U.S. patent application number 13/551310 was filed with the patent office on 2012-11-15 for composition comprising a combination of omeprazole and lansoprazole, and a buffering agent, and methods of using same.
This patent application is currently assigned to THE CURATORS OF THE UNIVERSITY OF MISSOURI. Invention is credited to Jeffrey O. Phillips.
Application Number | 20120289550 13/551310 |
Document ID | / |
Family ID | 40985901 |
Filed Date | 2012-11-15 |
United States Patent
Application |
20120289550 |
Kind Code |
A1 |
Phillips; Jeffrey O. |
November 15, 2012 |
COMPOSITION COMPRISING A COMBINATION OF OMEPRAZOLE AND
LANSOPRAZOLE, AND A BUFFERING AGENT, AND METHODS OF USING SAME
Abstract
The present disclosure relates to pharmaceutical compositions
comprising omeprazole, lansoprazole and sodium bicarbonate. Methods
of using such compositions are also provided
Inventors: |
Phillips; Jeffrey O.;
(Ashland, MO) |
Assignee: |
THE CURATORS OF THE UNIVERSITY OF
MISSOURI
Columbia
MO
|
Family ID: |
40985901 |
Appl. No.: |
13/551310 |
Filed: |
July 17, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12389243 |
Feb 19, 2009 |
8247440 |
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13551310 |
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61030045 |
Feb 20, 2008 |
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Current U.S.
Class: |
514/338 |
Current CPC
Class: |
A61K 9/2009 20130101;
A61K 31/415 20130101; A61P 11/06 20180101; A61P 11/14 20180101;
A61P 29/00 20180101; A61P 1/00 20180101; A61K 31/4439 20130101;
A61P 11/00 20180101; A61P 1/04 20180101; A61K 9/2054 20130101; A61K
31/44 20130101; A61K 9/2059 20130101; A61P 3/04 20180101; A61P
43/00 20180101; A61K 31/415 20130101; A61K 2300/00 20130101; A61K
31/4439 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/338 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; A61P 11/14 20060101 A61P011/14; A61P 11/06 20060101
A61P011/06; A61P 1/00 20060101 A61P001/00; A61P 1/04 20060101
A61P001/04 |
Claims
1. A method of treating a gastric acid-related disease or disorder
comprising administering to a subject in need thereof a
pharmaceutical composition comprising omeprazole in an amount of
about 60 mg to about 140 mg, lansoprazole in an amount of amount of
about 60 mg to about 140 mg, and at least one buffering agent in an
amount of about 100 mg to about 4000 mg.
2. The method of claim 1, wherein the at least one buffering agent
is selected from the group consisting of: sodium bicarbonate,
calcium carbonate, calcium formate, magnesium hydroxide, aluminum,
aluminum hydroxide/magnesium hydroxide co-precipitate, aluminum
hydroxide/sodium bicarbonate co-precipitate, calcium acetate,
calcium bicarbonate, calcium borate, calcium bicarbonate, calcium
citrate, calcium gluconate, calcium glycerophosphate, calcium
hydroxide, calcium lactate, calcium phthalate, calcium phosphates,
calcium succinate, calcium tartrate, calcium propionate, 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
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 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, and
mixtures of the foregoing.
3. The method of claim 1, wherein the at least one buffering agent
comprises calcium carbonate and is present in an amount of about
400 mg to about 2500 mg.
4. The method of claim 1, wherein the at least one buffering agent
comprises calcium formate and is present in an amount of about 400
mg to about 2500 mg.
5. The method of claim 1, wherein the at least one buffering agent
comprises calcium carbonate and calcium foimate.
6. The method of claim 5, wherein the calcium carbonate is present
in an amount of about 300 mg to about 3000 mg and the calcium
formate is present in an amount of about 100 mg to about 4000
mg.
7. The method of claim 1, further comprising one or more
pharmaceutically acceptable excipients.
8. The method of claim 7, wherein the one or more pharmaceutically
acceptable excipient is selected from the group consisting of:
diluents, disintegrants, binding agents, adhesives, wetting agents,
lubricants, glidants, surface modifying agents, substances added to
mask or counteract a disagreeable taste or odor, flavors, dyes,
fragrances, and substances added to improve appearance of the
composition.
9. The method of claim 8, wherein the disintegrant is selected from
the group consisting of: croscarmellose sodium and sodium
carboxymethylcellulose.
10. The method of claim 8, wherein the lubricant is magnesium
stearate.
11. The method of claim 1 wherein the composition is present in one
or more discrete dosage units.
12. The method of claim 11, wherein the one or more discrete dosage
units are selected from tablets, caplets, capsules, powder,
lozenges, sachets, cachets, troches, pellets, granules and mixtures
thereof
12. The method of claim 1 wherein the lansoprazole is present in an
amount of about 50 mg to about 150 mg.
13. The method of claim 1 wherein the omeprazole is present in an
amount of about 70 mg to about 100 mg and the lansoprazole is
present in an amount of about 70 mg to about 100 mg.
14. The method of claim 1 wherein the buffering agent comprises
sodium bicarbonate.
15. The method of claim 1 wherein the buffering agent comprises
sodium bicarbonate, calcium carbonate and/or calcium formate.
16. The method of claim 11 wherein the composition is administered
to the subject daily for a period effective to treat said disease
or disorder.
17. The method of claim 1, wherein the gastric acid-related disease
or disorder is selected from the group consisting of severe erosive
esophagitis (Los Angeles classification grade C & D), Barrett's
esophagus, reflux-related esophageal metaplasia with low or high
grade dysplasia, reflux-related adenocarcinoma of the esophagus,
acid-related adenocarcinoma of the stomach, duodenal ulcer, gastric
ulcer, gastric and duodenal erosions and ulcerations, acid
dyspepsia, gastroesophageal reflux disease (GERD), poorly
responsive symptomatic GERD, acid reflux, esophageal ulcers and
erosions, precancerous and canercous lesions of the esophagus
induced by acid exposure, radiation- or chemotherapy-induced
esophagitis, acid hypersecretory conditions, gastrointestinal
pathological hypersecretory conditions, Zollinger Ellison Syndrome,
non-ulcer dyspepsia, short-term eradication of Helicobacter pylori
(H. pylori), extraesophageal or atypical manifestations of
gastroesophageal reflux disease, nocturnal acid breakthrough (NAB),
sleep apnea, sleep disturbance, gastrointestinal bleeding,
rebleeding after gastrointestinal bleeding, stress ulcer
prevention, stress-related bleeding, seizure or apparent seizure
activity, Sandifer's syndrome, failure to thrive, anorexia,
anorexia nervosa, weight loss, apnea, and bradycardia.
18. The method of claim 1, wherein the subject has
gastroparesis.
19. The method of claim 1, wherein the subject does not have
gastropareises.
20. The method of claim 17, wherein the extraesophageal or atypical
manifestations of gastroesophageal reflux disease are selected from
the group consisting of eye pain, asthma, bronchitis, pneumonia,
chest pain, cough, recurrent laryngitis, globus pharyngeus,
sinusitis, otalgia, otitis media, eustachian tube dysfunction,
voice change, globus sensation, throat clearing, halitosis, sore
throat, and aphthous ulcers.
21. The method of claim 1, wherein the pharmaceutical composition
is administered prior to endoscopic evaluation of upper GI
bleeding.
Description
FIELD OF THE INVENTION
[0001] This application claims priority to U.S. Provisional
Application Ser. No 61/030,045, filed on Feb. 20, 2008, which is
hereby incorporated herein by reference
[0002] Described herein are pharmaceutical compositions comprising
omeprazole, lansoprazole and buffering agent. Methods of using such
compositions are also provided.
BACKGROUND
[0003] As used herein, the phrase "acid labile pharmaceutical
agent" refers to any pharmacologically active drug subject to
acid-catalyzed degradation. One class of acid labile pharmaceutical
agents is a class of antisecretory agents that do not exhibit
anticholinergic or H.sub.2 histamine antagonistic properties, but
that suppress gastric acid secretion by the specific inhibition of
the H.sup.+, K.sup.+-ATPase enzyme system at the secretory surface
of the gastric parietal cell (hereinafter "proton pump inhibitors"
or "PPIs"). These agents provide a more specific class of
inhibitors of gastric acid secretion in mammals, such as humans, by
blocking the final step of acid production.
[0004] One particular class of PPIs includes substituted
benzimidazole compounds that contain a sulfinyl group bridging
substituted benzimidazole and pyridine rings. Another class of PPIs
is the class of substituted aryl-imidazoles, such as substituted
bicyclic aryl-imidazoles. The mechanism of action of the PPIs
occurs when they reach parietal cells from the blood and diffuse
into the secretory canaliculi, where they become protonated and
thereby trapped. The protonated agent is then believed to rearrange
to form a sulfenic acid and a sulfenamide. The sulfenamide, in
turn, is thought to interact covalently with sulfhydryl groups at
critical sites in the extracellular (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,
p. 907, 9.sup.th ed. (1996).
[0005] Currently available PPI medications have a delay in reaching
maximal effect (for example, maintaining a gastric pH above about
3.5) such that it can take approximately five days to reach a
steady state effect. Therefore, it would be desirable to have a
significant effect on gastric pH before 5 days, beginning with the
first dose of the medication.
SUMMARY
[0006] In various embodiments, the present disclosure provides
pharmaceutical compositions comprising a first proton pump
inhibitor (PPI1), having a therapeutically effective portion, which
is optionally enteric coated; a subsequent proton pump inhibitor
(PPI2), having a therapeutically effective portion, which is
optionally enteric coated; and one or more buffering agents.
[0007] Another embodiment discloses a pharmaceutical composition
comprising omeprazole, having a therapeutically effective portion
which is optionally enteric coated, lansoprazole, having a
therapeutically effective portion which is optionally enteric
coated, and sodium bicarbonate or other buffering agents.
[0008] Methods of using such compositions for treating a patient,
including patients with or without gastroparesis (slow stomach
emptying), in need of therapy for various diseases and disorders,
including gastric acid related disorders such as, but not limited
to, severe erosive esophagitis (Los Angeles classification grade C
& D), Barrett's esophagus and reversal of Barrett's esophagus,
treatment to stop progression and encourage reversal of
reflux-related esophageal metaplasia with low or high grade
dysplasia, treatment to stop progression and encourage reversal of
reflux related adenocarcinoma of the esophagus or acid-related
adenocarcinoma of the stomach, treatment of patients undergoing
ablation in Barrett's esophagus to prevent recurrence, duodenal
ulcer, gastric ulcer, gastric and duodenal erosions and
ulcerations, acid dyspepia, gastroesophageal reflux disease (GERD),
poorly responsive symptomatic GERD, acid reflux, esophageal ulcers
and erosions, precancerous and canercous lesions of the esophagus
induced by acid exposure, radiation or chemotherapy-induced
esophagitis, acid hypersecretory conditions, gastrointestinal
pathological hypersecretory conditions (such as Zollinger Ellison
Syndrome), non-ulcer dyspepsia, short-term eradication of
Helicobacter pylori (H. pylori) (less than 5 days treatment with 2
antibiotics chosen from the following group, but are not limited
to, antibiotic penicillins (e.g. amoxicillin, benzylpenicillin,
piperacillin, mecillinam, etc.), antibiotic cefems or
cephalosporins (e.g. cefixime, cefuroxime, cefuroxime axetil,
cefaclor, ceftizoxime, cefotaxime, ceftazidime, etc.), antibiotic
macrolides (e.g. erythromycin, clarithromycin, azithromycin,
telithromycin, roxithromycin, etc.), antibiotic tetracylines (e.g.
tetracyline, minocycline, doxycycline, tigecycline, etc.),
antibiotic aminoglycosides (e.g. gentamicin, kanamycin, netilmicin,
amikacin, tobramycin, etc.), antibiotic carbapenems (e.g. imipenem,
meropenem, doripenem, etc.), carbapenem ester type prodrug (e.g.
tebipenem pivoxil, faropenem daloxate; other oral carbapenem
prodrugs include GV-118819, CS-834, L-084, DZ-2649, CL-191121,
etc.), antibiotic quinolones (e.g. norfloxacin, ofloxacin,
levofloxacin, ciprofloxacin, sitafloxacin, clinafloxacin,
gatifloxacin, moxifloxacin, pazufloxacin, prulifloxacin,
olamufloxacin, ganefloxacin, gemifloxacin, trovafloxacin, etc.),
antibiotic nitroimidazoles (e.g. metronidazole, tinidazole), and
antibiotic rifamycin or ansamycin analogues (e.g. rifabutin,
rifampicin, rifampin, rifaximin, rifalazil, and ryfamycin
derivatives such as
3'-hydroxy-5'(4-propylpiperazinyl)benzoxazinorifamycin)),
extraesophageal or atypical manifestations of gastroesophageal
reflux disease (such as but not limited to eye pain, asthma,
bronchitis, pneumonia, chest pain, cough, recurrent laryngitis,
globus pharyngeus, sinusitis, otalgia, otitis media, eustachian
tube dysfunction, voice change, globus sensation, throat clearing,
halitosis, sore throat, aphthous ulcers), nocturnal acid
breakthrough (NAB), sleep apnea, sleep disturbance, stopping of
gastrointestinal bleeding and prevention of rebleeding after
gastrointestinal bleeding, pretreatment prior to endoscopic
evaluation of upper GI bleeding, stress ulcer prevention, treatment
of stress-related bleeding, seizure or apparent seizure activity,
Sandifer's syndrome, failure to thrive, anorexia, anorexia nervosa,
weight loss, apnea, and bradycardia are provided.
