmax) 18 630
0.79 18 7.28 0.54 In[AUC(0-t)] 18 7.76 0.90 18 8.01 0.84
IN[AUC(0-inf)] 18 7.78 0.91 18 8.03 0.85
Example 16: Powder for Suspension
[0410] Following procedures similar to those set forth in Examples
14 and 15, above, 20 and 40 mg omeprazole immediate release powders
for suspension were prepared and tested in subjects. The powder
compositions tested are set forth in the following tables 16A and
16B.
TABLE-US-00095 TABLE 16A Omeprazole Powder for Suspension 20 mg per
dose Omeprazole Immediate Release Powder Ingredient 20 mg per dose
Omeprazole, Micronized USP 0.021 Sodium Bicarbonate 1.680 Xanthan
Gum 0.039 Sucrose 2.000 Xylitol 2.000 Crystalline Sucralose 0.080
Peppermint Flavor, Mane F94249 0.011 Peach flavor #57.695/AP 05.51
0.030 Totals 5.861
TABLE-US-00096 TABLE 16B Omeprazole Powder for Suspension 40 mg per
dose Omeprazole Immediate Release Powder Ingredient 40 mg per dose
Omeprazole, Micronized USP 0.042 Sodium Bicarbonate 1.680 Xanthan
Gum 0.039 Sucrose 2.000 Xylitol 2.000 Crystalline Sucralose 0.080
Peppermint Flavor, Mane F94249 0.011 Peach flavor #57.695/AP 05.51
0.030 Totals 5.882
[0411] The results of these clinical trials are set forth in FIGS.
16-23.
[0412] 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.
* * * * *