[0009] Other objects, features and advantages will be set forth in
the Detailed Description that follows, and in part will be apparent
from the description or may be learned by practice of the
embodiments disclosed herein. These objects and advantages will be
realized and attained by the processes and compositions
particularly pointed out in the written description and claims
hereof.
DETAILED DESCRIPTION
[0010] While the present invention is capable of being embodied in
various forms, the description below of several embodiments is made
with the understanding that the present disclosure is to be
considered as an exemplification of the invention, and is not
intended to limit the invention to the specific embodiments
illustrated. Headings are provided for convenience only and are not
to be construed to limit the invention in any way. Embodiments
illustrated under any heading may be combined with embodiments
illustrated under any other heading.
[0011] It has been discovered that a pharmaceutical composition
comprising omeprazole and lansoprazole, can provide superior
gastric acid inhibition than the use of a single type of proton
pump inhibitor, with or without a buffering agent.
[0012] It is therefore provided herein a pharmaceutical composition
comprising: [0013] a) a first proton pump inhibitor (PPI1), having
a therapeutically effective portion which is optionally enteric
coated; [0014] b) a second proton pump inhibitor (PPI2), having a
therapeutically effective portion which is optionally enteric
coated; and [0015] c) one or more buffering agents.
[0016] It is also provided herein a pharmaceutical composition
comprising: [0017] a) omeprazole, having a therapeutically
effective portion which is optionally enteric coated; [0018] b)
lansoprazole, having a therapeutically effective portion which is
optionally enteric coated; and [0019] c) sodium bicarbonate.
[0020] Methods of using such compositions for treating a patient,
including patients with or without gastroparesis (slow stomach
emptying), in need of therapy for various diseases and disorders,
including gastric acid related disorders such as, but not limited
to, severe erosive esophagitis (Los Angeles classification grade C
& D), Barrett's esophagus and reversal of Barrett's esophagus,
treatment to stop progression and encourage reversal of
reflux-related esophageal metaplasia with low or high grade
dysplasia, treatment to stop progression and encourage reversal of
reflux related adenocarcinoma of the esophagus or acid-related
adenocarcinoma of the stomach, treatment of patients undergoing
ablation in Barrett's esophagus to prevent recurrence, duodenal
ulcer, gastric ulcer, gastric and duodenal erosions and
ulcerations, acid dyspepia, gastroesophageal reflux disease (GERD),
poorly responsive symptomatic GERD, acid reflux, esophageal ulcers
and erosions, precancerous and canercous lesions of the esophagus
induced by acid exposure, radiation or chemotherapy-induced
esophagitis, acid hypersecretory conditions, gastrointestinal
pathological hydersecretory conditions (such as Zollinger Ellison
Syndrome), non-ulcer dyspepsia, short-term eradication of H. pylori
(less than 5 days treatment with 2 antibiotics chosen from the
following group, but are not limited to, antibiotic penicillins
(e.g. amoxicillin, benzylpenicillin, piperacillin, mecillinam,
etc.), antibiotic cefems or cephalosporins (e.g. cefixime,
cefuroxime, cefuroxime axetil, cefaclor, ceftizoxime, cefotaxime,
ceftazidime, etc.), antibiotic macrolides (e.g. erythromycin,
clarithromycin, azithromycin, telithromycin, roxithromycin, etc.),
antibiotic tetracylines (e.g. tetracyline, minocycline,
doxycycline, tigecycline, etc.), antibiotic aminoglycosides (e.g.
gentamicin, kanamycin, netilmicin, amikacin, tobramycin, etc.),
antibiotic carbapenems (e.g. imipenem, meropenem, doripenem, etc.),
carbapenem ester type prodrug (e.g. tebipenem pivoxil, faropenem
daloxate; other oral carbapenem prodrugs include GV-118819, CS-834,
L-084, DZ-2649, CL-191121, etc.), antibiotic quinolones (e.g.
norfloxacin, ofloxacin, levofloxacin, ciprofloxacin, sitafloxacin,
clinafloxacin, gatifloxacin, moxifloxacin, pazufloxacin,
prulifloxacin, olamufloxacin, ganefloxacin, gemifloxacin,
trovafloxacin, etc.), antibiotic nitroimidazoles (e.g.
metronidazole, tinidazole), and antibiotic rifamycin or ansamycin
analogues (e.g. rifabutin, rifampicin, rifampin, rifaximin,
rifalazil, and ryfamycin derivatives such as
3'-hydroxy-5'-(4-propylpiperazinyl)benzoxazinorifamycin)),
extraesophageal or atypical manifestations of gastroesophageal
reflux disease (such as but not limited to eye pain, asthma,
bronchitis, pneumonia, chest pain, cough, recurrent laryngitis,
globus pharyngeus, sinusitis, otalgia, otitis media, eustachian
tube dysfunction, voice change, globus sensation, throat clearing,
halitosis, sore throat, aphthous ulcers), nocturnal acid
breakthrough (NAB), sleep apnea, sleep disturbance, stopping of
gastrointestinal bleeding and prevention of rebleeding after
gastrointestinal bleeding, pretreatment prior to endoscopic
evaluation of upper GI bleeding, stress ulcer prevention, treatment
of stress-related bleeding, seizure or apparent seizure activity,
Sandifer's syndrome, failure to thrive, anorexia, anorexia nervosa,
weight loss, apnea, and bradycardia are provided.
Proton Pump Inhibitors
[0021] Compositions of the disclosure comprise at least one
pharmaceutically acceptable acid labile pharmaceutical agent. For
example, embodiments disclosed herein comprise at least one
H.sup.+, K.sup.+-ATPase proton pump inhibitor (PPI). The term
proton pump inhibitor or PPI means any acid labile pharmaceutical
agent possessing pharmacological activity as an inhibitor of
H.sup.+, K.sup.+-ATPase. Classes of PPIs include but are not
limited to: substituted aryl-imidazoles, substituted bicyclic
aryl-imidazoles, substituted benzimidazole compounds, and
substituted imidazopyridines.
[0022] A PPI can, if desired, be in any form such as a free base,
free acid, salt, ester, hydrate, anhydrate, salt hydrate, amide,
enantiomer, isomer, tautomer, prodrug, polymorph, derivative, or
the like, provided that the free base, free acid, salt, ester,
hydrate, anhydrate, salt hydrate, amide, enantiomer, isomer,
tautomer, prodrug, polymorph, or any other pharmacologically
suitable derivative is therapeutically active or undergoes
conversion within or outside of the body to a therapeutically
active form.
[0023] In one embodiment, illustrative PPIs are those compounds of
Formula (A):
##STR00001##
wherein
[0024] R.sup.1 is hydrogen, alkyl, halogen, cyano, carboxy,
carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy,
alkoxy which is optionally fluorinated, hydroxyalkyl,
trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy,
alkylthio, or alkylsulfinyl;
[0025] R.sup.2 is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino,
aralkyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl,
alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl;
[0026] R.sup.3 and R.sup.5 are the same or different and each is
hydrogen, alkyl, C.sub.1-4 lower alkyl (e.g. methyl, ethyl, etc.),
alkoxy, amino, or alkoxyalkoxy;
[0027] R.sup.4 is hydrogen, alkyl, C.sub.1-4 lower alkyl (e.g.
methyl, ethyl, etc.), alkoxy which may optionally be fluorinated,
or alkoxyalkoxy;
[0028] Q is nitrogen, CH, or CR.sup.1;
[0029] W is nitrogen, CH, or CR.sup.1;
[0030] y is an integer of 0 through 4; and
[0031] Z is nitrogen, CH, or CR.sup.1;
[0032] or a free base, salt, ester, hydrate, salt hydrate, amide,
enantiomer, isomer, tautomer, prodrug, polymorph, or derivative
thereof.
[0033] One specific example of a PPI is tenatoprazole (TU-199, also
called benatoprazole), or
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]imidazo[4-
,5-b]pyridine, described in EP 0254588, hereby incorporated by
reference herein in its entirety. An alternative IUPAC name for
tenatoprazole is
3-methoxy-8-[(4-methoxy-3,5-dimethyl-pyridin-2-yl)methyl
sulfinyl]-2,7,9-triazabicyclo[4.3.0]nona-2,4,8,10-tetraene. Because
of its relatively long elimination profile, tenatoprazole can be
used for the treatment of conditions such as gastroesophageal
reflux disease, gastrointestinal bleeding and dyspepsia, as
described in the French patent application 0213113, hereby
incorporated by reference herein in its entirety. Tenatoprazole is
a proton pump inhibitor which is similar to the chemical structure
of omeprazole (Merck Index No. 6913; CAS No. 73590-58-6), or
5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl)
methyl]sulfinyl]-1H benzimidazole. Omeprazole is a widely used
proton pump inhibitor of the class of substituted benzimidazoles.
Tenatoprazole belongs to the class of substituted imidazopyridines
and has an imidazo[4,5-b]pyridine moiety whereas omeprazole has a
benzimidazole moiety.
[0034] Specific examples of suitable PPIs include esomeprazole
(also referred to as S-omeprazole), ilaprazole (U.S. Pat. No.
5,703,097), tenatoprazole (or benatoprazole), omeprazole,
lansoprazole, s-lansoprazole, rabeprazole, hydroxyomeprazole,
pantoprazole, pariprazole, leminoprazole, dontoprazole,
habeprazole, perprazole, ransoprazole, and nepaprazole, or a free
base, a free acid, a salt, hydrate, ester, salt hydrate, amide,
enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of
such compounds.
[0035] Other acid labile pharmaceutical agents include, but are not
limited to: soraprazan (Altana); 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-thieny-
- 1) (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 (To
a Eiyo); HN-11203 (Nycomed Pharma); OPC-22575; pumilacidin A (BMS);
saviprazole (EP 234485) (Aventis); SKand F-95601 (GSK,
discontinued); Pharmaprojects No. 2522 (EP 204215) (Pfizer); S-3337
(Aventis); RS-13232A (Roche); AU-1363 (Merck); SKand F-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, salt hydrate, amide,
enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of
such compounds.
[0036] Still other embodiments contemplated by the present
disclosure include, but are not limited to 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; 5,840,737; 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; 6,489,346; 6,559,167; 6,645,988;
6,699,885; 7,101,573; 7,109,161.
[0037] Still other embodiments contemplated by the present
disclosure include, but are not limited to those described in the
following: EP 0254588; EP 0005129.
[0038] Other embodiments contemplated by the present disclosure
include, but are not limited to those described in the following
PCT Publications: WO 94/27988; WO 05/044223; WO 06/043280.
[0039] Still other embodiments contemplated by the present
disclosure include, but are not limited to those described in the
following U.S. Application Nos. 20020192299; 20040131675;
20040146554; 20040248939; 20040248942; 20050003005; 20050031700;
20050037070; 20050054682; 20050112193; 20050220870; 20050222210;
20050239845; 20050244517; 20050249806; 20050249811; 20050266071;
20050288334; 20050277672; 20050277673; 20050277671; 20060024238;
20060134210; 20060147522; 20060159760; 20060167262; 20060173045;
20060204585.
[0040] The foregoing lists of suitable acid inhibitors are meant to
be illustrative and not exhaustive as a person of ordinary skill in
the art would recognize that there are many other suitable acid
inhibitors that could be created.
[0041] Gastric acid inhibitors, including proton pump inhibitors as
well as their salts, hydrates, esters, salt hydrates, amides,
enantiomers, isomers, tautomers, polymorphs, prodrugs, and
derivatives may be prepared using standard procedures that a person
of ordinary skill in the art of synthetic organic chemistry would
recognize. 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).
[0042] "Pharmaceutically acceptable salts," or "salts," include 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.
[0043] In one embodiment, acid addition salts are prepared from the
free base forms using, for example, methodologies 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.
[0044] 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, for example, using
hydrochloric or hydrobromic acids. In still other embodiments, the
basic salts are alkali metal salts, e.g., sodium salt.
[0045] Salt forms of proton pump inhibitors include, but are not
limited to: a sodium salt form such as esomeprazole sodium,
omeprazole sodium, tenatoprazole sodium, rabeprazole sodium,
pantoprazole sodium; a magnesium salt form such as esomeprazole
magnesium or omeprazole magnesium, described in U.S. Pat. No.
5,900,424; a calcium salt form; a potassium salt form such as the
potassium salt of esomeprazole, described in U.S. Pat. No.
6,511,996; salt hydrate forms including but not limited to sodium
hydrate salt forms, for example tenatoprazole sodium hydrate or
omeprazole sodium hydrate. 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.
[0046] The foregoing list of suitable salts of proton pump
inhibitors is meant to be illustrative and not exhaustive as a
person of ordinary skill in the art would recognize that other
pharmaceutically acceptable salts of a proton pump inhibitor could
be created.
[0047] In one embodiment, preparation of esters involves
functionalizing hydroxyl and/or carboxyl groups that may be present
within the molecular structure of the drug. In another 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 procedures
including but not limited to hydrogenolysis or hydrolysis.
[0048] "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.
[0049] "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.
[0050] 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. WO 02/085889.
[0051] 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.
[0052] In one embodiment, at least one proton pump inhibitor is not
enteric coated. In another embodiment, a portion of at least one
proton pump inhibitor is optionally enteric coated. In another
embodiment, a therapeutically effective portion of at least one
proton pump inhibitor is optionally enteric coated. In another
embodiment, about 5%, about 15%, about 20%, about 30%, about 40%,
about 50% or about 60% of at least one proton pump inhibitor is
optionally enteric coated. In another embodiment, a portion of at
least one proton pump inhibitor comprises a "thin enteric coat."
The term "thin enteric coat" herein refers to a pH sensitive
coating that is applied in a manner or amount such that it delays
release of the coated substance in gastrointestinal fluid for a
period of time, but ultimately allows release of some of the coated
substance prior to passage into the duodenum.
[0053] In one embodiment, at least one proton pump inhibitor has a
D.sub.90, D.sub.80, D.sub.70 or D.sub.50 particle size, by weight
or by number, of less than about 900 .mu.m, less than about 800
.mu.m, less than about 700 .mu.m, less than about 600 .mu.m, less
than about 500 .mu.m, less than about 400 .mu.m, less than about
300 .mu.m, less than about 200 .mu.m, less than about 150 .mu.m,
less than about 100 .mu.m, less than about 80 .mu.m, less than
about 60 .mu.m, less than about 40 .mu.m, less than about 35 .mu.m,
less than about 30 .mu.m, less than about 25 .mu.m, less than about
20 .mu.m, less than about 15 .mu.m, less than about 10 .mu.m, or
less than about 5 .mu.m.
[0054] In another embodiment, compositions are provided wherein a
micronized proton pump inhibitor is of a size which allows greater
than about 90%, greater than about 75%, or greater than about 50%
of the proton pump inhibitor to be released from the dosage unit
within about 1 hour, within about 50 minutes, within about 40
minutes, within about 30 minutes, within about 20 minutes, within
about 10 minutes, or within about 5 minutes after placement in a
standard dissolution test.
[0055] In still another embodiment, compositions of the disclosure
comprise two PPIs in a total amount of about 1 mg to about 3000 mg,
about 1 mg to about 2000 mg, about 1 mg to about 1000 mg, about 1
mg to about 750 mg, about 1 mg to about 500 mg, about 1 mg to about
300 mg, about 5 mg to about 250 mg, about 5 mg to about 200 mg,
about 5 mg to about 175 mg, about 5 mg to about 120 mg, about 5 mg
to about 100 mg, about 5 mg to about 80 mg, or about 5 mg to about
50 mg, for example about 5 mg, about 7.5 mg, about 10 mg, about 15
mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60
mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110
mg about 120, mg about 130 mg, about 140 mg, about 150 mg, about
160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200
mg.
[0056] In still another embodiment, compositions of the disclosure
comprise two PPIs where each is present in an amount of about 40 mg
to about 160 mg, about 50 mg to about 150 mg, about 60 mg to about
140 mg, about 60 to about 130 mg, about 60 mg to about 120 mg,
about 60 to about 110 mg, about 60 mg to about 100 mg, about 70 mg
to about 100 mg, or about 80 to about 100 mg.
Buffering Agent
[0057] Compositions of the disclosure comprise one or more
pharmaceutically acceptable buffering agents. Buffering agents
useful in the present disclosure include agents possessing
pharmacological activity as a weak or strong base. In one
embodiment, the buffering agent, when formulated with or
administered substantially simultaneous with a PPI, functions to
raise the pH of gastrointestinal fluid and thereby to substantially
prevent or inhibit acid degradation of the PPI by gastrointestinal
fluid for a period of time.
[0058] In another embodiment, buffering agents useful in accordance
with the present disclosure comprise, but are not limited to, a
salt of a Group IA metal including, for example, a bicarbonate salt
of a Group IA metal, a carbonate salt of a Group IA metal, an
alkaline earth metal buffering agent, an amino acid, an alkaline
salt of an ammo acid, an aluminum buffering agent, a calcium
buffering agent, a sodium buffering agent, or a magnesium buffering
agent. Other suitable buffering agents include alkali (sodium and
potassium) or alkaline earth (calcium and magnesium) carbonates,
phosphates, bicarbonates, citrates, borates, acetates, phthalates,
tartrates, succinates and the like, such as sodium or potassium
phosphate, citrate, borate, acetate, bicarbonate and carbonate.
[0059] Non-limiting examples of suitable buffering agents include
aluminum, magnesium hydroxide, aluminum hydroxide/magnesium
hydroxide co-precipitate, aluminum hydroxide/sodium bicarbonate
co-precipitate, calcium acetate, calcium bicarbonate, calcium
borate, calcium carbonate, calcium bicarbonate, calcium citrate,
calcium gluconate, calcium glycerophosphate, calcium hydroxide,
calcium lactate, calcium phthalate, calcium phosphates (including
Calcium dihydrogen phosphate, tricalcium phosphate and the like),
calcium succinate, calcium tartrate, calcium formate, calcium
propionate, 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, and trometamol. (Based
in part upon the list provided in The Merck Index, Merck & Co.
Rahway, N.J. (2001)). In addition, due to the ability of proteins
or protein hydrolysates to react with stomach acids, they too can
serve as buffering agents in the present embodiments. Furthetinore,
combinations or mixtures of the above mentioned buffering agents
can be used in the pharmaceutical formulations described
herein.
[0060] Buffering agents also include buffering agents or
combinations of buffering agents 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 buffering agents produce and maintain a
pH greater than the pKa of the proton pump inhibitor.
[0061] Buffering agents also include peptides, such as L-carnosine.
In one embodiment, a composition of the disclosure comprises
L-carnosine. Still another embodiment of the disclosure comprises
L-carnosine in a ratio of greater than about 20 parts L-carnosine
to about 1 part PPL Other embodiments comprise L-carnosine and PPI
in an amount of about 20:1, about 25:1, about 30:1, about 35:1,
about 40:1, about 45:1, or about 50:1.
[0062] Other embodiments of the disclosure comprises a PPI, at
least one buffering agent in an amount of about 20 parts to about 1
part PPI, and a protein component in an amount of about 20 parts to
about 1 part PPI. For example, an embodiment of the disclosure
comprises tenatoprazole, sodium bicarbonate in an amount of about
20 parts to about 1 part tenatoprazole, and L-carnosine in an
amount of about 20 parts to about 1 part tenatoprazole. Another
embodiment of the disclosure comprises about 40 mg tenatoprazole,
about 1600 mg sodium bicarbonate, and about 1600 mg L-carnosine.
Still another embodiment of the disclosure comprises about 40 mg
tenatoprazole, about 1600 mg sodium bicarbonate and magnesium
hydroxide, and about 1600 mg L-carnosine. Yet another embodiment of
the disclosure comprises about 40 mg omeprazole, about 1600 mg
sodium bicarbonate and magnesium hydroxide, and about 1600 mg
L-carnosine.
[0063] Other embodiments of the disclosure comprise omeprazole,
sodium bicarbonate in an amount of about 20 parts to about 1 part
omeprazole, and L-carnosine in an amount of about 20 parts to about
1 part omeprazole. For example, an embodiment of the disclosure
comprises about 40 mg omeprazole, about 1600 mg sodium bicarbonate,
and about 1600 mg L-carnosine.
[0064] The foregoing list of suitable buffering agents is meant to
be illustrative and not exhaustive as a person of ordinary skill in
the art would recognize that other pharmaceutically acceptable
buffering agents could be created.
[0065] In various other embodiments, the buffering agent is present
in a total amount of about 0.1 mEq/mg to about 5 mEq/mg of the
proton pump inhibitor, about 0.5 mEq/mg to about 3 mEq/mg of the
proton pump inhibitor, about 0.6 mEq/mg to about 2.5 mEq/mg of the
proton pump inhibitor, about 0.7 mEq/mg to about 2.0 mEq/mg of the
proton pump inhibitor, about 0.8 mEq/mg to about 1.8 mEq/mg of the
proton pump inhibitor, about 1.0 mEq/mg to about 1.5 mEq/mg of the
proton pump inhibitor. In another embodiment, the buffering agent
is present in an amount of about 0.5 mEq/mg of the proton pump
inhibitor, about 0.75 mEq/mg of the proton pump inhibitor, or about
1 mEq/mg of the proton pump inhibitor on a dry weight basis.
[0066] In still another embodiment, one or more buffering agents
are present in a total amount of about 0.5 mEq to about 160 mEq,
about 1 mEq to about 150 mEq, about 10 mEq to about 150 mEq, about
10 mEq to about 75 mEq, about 10 mEq to about 60 mEq, or about 10
mEq to about 50 mEq. Illustratively, a composition of the
disclosure can comprise about 1 mEq, about 5 mEq, about 10 mEq,
about 15 mEq, about 20 mEq, about 25 mEq, about 30 mEq, about 35
mEq, about 40 mEq, about 45 mEq, about 50 mEq, about 60 mEq, about
70 mEq, about 80 mEq, about 90 mEq, about 100 mEq, about 110 mEq,
about 120 mEq, about 130 mEq, about 140 mEq, about 150 mEq, or
about 160 mEq of buffering agent.
[0067] In yet another embodiment, one or more buffering agents are
present in a total amount of about 10 mEq, about 11 mEq, about 12
mEq, about 13 mEq, about 14 mEq, about 15 mEq, or at least about 16
mEq.
[0068] In another embodiment, one or more buffering agents and the
mixture of the first and subsequent proton pump inhibitors are
present in a weight ratio of about 5:1, about 7:1, about 10:1,
about 20:1, greater than about 20:1, about 21:1, about 22:1, about
23:1, about 25:1, about 30:1, about 35:1, about 40:1, greater than
about 40:1, about 45:1, about 53:3; about 11:1, about 28:3, about
28:5, about 23:3, about 26:1, about 27:2, or about 31:1.
[0069] In still another embodiment, PPI1, PPI2, and one or more
buffering agents are present in a weight ratio of about 2:1:50,
about 3:2:50, about 2:1:25, about 2:1:60, about 3:2:25, about
2:1:20, about 1:1:50, about 1:2:50, about 1:1:25, about 1:1:60,
about 1:2:25, or about 1:1:20.
[0070] In another embodiment, the amount of buffering agent present
in a composition of the disclosure ranges from about 100 to about
4000 mg, about 200 to about 3500 mg, about 300 to about 3000 mg,
about 400 to about 2500 mg, or about 500 to about 2200 mg, about
600 to about 2000, or about 700 to about 1800 mg. In other
embodiments, the amount of buffering agent present in a composition
of the disclosure is about 100 mg, about 200 mgs, or about 300 mgs,
or about 400 mgs, or about 500 mgs, 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, about
3500 mgs, or about 4000 mgs.
[0071] In another embodiment, the amount of buffering agent present
is an amount of about 100 mg to about 2000 mg, about 200 mg to
about 1750 mg, about 300 mg to about 1500 mg, about 400 mg to about
1250 mg, or about 500 mg to about 1000 mg.
[0072] In another embodiment, the amount of buffering agent present
is an amount of about 100 mg to about 500 mg, about 200 mg to 400
mg, about 300 mg to about 400 mg, about 100 mg to about 350 mg,
about 100 mg to about 300 mg, about 100 mg to about 250 mg, or 100
mg to about 200 mg.
[0073] In another embodiment, one or more buffering agents are
present in a composition of the disclosure in a total amount that
is greater than 800 mg, for example about 920 mg or at least about
1000 mg.
[0074] In still another embodiment, the buffering agent and the
mixture of PPI1 and PPI2 (hereinafter "proton pump inhibitor
mixture") are present in a weight ratio greater than 20:1, not less
than about 21:1, not less than about 22:1, not less than about
23:1, not less than about 24:1, not less than about 25:1, not less
than about 26:1, not less than about 27:1, not less than about
28:1, not less than about 29:1, not less than about 30:1, not less
than about 31:1, not less than about 32:1, not less than about
33:1, not less than about 34:1, not less than about 35:1, not less
than about 36:1, not less than about 37:1, not less than about
38:1, not less than about 39:1, not less than about 40:1, not less
than about 41:1, not less than about 42:1, not less than about
43:1, not less than about 44:1, not less than about 45:1, not less
than about 46:1, not less than about 47:1, not less than about
48:1, not less than about 49:1, not less than about 50:1, not less
than about 53:3; not less than about 11:1, not less than about
28:3, not less than about 21;1, not less than about 28:5, not less
than about 23:3, not less than about 26:1, not less than about
53:3, not less than about 27:2, or not less than about 31:1.
[0075] In yet another embodiment, a composition is provided that
comprises a combination of 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 a related
embodiment, if such a composition comprises a
poly[phosphoryl/sulfon]-ated carbohydrate, 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. In another
embodiment, the composition contains no
poly[phosphoryl/sulfon]-ated carbohydrate.
[0076] In other embodiments, if the pharmaceutical composition
comprises an amino acid buffering agent, the total amount of amino
acid 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.
[0077] The phrase "amino acid buffering agent" as used herein
includes, but is not limited to, amino acids, amino acid salts, and
amino acid alkali salts including, for example: glycine, alanine,
threonine, isoleucine, valine, phenylalanine, glutamic acid,
asparagininic acid, lysine 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.
[0078] The foregoing list of amino acid buffering agents is meant
to be illustrative and not exhaustive as a person of ordinary skill
in the art would recognize that other pharmaceutically acceptable
amino acid buffering agents could be created.
[0079] In another embodiment, a composition of the disclosure
comprises at least one non-amino acid buffering agent wherein the
non-amino acid buffering agent is present in the composition in a
total amount greater than 800 mg. In a related embodiment, if such
a composition comprises a poly[phosphoryl/sulfon]-ated
carbohydrate, 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.
[0080] In still another embodiment, a composition is provided which
comprises at least one buffering agent in a total amount of at
least about 10 mEq. In a related embodiment, if an amino acid
buffering agent is present in the composition, at least one of the
following conditions is met: (1) the weight ratio of amino acid
buffering agent:proton pump inhibitor mixture is greater than 20:1;
(2) the composition comprises at least two non-amino acid buffering
agents; (3) the composition comprises at least one non-amino acid
buffering agent wherein the weight ratio of the at least one
non-amino acid buffering agent:proton pump inhibitor mixture is
greater than 20:1; and/or (4) the weight ratio of total buffering
agent:proton pump inhibitor mixture is greater than 40:1.
[0081] In yet another embodiment, a composition is provided which
comprises at least one buffering agent in a total amount of at
least about 10 mEq. In a related embodiment, if an amino acid
buffering agent is present in the composition, at least one of the
following conditions is met: (1) the weight ratio of
PPI1:PPI2:amino acid buffering agent is about 2:1:50, about 3:2:50,
about 2:1:25, about 2:1:60, about 3:2:25, about 2:1:20, about
1:1:50, about 1:2:50, about 1:1:25, about 1:1:60, about 1:2:25, or
about 1:1:20; (2) the composition comprises at least two non-amino
acid buffering agents; (3) the composition comprises at least one
non-amino acid buffering agent wherein the weight ratio of
PPI1:PPI2:non-amino acid buffering agent is about 2:1:50, about
3:2:50, about 2:1:25, about 2:1:60, about 3:2:25, about 2:1:20,
about 1:1:50, about 1:2:50, about 1:1:25, about 1:1:60, about
1:2:25, or about 1:1:20; and/or (4) the weight ratio of
PPI1:PPI2:total buffering agent is about 2:1:50, about 3:2:50,
about 2:1:25, about 2:1:60, about 3:2:25, about 2:1:20, about
1:1:50, about 1:2:50, about 1:1:25, about 1:1:60, about 1:2:25, or
about 1:1:20.
[0082] In other embodiments, where two or more buffering agents are
present, the two or more buffering agents comprise 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.
[0083] In still another embodiment, the buffering agent comprises a
mixture of sodium bicarbonate, calcium carbonate, and magnesium
hydroxide, wherein the sodium bicarbonate, calcium carbonate, and
magnesium hydroxide are each present in an amount of about 0.1
mEq/mg proton pump inhibitor mixture to about 5 mEq/mg of the
proton pump inhibitor mixture.
[0084] In another embodiment, the buffering agent comprises a
mixture of sodium bicarbonate, calcium carbonate, and magnesium
hydroxide, wherein the sodium bicarbonate, calcium carbonate, and
magnesium hydroxide are each present in an amount of about 0.1
mEq/mg proton pump inhibitor to about 5 mEq/mg of the either proton
pump inhibitor.
[0085] Also provided herein are pharmaceutical compositions
comprising at least one soluble buffering agent. The term "soluble
buffering agent" as used herein refers to an antacid that has a
solubility of at least about 500 mg/mL, or at least about 300
mg/mL, or at least about 200 mg/mL, or at least about 100 mg/mL in
gastrointestinal fluid or simulated gastrointestinal fluid.
[0086] In some embodiments, the buffering agent has a defined
particle size distribution. For example, in one embodiment, the
D.sub.50, D.sub.70, D.sub.80, or D.sub.90 particle size of the
buffering agent, by weight or by number, is no greater than about
10 .mu.m, is no greater than about 20 .mu.m, no greater than about
30 .mu.m, no greater than about 40 .mu.m, no greater than about 50
.mu.m, no greater than about 60 .mu.m, no greater than about 70
.mu.m, no greater than about 80 .mu.m, no greater than about 90
.mu.m, no greater than about 100 .mu.m in diameter, no greater than
about 200 .mu.m in diameter, no greater than about 300 .mu.m in
diameter, no greater than about 400 .mu.m in diameter, no greater
than about 1000 .mu.m in diameter, no greater than about 2000 .mu.m
in diameter, no greater than about 3000 .mu.m in diameter, no
greater than about 4000 .mu.m in diameter, no greater than about
6000 .mu.m in diameter, or no greater than about 9000 .mu.m in
diameter.
[0087] The foregoing list of suitable buffering agents is meant to
be illustrative and not exhaustive as a person of ordinary skill in
the art would recognize that other pharmaceutically acceptable
buffering agents could be created.
NSAIDs and Aspirins
[0088] In one embodiment, compositions of the invention comprise an
NSAID. The term "NSAID" as used herein refers to compounds acting
as a non-steroidal anti-inflammatory agent as identified as such by
one of ordinary skill in the art.
[0089] Illustratively, the Merck Manual, 16th Edition, Merck
Research Laboratories (1990) pp 1308-1309 provides well known
examples of NSAIDs. Exemplary NSAIDs include, but are not limited
to, salicylates, indomethacin, flurbiprofen, diclofenac, ketorolac,
naproxen, piroxicam, tebufelone, ibuprofen, etodolac, nabumetone,
tenidap, alcofenac, antipyrine, aminopyrine, dipyrone, aminopyrone,
phenylbutazone, clofezone, oxyphenbutazone, prexazone, apazone,
benzydamine, bucolome, cinchopen, clonixin, ditrazol, epirizole,
fenoprofen, floctafeninl, flufenamic acid, glaphenine, indoprofen,
ketoprofen, meclofenamic acid, mefenamic acid, niflumic acid,
phenacetin, salidifamides, sulindac, suprofen and tolmetin. The
salicylates may include acetylsalicylic acid, sodium
acetylsalicylic acid, calcium acetylsalicylic acid, salicylic acid,
and sodium salicylate.
[0090] In one embodiment, an NSAID, if present, is present in a
total amount of about 0.1% to about 85%, about 0.5% to about 75%,
or about 1% to about 60%, by total weight of the composition.
Illustratively, the NSAID can be present in an amount of about 1%,
about 2% about 3%, about 4%, about 5%, about 6%, about 7%, about
8%, about 9%, about 10%, about 11%, about 12%, about 13%, about
14%, about 15%, about 16%, about 17%, about 18%, about 19%, about
20%, about 21%, about 22%, about 23%, about 24%, about 25%, about
26%, about 27%, about 28%, about 29%, about 30%, about 31%, about
32%, about 33%, about 34%, about 35%, about 36%, about 37%, about
38%, about 39%, about 40%, about 41%, about 42%, about 43%, about
44%, about 45%, about 46%, about 46%, about 48%, about 49%, about
50%, about 51%, about 52%, about 53%, about 54%, about 55%, about
56%, about 57%, about 58%, about 59%, about 60%, about 61%, about
62%, about 63%, about 64%, about 65%, about 66%, about 67%, about
68%, about 69%, about 70%, about 71%, about 72%, about 73%, about
74%, about 75%, about 76%, about 77%, about 78%, about 79%, about
80%, about 81%, about 82%, about 83% about 84%, or about 85%, by
weight of the total composition.
[0091] In another embodiment, an NSAID, if present, is present in a
total amount of about 1 mg to about 1500 mg, about 1 mg to about
1200 mg, about 1 mg to about 1000 mg, about 1 mg to about 800 mg or
about 1 mg to about 500 mg.
[0092] In other embodiments, the NSAID is present in a composition
of the invention in an amount of about 50 mg, about 100 mg about
150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg,
about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650
mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about
900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg,
about 1150 mg, or about 1200 mg.
[0093] In one embodiment, no portion of the NSAID is enteric
coated. In another embodiment, at least a portion of the NSAID is
not enteric coated. In another embodiment, at least a
therapeutically effective portion of the NSAID is not enteric
coated. In another embodiment, at least about 5%, about 15%, about
20%, about 30%, about 40%, about 50% or about 60% of the NSAID is
not enteric coated. In another embodiment, a portion of the NSAID
comprises a "thin enteric coat" as is defined above.
[0094] The term "pain" includes all types of pain, including, but
not limited to, chronic pain, such as arthritis pain (e.g. pain
associated with osteoarthritis and rheumatoid arthritis),
neuropathic pain, post-operative pain, chronic lower back pain,
cluster headaches, herpes neuralgia, phantom limb pain, central
pain, dental pain, opioid-resistant pain, visceral pain, surgical
pain, bone injury pain, pain during labor and delivery, pain
resulting from burns, including sunburn, post partum pain,
migraine, angina pain, and genitourinary tract-related pain
including cystitis, the term also refers to nociceptive pain or
nociception.
[0095] In other embodiments, the aspirin is present in a
composition of the invention in an amount of about 50 mg to about
400 mg, about 60 mg to about 375 mg, about 70 mg to about 350 mg,
about 80 mg to about 325 mg, about 90 to about 300 mg, or about 100
mg about 275 mg.
Pharmaceutical Excipients
[0096] Various embodiments can, if desired, include one or more
pharmaceutically acceptable excipients. The term "excipient" herein
means any substance, not itself a therapeutic agent, used as a
carrier or vehicle for delivery of a therapeutic agent to a subject
or added to a pharmaceutical composition to improve its handling or
storage properties or to permit or facilitate formation of a dose
unit of the composition. Excipients include, by way of illustration
and not limitation, diluents, disintegrants, binding agents,
adhesives, wetting agents, lubricants, glidants, surface modifying
agents, substances added to mask or counteract a disagreeable taste
or odor, flavors, dyes, fragrances, and substances added to improve
appearance of the composition. Any such excipients can be used in
any dosage forms according to the present disclosure, including
liquid, solid or semi-solid dosage forms.
[0097] Excipients optionally employed in various embodiments can be
solids, semi-solids, liquids or combinations thereof. Compositions
of the disclosure including excipients can be prepared by various
pharmaceutical techniques such as admixing an excipient with a drug
or therapeutic agent.
[0098] In various embodiments, compositions optionally comprise one
or more pharmaceutically acceptable diluents as excipients.
Suitable diluents illustratively include, without limitation,
either individually or in combination, lactose, including anhydrous
lactose and lactose monohydrate; starches, including directly
compressible starch and hydrolyzed starches (e.g., Celutab.TM. and
Emdex.TM.); mannitol; sorbitol; xylitol; dextrose (e.g.,
Cerelose.TM. 2000) and dextrose monohydrate; dibasic calcium
phosphate dihydrate; sucrose-based diluents; confectioner's sugar;
monobasic calcium sulfate monohydrate; calcium sulfate dihydrate;
granular calcium lactate trihydrate; dextrates; inositol;
hydrolyzed cereal solids; amylose; celluloses including
microcrystalline cellulose, food grade sources of a- and amorphous
cellulose (e.g., Rexcel.TM.) and powdered cellulose; calcium
carbonate; glycine; bentonite; polyvinylpyrrolidone; and the like.
Such diluents, if present, may constitute in total about 5% to
about 99%, about 10% to about 85%, or about 20% to about 80%, of
the total weight of the composition. In various embodiments, the
diluent or diluents selected may exhibit suitable flow properties
and, where tablets are desired, compressibility.
[0099] The use of extragranular microcrystalline cellulose (that
is, microcrystalline cellulose added to a wet granulated
composition after a drying step) can be used to alter or control
hardness (for tablets) and/or disintegration time.
[0100] In various embodiments, compositions optionally comprise one
or more pharmaceutically acceptable disintegrants as excipients,
such as in tablet formulations. Suitable disintegrants include,
without limitation, either individually or in combination,
starches, including crosslinked polyvinylpyrrolidone (crospovidone
USP/NF), carboxymethyl cellulose (sodium CMC), chitin, chitosan,
sodium starch glycolate (e.g., Explotab.TM. of PenWest) and
pregelatinized corn starches (e.g., National.TM. 1551, National.TM.
1550, and Colocorn.TM. 1500), clays (e.g., Veegum.TM. HV),
celluloses such as purified cellulose, microcrystalline cellulose,
methylcellulose, carboxymethylcellulose and sodium
carboxymethylcellulose, croscarmellose sodium (e.g., Ac-Di-Sol.TM.
of FMC), alginates, and gums such as agar, guar, xanthan, locust
bean, karaya, pectin and tragacanth gums.
[0101] Disintegrants may be added at any suitable step during the
preparation of the composition, particularly prior to a granulation
step or during a lubrication step prior to compression. Such
disintegrants, if present, may constitute in total about 0.2% to
about 30%, about 0.2% to about 10%, or about 0.2% to about 5%, of
the total weight of the composition.
[0102] In one embodiment, crosslinked polyvinylpyrrolidone
(crospovidone USP/NF) is an optional disintegrant for tablet or
capsule disintegration, and, if present, may optionally constitute
about 1% to about 5% of the total weight of the composition.
[0103] In another embodiment, chitin is an optional disintegrant
for tablet or capsule disintegration.
[0104] In still another embodiment, chitosan is an optional
disintegrant for tablet or capsule disintegration.
[0105] In still another embodiment, carboxymethyl cellulose (sodium
CMC) is an optional disintegrant for tablet or capsule
disintegration.
[0106] In another embodiment, croscarmellose sodium is a
disintegrant for tablet or capsule disintegration, and, if present,
may optionally constitute about 0.2% to about 10%, about 0.2% to
about 7%, or about 0.2% to about 5%, of the total weight of the
composition.
[0107] Various embodiments described herein optionally comprise one
or more pharmaceutically acceptable binding agents or adhesives as
excipients, particularly for tablet formulations. Such binding
agents and adhesives may impart sufficient cohesion to the powder
being tableted to allow for normal processing operations such as
sizing, lubrication, compression and packaging, but still allow the
tablet to disintegrate and the composition to be absorbed upon
ingestion. Suitable binding agents and adhesives include, without
limitation, either individually or in combination, acacia;
tragacanth; sucrose; gelatin; glucose; starches such as, but not
limited to, pregelatinized starches (e.g., National.TM. 1511 and
National.TM. 1500); celluloses such as, but not limited to,
methylcellulose and carmellose sodium (e.g., Tylose.TM.); alginic
acid and salts of alginic acid; magnesium aluminum silicate; PEG;
guar gum; polysaccharide acids; bentonites; povidone, for example
povidone K-15, K-30 and K-29/32; polymethacrylates; HPMC;
hydroxypropylcellulose (e.g.,Klucel.TM.); and ethylcellulose (e.g.,
Ethocel.TM.). Such binding agents and/or adhesives, if present, may
constitute in total about 0.5% to about 25%, about 0.75% to about
15%, or about 1% to about 10%, of the total weight of the
composition.
[0108] Compositions described herein optionally comprise one or
more pharmaceutically acceptable wetting agents as excipients.
Non-limiting examples of surfactants that can be used as wetting
agents in various compositions include quaternary ammonium
compounds, for example benzalkonium chloride, benzethonium chloride
and cetylpyridinium chloride, dioctyl sodium sulfosuccinate,
polyoxyethylene alkylphenyl ethers, for example nonoxynol 9,
nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and
polyoxypropylene block copolymers), polyoxyethylene fatty acid
glycerides and oils, for example polyoxyethylene (8)
caprylic/capric mono- and diglycerides (e.g., Labrasol.TM. of
Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene
(40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for
example polyoxyethylene (20) cetostearyl ether, polyoxyethylene
fatty acid esters, for example polyoxyethylene (40) stearate,
polyoxyethylene sorbitan esters, for example polysorbate 20 and
polysorbate 80 (e.g., Tween.TM. 80 of ICI), propylene glycol fatty
acid esters, for example propylene glycol laurate (e.g.,
Lauroglycol.TM. of Gattefosse), sodium lauryl sulfate, fatty acids
and salts thereof, for example oleic acid, sodium oleate and
triethanolamine oleate, glyceryl fatty acid esters, for example
glyceryl monostearate, sorbitan esters, for example sorbitan
monolaurate, sorbitan monooleate, sorbitan monopalmitate and
sorbitan monostearate, tyloxapol, and mixtures thereof. Such
wetting agents, if present, may constitute in total about 0.25% to
about 15%, about 0.4% to about 10%, or about 0.5% to about 5%, of
the total weight of the composition.
[0109] Compositions described herein optionally comprise one or
more pharmaceutically acceptable lubricants (including
anti-adherents and/or glidants) as excipients. Suitable lubricants
include, without limitation, either individually or in combination,
glyceryl behapate (e.g., Compritol.TM. 888); stearic acid and salts
thereof, including magnesium (magnesium stearate), calcium and
sodium stearates; hydrogenated vegetable oils (e.g., Sterotex.TM.);
colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium
acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g.,
Carbowax.TM. 4000 and Carbowax.TM. 6000); sodium oleate; sodium
lauryl sulfate; and magnesium lauryl sulfate. Such lubricants, if
present, may constitute in total about 0.1% to about 10%, about
0.2% to about 8%, or about 0.25% to about 5%, of the total weight
of the composition.
[0110] Suitable anti-adherents include, without limitation, talc,
cornstarch, DL-leucine, sodium lauryl sulfate and metallic
stearates. Talc is a anti-adherent or glidant used, for example, to
reduce formulation sticking to equipment surfaces and also to
reduce static in the blend. Talc, if present, may constitute about
0.1% to about 10%, about 0.25% to about 5%, or about 0.5% to about
2%, of the total weight of the composition.
[0111] Glidants can be used to promote powder flow of a solid
formulation. Suitable glidants include, without limitation,
colloidal silicon dioxide, starch, talc, tribasic calcium
phosphate, powdered cellulose and magnesium trisilicate.
[0112] Compositions described herein can comprise one or more
flavoring agents, sweetening agents, and/or colorants. Flavoring
agents useful in the present embodiments include, without
limitation, acacia syrup, alitame, anise, apple, aspartame, banana,
Bavarian cream, berry, black currant, butter, butter pecan,
butterscotch, calcium citrate, camphor, caramel, cherry, cherry
cream, chocolate, cinnamon, citrus, citrus punch, citrus cream,
cocoa, coffee, 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, MagnaSweet.RTM., maltol,
mannitol, maple, menthol, mint, mint cream, mixed berry, nut,
orange, peanut butter, pear, peppermint, peppermint cream,
Prosweet.RTM. Powder, raspberry, root beer, rum, saccharin,
safrole, sorbitol, spearmint, spearmint cream, strawberry,
strawberry cream, stevia, sucralose, sucrose, Swiss cream,
tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut,
watermelon, wild cherry, wintergreen, xylitol, and combinations
thereof, for example, anise-menthol, cherry-anise, cinnamon-orange,
cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime,
lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint,
etc.
[0113] Sweetening agents that can be used in the present
embodiments include, by way of example and not limitation,
acesulfame potassium (acesulfame K), alitame, aspartame, cyclamate,
cylamate, dextrose, isomalt, MagnaSweet.RTM., maltitol, mannitol,
neohesperidine DC, neotame, Prosweet0 Powder, saccharin, sorbitol,
stevia, sucralose, sucrose, tagatose, thaumatin, xylitol, and the
like.
[0114] The foregoing excipients can have multiple roles. For
example, starch can serve as a filler as well as a disintegrant.
The classification of excipients listed herein is not to be
construed as limiting in any manner.
Pharmaceutical Dosage Forms
[0115] In various embodiments, compositions can be formulated as
oral solid, liquid, or semi-solid dosage forms. In one embodiment,
such compositions are in the form of discrete dose units or dosage
units (e.g., tablet, capsule). The terms "dose unit" and/or "dosage
unit" herein refer to a portion of a pharmaceutical composition
that contains an amount of a therapeutic agent suitable for a
single administration to provide a therapeutic effect. Such dosage
units may be administered one to a small plurality (i.e. 1 to about
4) of times per day, or as many times as needed to elicit a
therapeutic response. A particular dosage form can be selected to
accommodate any desired frequency of administration to achieve a
specified daily dose. Typically one dose unit, or a small plurality
(i.e. up to about 4) of dose units, provides a sufficient amount of
the active drug (e.g. at least one PPI) to result in the desired
response or effect.
[0116] Alternatively, compositions of the disclosure can also be
formulated for rectal, topical, or parenteral (e.g. subcutaneous,
intramuscular, intravenous and intradermal or infusion)
delivery.
[0117] In one embodiment, compositions of the disclosure are
suitable for rapid onset of therapeutic effect, particularly with
respect to the PPI components. In another embodiment, upon oral
administration of a composition to a subject, at least a
therapeutically effective amount of the PPIs is available for
absorption by the subject. As discussed above, most commercially
available PPIs require enteric coating to prevent exposure of the
PPI to gastrointestinal fluids (and consequent drug degradation) by
way of pH dependent coatings. Such coating, in turn, prevents rapid
PPI absorption and therapeutic onset of action. Compositions of the
present disclosure, by contrast, do not require enteric coating to
maintain drug stability in gastrointestinal fluids and thereby
provide for rapid absorption and onset of therapeutic effect. In
fact, in one embodiment, a composition comprises at least a
therapeutically effective amount of at least one PPI that is not
enteric coated. However, other embodiments are compositions which
optionally include at least part of one proton pump inhibitor that
is enteric coated.
[0118] In another embodiment, a single dosage unit, be it solid or
liquid, comprises a therapeutically and/or prophylactically
effective amount of PPIs. The term "therapeutically effective
amount" or "therapeutically and/or prophylactically effective
amount" as used herein refers to an amount of compound or agent
that is sufficient to elicit the required or desired therapeutic
and/or prophylactic response, as the particular treatment context
may require.
[0119] It will be understood that a therapeutically and/or
prophylactically effective amount of a drug for a subject is
dependent, inter alia, on the body weight of the subject. A
"subject" herein to which a therapeutic agent or composition
thereof can be administered includes a human subject of either sex
and of any age, and also includes any nonhuman animal, particularly
a domestic or companion animal, illustratively a cat, dog or a
horse.
Solid Dosage Forms
[0120] In various embodiments, compositions of the disclosure are
in the form of solid dosage forms or units. Non-limiting examples
of suitable solid dosage forms include tablets (e.g. suspension
tablets, bite suspension tablets, rapid dispersion tablets,
chewable tablets, effervescent tablets, bilayer tablets, etc),
caplets, capsules (e.g. a soft or a hard gelatin capsule), powder
(e.g. a packaged powder, a dispensable powder or an effervescent
powder), lozenges, sachets, cachets, troches, pellets, granules,
microgranules, encapsulated microgranules, powder aerosol
formulations, or any other solid dosage form reasonably adapted for
oral administration.
[0121] Tablets are an illustrative dosage form for compositions of
the disclosure. Tablets can be prepared according to any technique
used in the pharmaceutical industry. In one embodiment, tablets or
other solid dosage forms can be prepared by processes that employ
one or a combination of methods including, without limitation, (1)
dry mixing, (2) direct compression, (3) milling, (4) dry or
non-aqueous granulation, (5) wet granulation, or (6) fusion.
[0122] The individual steps in the wet granulation process of
tablet preparation typically include milling and sieving of the
ingredients, dry powder mixing, wet massing, granulation and final
grinding. Dry granulation involves compressing a powder mixture
into a rough tablet or "slug" on a heavy-duty rotary tablet press.
The slugs are then broken up into granular particles by a grinding
operation, usually by passage through an oscillation granulator.
The individual steps include mixing of the powders, compressing
(slugging) and grinding (slug reduction or granulation). Typically,
no wet binder or moisture is involved in any of the steps.
[0123] In another embodiment, solid dosage forms such as tablets
can be prepared by mixing PPI1 and PPI2 with at least one buffering
agent as described herein above and, if desired, with one or more
optional pharmaceutical excipient to form a substantially
homogeneous preformulation blend. The preformulation blend can then
be subdivided and optionally further processed (e.g. compressed,
encapsulated, packaged, dispersed, etc.) into any desired dosage
forms.
[0124] Compressed tablets can be prepared by compacting a powder or
granulation composition of the disclosure. The term "compressed
tablet" generally refers to a plain, uncoated tablet suitable for
oral ingestion, prepared by a single compression or by
pre-compaction tapping followed by a final compression. Tablets of
the present disclosure may be coated or otherwise compounded to
provide a dosage form affording the advantage of improved handling
or storage characteristics. In one embodiment, such coating will be
selected so as to not substantially delay onset of therapeutic
effect of a composition upon administration to a subject. The term
"suspension tablet" as used herein refers to a compressed tablet
that rapidly disintegrates after placement in water.
[0125] In one embodiment, a composition comprises a multi-layer
tablet having a core comprising two proton pump inhibitors; the
core is substantially or completely surrounded by the buffering
agent. The buffering agent layer can optionally be coated with one
or more coating materials. In one embodiment, the optional coating
is optionally an enteric coating. In a related embodiment, the
buffering agent layer completely surrounds the core. In another
embodiment, the buffering agent layer partially surrounds the core.
In yet another embodiment, the buffering agent layer is in contact
with a portion of or with all of the surface area of the core.
[0126] In another embodiment, a composition comprises a multi-layer
tablet having a core comprising the first proton pump inhibitor.
The core is substantially or completely surrounded by a second
layer comprising a buffering agent. A third layer comprising the
subsequent proton pump inhibitor substantially or completely
surrounds the second layer comprising the buffering agent. The
third layer is substantially or completely surrounded by a fourth
layer comprising the same or different buffering agent. The fourth
layer can optionally be coated with one or more coating materials.
The successive layering of additional proton pump inhibitors and
buffering agents can be continued for any number of iterations with
the same or different proton pump inhibitors and buffering agents.
In one embodiment, the optional coating is optionally an enteric
coating. In a related embodiment, the second layer comprising
buffering agent completely surrounds the core. In another
embodiment, the second layer comprising buffering agent partially
surrounds the core. In yet another embodiment, the second layer
comprising buffering agent is in contact with a portion of or with
all of the surface area of the core. In a related embodiment, the
fourth layer comprising buffering agent completely surrounds the
third layer comprising the subsequent proton pump inhibitor. In
another embodiment, the fourth layer comprising buffering agent
partially surrounds the third layer comprising the subsequent
proton pump inhibitor. In yet another embodiment, the fourth layer
comprising buffering agent is in contact with a portion of or with
all of the third layer comprising the subsequent proton pump
inhibitor.
[0127] In another embodiment, a composition comprises a multi-layer
tablet having a core comprising either omeprazole or lansoprazole.
The core is substantially or completely surrounded by a second
layer comprising a buffering agent. A third layer comprising
another form of PPI substantially or completely surrounds the
second layer comprising the buffering agent. The third layer is
substantially or completely surrounded by a fourth layer comprising
the same or different buffering agent. The fourth layer can
optionally be coated with one or more coating materials. The
successive layering of additional forms proton pump inhibitors and
buffering agents can be continued for any number of iterations with
the same or different proton pump inhibitors and buffering agents.
In one embodiment, the optional coating is optionally an enteric
coating. In a related embodiment, the second layer comprising
buffering agent completely surrounds the core. In another
embodiment, the second layer comprising buffering agent partially
surrounds the core. In yet another embodiment, the second layer
comprising buffering agent is in contact with a portion of or with
all of the surface area of the core. In a related embodiment, the
fourth layer comprising buffering agent completely surrounds the
third layer comprising the subsequent proton pump inhibitor. In
another embodiment, the fourth layer comprising buffering agent
partially surrounds the third layer comprising the subsequent
proton pump inhibitor. In yet another embodiment, the fourth layer
comprising buffering agent is in contact with a portion of or with
all of the third layer comprising the subsequent proton pump
inhibitor.
[0128] In still another embodiment, one or more intermediate layers
exists in between the core and the buffering agent. The
intermediate layers can comprise any pharmaceutically acceptable
material, particularly inert and non-pH sensitive coating materials
such as polymer based coatings.
[0129] In yet another embodiment, a composition comprises a
multi-layer tablet having a core comprising a first PPI; the core
is substantially or completely surrounded by the subsequent PPI and
the buffering agent. Optionally, an intermediate layer can exist
between the first PPI core and the subsequent PPI/buffering agent
surrounding the core. In one embodiment, the optional intermediate
layer is a coating layer. In another embodiment, the coating layer
is optionally an enteric coating.
[0130] In another embodiment, a composition comprises a multi-layer
tablet having a core comprising either omeprazole or lansoprazole;
the core is substantially or completely surrounded by another form
of PPI and the buffering agent. Optionally, an intermediate layer
can exist between the omeprazole or lansoprazole core and the other
PPI/buffering agent surrounding the core. In one embodiment, the
optional intermediate layer is a coating layer. In another
embodiment, the coating layer is optionally an enteric coating.
[0131] In one such embodiment, the buffering agent/PPI layer
completely surrounds the core. In another embodiment, the buffering
agent/PPI layer partially surrounds the core. In yet another
embodiment, the buffering agent/PPI layer is in contact with a
portion of or with all of the surface area of the core.
[0132] In another embodiment, compositions can be microencapsulated
wherein the first PPI, subsequent PPI, and one or more buffering
agents are microencapsulated together, for example as modified from
the description in U.S. Patent Publication No. 2005/0037070, hereby
incorporated by reference herein in its entirety.
[0133] In still another embodiment, compositions can be
microencapsulated wherein the omeprazole, lansoprazole, and one or
more buffering agents are microencapsulated together, for example
as modified from the description in U.S. Patent Publication No.
2005/0037070, hereby incorporated by reference herein in its
entirety.
[0134] In another embodiment, a composition comprises a first
proton pump inhibitor, one or more additional proton pump
inhibitors, and one or more buffering agents mixed together in
powder form and optionally filled into a capsule, for example a
hard or soft gelatin or HPMC capsule.
[0135] In another embodiment, a composition of the invention is in
the form of a molded article, for example a pellet. The term
"molded article" herein refers to a discrete dosage form that can
be formed by compression, extrusion, or other similar processes. In
one embodiment, the molded article is moldable. The term "moldable"
in the present context means capable of being shaped or molded by
hand. A moldable article herein will therefore have a hardness
lower than a conventional pharmaceutical tablet. Such a moldable
article will also be capable of being chewed by an animal, for
example a horse.
[0136] Such an article can comprise, in addition to the PPI and
buffering agent, and other excipients described herein, a filler, a
sweetener and a flavoring agent. Extrusion is a process of shaping
material by forcing it to flow through a shaped opening in a die or
other solid. Extruded material emerges as an elongated article with
substantially the same profile as the die opening.
[0137] In yet another embodiment, a composition comprises
omeprasole, lansoprasole, and one or more buffering agents mixed
together in powder form and optionally filled into a capsule, for
example a hard or soft gelatin or HPMC capsule.
Liquid Dosage Forms
[0138] In another embodiment, compositions described herein can be
in the form of liquid dosage forms or units. Non-limiting examples
of suitable liquid dosage forms include solutions, suspension,
elixirs, syrups, liquid aerosol formulations, etc.
[0139] In one embodiment, a liquid composition comprising water or
other solvent, first PPI, one or more additional PPIs and a
buffering agent can be prepared. In another embodiment,
compositions described herein are in the form of a powder for
suspension that can be suspended in a liquid vehicle prior to
administration to a subject. While the powder for suspension
itself, can be a solid dosage form of the present disclosure, the
powder dispersed in liquid also comprises a liquid embodiment of
the disclosure.
[0140] In another embodiment, a liquid composition comprising water
or other solvent, omeprazole, lansoprazole and one or more
buffering agents can be prepared. In another embodiment,
compositions described herein are in the form of a powder for
suspension that can be suspended in a liquid vehicle prior to
administration to a subject. While the powder for suspension
itself, can be a solid dosage form of the present disclosure, the
powder dispersed in liquid also comprises a liquid embodiment of
the disclosure.
[0141] Suspension compositions comprise a first PPI, one or more
additional PPIs, one or more buffering agents, a liquid media (e.g.
water, de-ionized water, etc.), and one or more optional
pharmaceutical excipients. Such compositions, upon storage in a
closed container maintained at either room temperature,
refrigerated (e.g. about 5-10.degree. C.) temperature, or freezing
temperature for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12 months, exhibit about 90%, about 92.5%, about 95%, or
about 97.5% of the original first PPI and/or the one or more
additional PPIs present therein.
[0142] Other suspension compositions comprise omeprazole,
lansoprazole, one or more buffering agents, a liquid media (e.g.
water, de-ionized water, etc.), and one or more optional
pharmaceutical excipients. Such compositions, upon storage in a
closed container maintained at either room temperature,
refrigerated (e.g. about 5-10.degree. C.) temperature, or freezing
temperature for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12 months, exhibit about 90%, about 92.5%, about 95%, or
about 97.5% of the original omeprazole and/or the lansoprazole
present therein.
Storage Stability
[0143] In one embodiment, compositions are in the form of a powder
for suspension that is ultimately to be suspended in a liquid
vehicle prior to administration to a subject. Liquid compositions
comprising an acid labile PPI suspended in a liquid vehicle,
without more, would typically exhibit relatively short periods of
stability, even when maintained under refrigerated conditions. This
is particularly inconvenient in the hospital setting as fresh
batches of suspension are continually required. Suspension
compositions of the disclosure are believed to exhibit improved
storage stability.
[0144] Illustrative suspension compositions comprise a first PPI,
one or more additional PPIs, at least one buffering agent, water,
and one or more optional pharmaceutical excipients. Such
compositions, upon storage in a closed container maintained at room
temperature, refrigerated (e.g. about 5 to about 5-10.degree. C.)
temperature, or frozen for a period of about 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, or 12 months, may exhibit about 90%, about 92.5%,
about 95%, or about 97.5% of the original first PPI and/or
subsequent PPI present therein.
Administration and Bioavailability
[0145] In one embodiment, compositions of the disclosure are
suitable for rapid onset of therapeutic effect, particularly with
respect to the PPI components. In another embodiment, upon oral
administration of a composition to a subject, at least a
therapeutically effective amount of at least one PPI is available
for absorption and metabolism by the subject. The phrase "available
for absorption" in reference to an active ingredient such as a PPI
means that the ingredient remains intact and in active form in the
stomach for a sufficient amount of time to allow for absorption
into the blood. As discussed above, most commercially available
PPIs require enteric coating to prevent exposure of the PPI to
gastrointestinal fluids (and consequent drug degradation) by way of
pH dependent coatings. Such coating, in turn, prevents rapid PPI
absorption and therapeutic onset of action. Compositions of the
present disclosure, by contrast, do not require but can optionally
include an enteric coating to maintain drug stability in
gastrointestinal fluids and thereby provide for rapid absorption
and onset of therapeutic effect. In fact, in one embodiment, a
composition comprises at least a therapeutically effective amount
of at least one PPI that is not enteric coated. Another embodiment
provides for compositions having at least one PPI which is
optionally enteric coated.
[0146] In another embodiment, upon oral administration of a
composition described herein to a plurality of fasted adult human
subjects, the subjects exhibit an average T.sub.max of active
ingredient, (e.g. at least one PPI) within about 30 seconds to
about 90 minutes, within about 1 minute to about 80 minutes, within
about 5 minutes to about 60 minutes, within about 10 minutes to
about 50 minutes, or within about 15 minutes to about 45
minutes.
[0147] In still another embodiment, upon administration of a
composition described herein to a plurality of fasted adult human
subjects, the subjects exhibit an average plasma concentration of
at least one PPI of about 0.1 .mu.g/ml, about 0.15 .mu.g/ml, about
0.2 .mu.g/ml, about 0.3 .mu.g/ml, about 0.4 .mu.g/ml, about 0.5
.mu.g/ml, about 0.6 .mu.g/ml, about 0.7 .mu.g/ml, about 0.8
.mu.g/ml, about 0.9 .mu.g/ml, about 1 .mu.g/ml, about 1.5 .mu.g/ml,
or about 2.0 .mu.g/ml at any time within about 90 minutes, within
about 75 minutes, within about 60 minutes, within about 55 minutes,
within about 50 minutes, within about 45 minutes, within about 40
minutes, within about 35 minutes, within about 30 minutes, within
about 25 minutes, within about 20 minutes, within about 17 minutes,
within about 15 minutes, within about 12 minutes, or within about
10 minutes after administration.
[0148] In yet another embodiment, upon administration of a
composition described herein to a plurality of fasted adult human
subjects, the subjects exhibit a plasma concentration of active
ingredient (e.g. at least one PPI) of about 0.1 .mu.g/ml, about
0.15 .mu.g/ml, about 0.2 .mu.g/ml, about 0.3 .mu.g/nil, about 0.4
.mu.g/ml, about 0.5 .mu.g/ml, about 0.6 .mu.g/ml, about 0.7
.mu.g/ml, about 0.8 .mu.g/ml, about 0.9 .mu.g/ml, about 1.0
.mu.g/ml, about 1.5 .mu.g/ml or about 2.0 .mu.g/ml, maintained from
about 15 minutes to about 60 minutes after administration, about 15
minutes after administration to about 90 minutes after
administration, about 15 minutes to about 120 minutes after
administration, or about 15 minutes to about 180 minutes after
administration.
[0149] In another embodiment, upon administration of a composition
described herein to a plurality of fasted adult human subjects, the
subjects exhibit at least one of: a mean C.sub.max of PPI1 and/or
PPI2 of about 500 .mu.g/ml to about 2000 .mu.g/ml, about 600
.mu.g/ml to about 1900 .mu.g/ml, or about 700 ng/ml to about 1800
.mu.g/ml; a mean T.sub.max of PPI and/or PPI2 of about 0.15 to
about 2 hours, about 0.25 to about 1.75 hours, or about 0.3 hours
to about 1 hour; and/or a mean AUC.sub.(0-inf) of PPI and/or PPI2
of about 1000 to about 3000 .mu.ghr/ml, about 1500 to about 2700
.mu.ghr/ml, or about 1700 to about 2500 .mu.ghr/ml.
[0150] In another embodiment, upon administration of a composition
described herein to a plurality of fasted adult human subjects, the
subjects exhibit: a mean C.sub.max of PPI1 and/or PPI2 of about 500
.mu.g/ml to about 2000 .mu.g/ml, about 600 .mu.g/ml to about 1900
.mu.g/ml, or about 700 .mu.g/ml to about 1800 .mu.g/ml; a mean
T.sub.max of PPI1 and/or PPI2 of about 0.15 to about 2 hours, about
0.25 to about 1.75 hours, or about 0.3 hours to about 1 hour; and a
mean AUC.sub.(0-inf) of PPI1 and/or PPI2 of about 1000 to about
3000 .mu.ghr/ml, about 1500 to about 2700 .mu.ghr/ml, or about 1700
to about 2500 .mu.ghr/ml.
Parietal Cell Activators
[0151] In one embodiment, a composition of the present disclosure
can further include one or more parietal cell activators. Parietal
cell activators such as chocolate, calcium and sodium bicarbonate
and other alkaline substances stimulate the parietal cells and
enhance the pharmacologic activity of the PPI administered. For the
purposes of this application, "parietal cell activator" or
"activator" shall mean any compound or mixture of compounds
possessing such stimulatory effect including, but not limited to,
chocolate, sodium bicarbonate, calcium (for example, calcium
carbonate, calcium bicarbonate, calcium gluconate, calcium
hydroxide, calcium acetate and calcium glycerophosphate, calcium
formate), peppermint oil, spearmint oil, coffee, tea and colas
(even if decaffeinated), caffeine, theophylline, theobromine, and
amino acids (particularly aromatic amino acids such as
phenylalanine and tryptophan) and combinations thereof.
[0152] Parietal cell activators, if desired, are typically present
in a composition of the disclosure in an amount sufficient to
produce the desired stimulatory effect without causing untoward
side effects to subjects. For example, chocolate, such as raw
cocoa, is administered in an amount of about 5 mg to 2.5 g per 20
mg dose of omeprazole (or comparable pharmacologic dose of another
proton pump inhibiting agent). The dose of activator administered
to a subject, for example, a human, in the context of the present
disclosure should be sufficient to result in enhanced effect of a
PPI over a desired time frame.
[0153] Illustratively, the approximate effective ranges for various
parietal cell activators per 20 mg dose of omeprazole (or
comparable dose of other PPI) include, Chocolate (raw cocoa)--about
5 mg to about 2.5 g; Sodium bicarbonate--about 7 mEq to about 25
mEq; Calcium carbonate--about 1 mg to about 1.5 g; Calcium
gluconate--about 1 mg to about 1.5 g; Calcium lactate--about 1 mg
to about 1.5 g; Calcium hydroxide--about 1 mg to about 1.5 g;
Calcium acetate--about 0.5 mg to about 1.5 g; Calcium
glycerophosphate--about 0.5 mg to about 1.5 g; Peppermint
oil--(powdered form) about 1 mg to about 1 g; Spearmint
oil--(powdered form) about 1 mg to about 1 g; Coffee--about 20 ml
to about 240 ml; Tea--about 20 ml to about 240 ml; Cola--about 20
ml to about 240 ml; Caffeine--about 0.5 mg to about 1.5 g;
Theophylline--about 0.5 mg to about 1.5 g; Theobromine--about 0.5
mg to about 1.5g; Phenylalanine--about 0.5 mg to about 1.5 g; and
Tryptophan--about 0.5 mg to about 1.5 g.
Gastrointestinal Disorders
[0154] In various embodiments, the present disclosure provides for
therapy of various diseases and disorders. Such diseases and
disorders include, inter alia, gastrointestinal disorders and, in
particular, acid related gastrointestinal disorders. The phrase
"acid related gastrointestinal disorder" or "acid related
gastrointestinal disease" refers generally to a disease or disorder
that occurs due to an imbalance between acid and pepsin production
on the one hand, so-called aggressive factors, and mucous,
bicarbonate, and prostaglandin production on the other hand,
so-called defensive factors.
[0155] The term "therapy" as used herein refers to treatment and/or
prevention of a disorder or disease, such as a gastrointestinal
disorder.
[0156] The term "treat" or "treatment" as used herein refers to any
treatment of a disorder or disease, and includes, but is not
limited to, preventing the disorder or disease from occurring in a
subject that 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, for example, arresting the
development of the disorder or disease; relieving the disorder or
disease, for example, causing regression of the disorder or
disease; or relieving the condition caused by the disease or
disorder, for example, stopping the symptoms of the disease or
disorder.
[0157] The term "prevent" or "prevention," in relation to a
disorder or disease, means preventing the onset of gastrointestinal
disorder or disease development if none had occurred, or preventing
further disorder or disease development if the disorder or disease
was already present.
[0158] Compositions of the present disclosure can be in the form of
an orally deliverable dosage unit. The terms "oral administration"
or "orally deliverable" herein include any form of delivery of a
therapeutic agent or a composition thereof to a subject wherein the
agent or composition is placed in the mouth of the subject, whether
or not the agent or composition is swallowed. Thus, "oral
administration" includes buccal and sublingual as well as
esophageal administration.
[0159] Chronic GERD can lead to Barrett's esophagus, dysplasia and
eventually adenocarcinoma. (Devesa S S, et al., "Changing patterns
in the incidence of esophageal and gastric carcinoma in the United
States", Cancer Vol. 83, pp. 2049-53 (1998)) (National Cancer
Institute's Surveillance, Epidemiology, and End Results program
with age-adjustment using the 2000 U.S. standard population.).
Indeed, "The incidence of adenocarcinoma of the esophagus is
continuing to rise rapidly in the United States and Western Europe.
We desperately need to detect these patients at an earlier stage
AND find effective ways of preventing this disease. Attacking the
progression of this disease in its earliest stage will be key to
preventing the reflux-induced adenocarcinoma." Tom DeMeester and
Parakrama Chandrasoma, "GERD; Reflux to Esophageal Adenocarcinoma",
Academic Press (2006).
[0160] Sampliner has reported that extended treatment (years) with
powerful PPI drugs, omeprazole and lansoprazole, given twice per
day or more, only reversed Barrett's esophagus in 3 of 123 patients
with Barrett's esophagus, with or without surgery. Sampliner, R.,
"Reduction of Acid Exposure and Regression of Barrett's Esophagus",
Digestive Diseases, Vol. 18(4), pp. 203-207, (2000-2001).
[0161] Fackler, W., et al. investigated the therapeutic efficacy of
the addition of a histamine 2 receptor antagonists ("H2RAs") to a
PPI to block nocturnal acid breakthrough ("NAB") in 23 healthy
volunteers and 20 GERD patients. Fackler, W., et al., Long-term
Effect of H.sub.2RA Therapy on Nocturnal Gastric Acid Breakthough",
Gastroenterology, Vol. 122(3), pp. 625-632(2002). All subjects then
received 28 days of PPI (omeprazole 20 mg) plus H2RA (ranitidine
300 mg) nightly ("QHS") and monitored with an ambulatory pH
monitor. The results of the study found that the combination of
H2RA and PPI therapy reduced NAB only at the introduction of
therapy. Due to H2RA tolerance, there was no difference in acid
suppression between PPI twice daily and PPI twice daily+H2RA after
one week of combination therapy.
[0162] Spechler S J, et al. evaluated the effect of three times per
day ("TID") dosing of esomeprazole on esophageal acidity in
patients with Barrett's esopagus. It was found that despite the
significant decrease in gastric acidity by high dose esomeprazole
treatment, abnormal esophageal acid exposure continued in 16% to
23% of patients. Spechler, S., et al., "Gastric and Esophageal pH
in Patients With Barrett's Esophagus Treated With Three
Esomeprazole Dosages: A Randomized, Double-Blind, Crossover Trial",
Am J Gastroenterol., Vol. 101, pp. 1964-1971 (2006). It is
important to note that compliance with TID regimens is
significantly lower than once daily regimens. Further, compliance
continues to be reduced over time such that compliance at 14 days
is higher than that at 30 or 60 days. To complicate this further it
is recommended that the delayed release PPI medications he taken
1/2 hour prior to a meal to achieve optimal acid inhibition. Prior
research has demonstrated that only 10% of patients comply with
this recommendation. These studies illustrate that there is a need
for a once daily treatment that can inhibit the esophageal acid
sufficiently in patients with Barrett's esophagus such that a
reversal of the Barrett's columnar esophagus can be achieved.
[0163] Compositions of the present disclosure can be employed to
stop progression and encourage reversal of reflux-related
esophageal metaplasia with low or high grade dysplasia.
Compositions of the present disclosure can also be used to stop
progression and encourage reversal of reflux related adenocarcinoma
of the esophagus or acid-related adenocarcinoma of the stomach. In
addition, compositions of the present disclosure can be used in the
treatment of patients undergoing ablation in Barrett's esophagus to
prevent recurrence. Compositions of the disclosure can further be
used for treating a patient, including patients with or without
gastroparesis (slow stomach emptying) and severe erosive
esophagitis (Los Angeles classification grade C & D).
[0164] Non-steroidal anti-inflammatory Drugs (NSAIDs) are commonly
used for their antiinflammatory, analgesic, and/or antipyretic
effects. However, NSAIDs are known to have the potential to cause
gastrointestinal (GI) bleeding and/or ulceration through a variety
of mechanisms related to their topical and systemic effects. Once
ulcerated, gastric acid in the stomach can cause painful irritation
and upset stomach. Such GI bleeding and ulceration may depend on
the length of the treatment as well as on the particular drug used.
As a result, many subjects taking NSAIDs, particularly those
subjects on chronic NSAID therapy, are at high risk of developing
gastric ulcers.
[0165] Besides NSAID use, overproduction of gastric acid can also
lead to gastric ulceration and other GI diseases and disorders.
Moreover, overproduction of stomach acid can particularly irritate
subjects with NSAID-related gastric irritation or ulceration.
[0166] Various diseases and disorders, including gastric acid
related disorders such as, but not limited to, severe erosive
esophagitis (Los Angeles classification grade C & D), Barrett's
esophagus, reflux-related esophageal metaplasia with low or high
grade dysplasia, related adenocarcinoma of the esophagus or
acid-related adenocarcinoma of the stomach, duodenal ulcer, gastric
ulcer, gastric and duodenal erosions and ulcerations, acid
dyspepia, gastroesophageal reflux disease (GERD), poorly responsive
symptomatic GERD, acid reflux, esophageal ulcers and erosions,
precancerous and cancerous lesions of the esophagus induced by acid
exposure, radiation or chemotherapy-induced esophagitis, acid
hypersecretory conditions, gastrointestinal pathological
hypersecretory conditions (such as Zollinger Ellison Syndrome),
non-ulcer dyspepsia, H. pylori infection, extraesophageal or
atypical manifestations of gastroesophageal reflux disease (such as
but not limited to eye pain, asthma, bronchitis, pneumonia, chest
pain, cough, recurrent laryngitis, globus pharyngeus, sinusitis,
otalgia, otitis media, eustachian tube dysfunction, voice change,
globus sensation, throat clearing, halitosis, sore throat, aphthous
ulcers), nocturnal acid breakthrough (NAB), sleep apnea, sleep
disturbance, stopping of gastrointestinal bleeding and prevention
of rebleeding after gastrointestinal bleeding, pretreatment prior
to endoscopic evaluation of upper GI bleeding, stress ulcer
prevention, treatment of stress-related bleeding, seizure or
apparent seizure activity, Sandifer's syndrome, failure to thrive,
anorexia, anorexia nervosa, weight loss, apnea, and
bradycardia.
[0167] The foregoing lists of disorders or diseases are meant to be
illustrative and not exhaustive as a person of ordinary skill in
the art would recognize that there are many other disorders or
diseases to which the embodiments of the present disclosure could
treat and/or prevent.
[0168] In one embodiment, compositions provide a method for
treating and/or preventing a disorder or disease by administering a
pharmaceutical composition comprising a first proton pump
inhibitor, having a therapeutically effective portion which is
optionally enteric coated, a second proton pump inhibitor, having a
therapeutically effective portion which is optionally enteric
coated, and at least one buffering agent, such as sodium
bicarbonate.
[0169] In yet another embodiment, compositions provide a method for
treating and/or preventing a disorder or disease by administering a
pharmaceutical composition comprising omeprazole, having a
therapeutically effective portion which is optionally enteric
coated, lansoprazole, having a therapeutically effective portion
which is optionally enteric coated, and sodium bicarbonate.
[0170] In another embodiment, compositions provide a method for
treating and/or preventing a disorder or disease by administering a
pharmaceutical composition comprising about 20 mg, about 30 mg,
about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg,
about 90 mg, or about 100 mg omeprazole, having a therapeutically
effective portion which is optionally enteric coated.
[0171] In another embodiment, compositions provide a method for
treating and/or preventing a disorder or disease by administering a
pharmaceutical composition comprising about 20 mg, about 30 mg,
about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg,
about 90 mg, or about 100 mg omeprazole, having a therapeutically
effective portion which is optionally enteric coated, about 20 mg,
about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg,
about 80 mg, about 90 mg, or about 100 mg lansoprazole, having a
therapeutically effective portion which is optionally enteric
coated, and sodium bicarbonate in an amount of about 100 mg to
about 2500 mg sodium bicarbonate.
[0172] In another embodiment, either or both PPIs could be enteric
coated as tablets.
[0173] In various embodiments, the acid labile pharmaceutical
agents can be mixed together and then enteric-coated as
granules.
[0174] In still another embodiment, tenatoprazole can be enteric
coated as granules and the other one or more proton pump inhibitors
could be enteric coated as granules.
Integrated Gastric Acidity
[0175] Integrated gastric acidity (hereinafter "IGA") is a
sensitive measure of gastric acid inhibition. It is calculated as
the cumulative time-weighted average of the gastric acid
concentration. IGA is sensitive to the change from baseline for
gastric acidity, whereas mean or median gastric pH has low
sensitivity in detecting change (i.e., drug induced) from baseline.
IGA or intragastric acidity can be expressed as mmolh/L. For
example, the following values were found for IGA after a single
dose of PPI is administered (i.e., Day 1). See Sercombe W. J., et
al., "A placebo-controlled trial to assess the effects of 8 days of
dosing with raberprazole vs. omeprazole on 24-hour intragastric
acidity and gastrin concentration in young health male subjects",
Aliment Pharmacol. Ther., Vol. 12, pp. 1079-1089 (1998).
TABLE-US-00001 Rabeprazole 20 mg delayed Omeprazole Placebo release
20 mg delayed release IGA-24.sub.Day 1 997 mmol h/L 331 mmol h/L
640 mmol h/L
[0176] F.F.I. Rebecchi et al. investigated the prognostic value of
the area under the H.sup.+ curve (i.e., integrated acidity) in 36
healthy volunteers and 60 GERD patients. Based on a receiver
operating characteristic analysis, the authors found that an area
under the curve of hydrogen ion activity of above 100 mmol/Lmin was
very sensitive and specific (100% and 97%, respectively) for
identifying patients with erosive esophagitis, and also had a good
sensitivity and specificity (76% and 93%) for identifying patients
with non-erosive GERD. See F.F.I. Rebecchi et al., "Improving the
analysis of esophageal acid exposure by a new parameter: area under
H.sup.+", Am. J. Gastroenterol., Vol. 97, pp. 568-74 (2002); J. D.
Gardner et al., "Determination of the reduction in gastric acidity
necessary to prevent pathological oesophageal reflux in patients
with gastro-oesophageal reflux disease treated with a proton pump
inhibitor", Aliment. Pharmacol. Ther., Vol. 17, pp. 955-64 (2003);
J. D. Gardner at al., "Integrated acidity and rabeprazole
pharmacology", Aliment Pharmacol Ther., Vol. 16, pp. 455-64 (2002);
J. D. Gardner at al., "Integrated acidity and the pathophysiology
of GERD", Am J Gastroenterol., Vol. 96, pp. 1363-70 (2001).
[0177] The pharmacodynamic parameter that best demonstrates the
efficacy of an agent that works by inhibiting gastric acid is the
"24 hour Integrated Gastric Acidity" ("IGA-24"). The most important
measure of IGA is in the first 24 hours after the initial dose as
PPI medicines have routinely not demonstrated a significant effect
on inhibiting gastric acid secretion in the first 24 hours after an
initial dose. Therefore, the IGA-24 on Day 1 ("IGA-24.sub.Day 1")
is the most stringent measure of efficacy of PPI compositions. It
is important to note that many studies performed on PPI drugs
concomitantly administer pentagastrin to artificially stimulate the
parietal cell in order to induce or artificially create efficacy on
Day 1 of administration of the PPI. This creates an artificial
effect on Day 1 and is not correlative to normal patients.
[0178] The pharmacokinetic parameter that predicts the efficacy of
PPIs is area under the serum concentration vs. time curve, or area
under the curve (AUC). See Cederberg et al., "Effect of
omeprazole--a gastrin proton pump inhibitor--on pentagastrin
stimulated acid secretion in man", Gut, Vol. 24, pp. 270-76 (1983);
Cederberg et al., "Acid inhibitory characteristics of omeprazole in
man", Scand. J. Gastroenterol. Suppl., Vol. 20, pp. 105-12 (1985);
Cederberg et al., "Comparison of once-daily intravenous and oral
omeprazole on pentagastrin-stimulated acid secretion in duodenal
ulcer patients", Digestion, Vol. 53, pp. 171-78 (1985). Further,
AUC above 1 micromolar of PPI (for substituted benzimidazoles) is
an excellent predictor of efficacy. Further, the time that the AUC
is above 1 micromolar of PPI (for substituted benzimidazoles)
defines time that the PPI is significantly efficient at binding to
the proton pumps in the parietal cell secretory canalicular
membrane ("active proton pumps").
[0179] The pharmacokinetic equation for determining AUC is depicted
below:
AUC = ( f ) Dose .times. t 1 / 2 0.693 .times. V , ##EQU00001##
[0180] where f is bioavailability, t.sub.1/2 is the half-life of
the drug, and V is the volume of distribution of the drug. AUC is
directly proportional to t.sub.1/2, and as the t.sub.1/2 increases,
AUC gets larger. Since AUC is the major predictor of efficacy for
PPI drugs, the prolongation of the half-life of the PPI (and as
such increasing the AUC) directly results in the improvement of
efficacy of PPIs.
[0181] Another more pharmacokinetic parameter that predicts
efficacy is the AUC greater than concentration required to produce
50% inhibition (IC50), which is specific for each PPI.
[0182] Conversion rate of PPIs to the active moiety is also a
determinant of efficacy, specifically as it relates to time and
speed of onset after dosing. Therefore, it is desirable to combine
two PPIs that have different half-lifes related to activation
(activation half-lifes). For example, the activation half-life of
lansoprazole and omeprazole complement one another with
lansoprazole reaching 90% activity at an approximate pH of 1 to 1.5
in 7 to 8 minutes while omeprazole reaches 90% activity, at an
approximate pH of 1 to 1.5, in 15 to 20 minutes. Unexpectedly,
applicant found that when these two drugs are used together in the
formulations herein described (as an example, 80 mg lansoprazole+80
mg omeprazole+1680 mg sodium bicarbonate) the half-life of both
drugs in significantly prolonged. Normally the half-life of
elimination of lansoprazole is 1 to 1.4 hrs (mean of approximately
1.2 hrs) and similarly for omeprazole, the elimination half-life is
0.7 to 1.2 hrs (mean of approximately 0.95 hr). When administered
together, there is pharmacokinetic produce synergy. Omeprazole
elimination half-life is prolonged to 1.9 hours (a prolongation
factor of 200%) and the lansoprazole elimination half-life is
prolonged to 3.7 hours (a prolongation factor of 300%).
[0183] Pharmacokinetic synergism refers to the enhancement in
action or effect of a particular drug(s) compared to the individual
effect of both the drugs combined. As provided in the Examples,
combinations of omeprazole and lansoprazole significantly prolonged
half-life of both drugs and improved AUC.sub.0.24 and IGA-24
values, indicating enhanced efficacy of the PPIs. Individual values
alone cannot account for this dramatic and unexpected increase in
efficacy as demonstrated in the Examples. Rather, omeprazole and
lansoprazole together affect and enhance the efficacy of the
PPIs.
EXAMPLES
[0184] The examples below are for illustrative purposes only and
are not to be construed as limiting the invention in any
manner.
Example 1
[0185] The following table lists the daily dose half-life of
various PPIs. Since half-life (t.sub.1/2) and AUC have a high
intersubject variability, it is important that t.sub.1/2 be
compared in the same subject in the same conditions with
appropriate washout between studies.
TABLE-US-00002 TABLE 1 PPI Daily Dose t.sub.1/2 Rabeprazole 20-160
mg 0.8-1 hr Omeprazole 20-160 mg 0.9-1.5 hrs Lansoprazole 15-160 mg
1-1.5 hrs Tentaoprazole 40-160 mg 6.8-8 hrs Pantoprazole 40-160 mg
1.2-1.5 hrs Esomerprazole 20-160 mg 1.1-1.6 hrs Dexlansoprazole
15-160 mg 1-1.6 hrs
[0186] A list of drug combinations that produce prolonged
half-lives, and found to be synergistic is shown in Table 2. Both
PPIs can be delayed and/or immediate release. The doses of each PPI
and cimetidine can range from 10 to 300 mg and 10 to 1500 mg,
respectively.
TABLE-US-00003 TABLE 2 PPI 1 PPI 2 Cimetidine Ilaprazole Omeprazole
No Ilaprazole Lansoprazole No Ilaprazole Rabeprazole No Ilaprazole
Tenatoprazole No Ilaprazole Pantoprazole No Ilaprazole Esomeprazole
No Ilaprazole None Yes Ilaprazole Omeprazole Yes Ilaprazole
Lansoprazole Yes Ilaprazole Rabeprazole Yes Ilaprazole
Tenatoprazole Yes Ilaprazole Pantoprazole Yes Ilaprazole
Esomeprazole Yes Lansoprazole Omeprazole No Lansoprazole
Esomeprazole No Lansoprazole Rabeprazole No Lansoprazole
Tenatoprazole No Lansoprazole Pantoprazole No Lansoprazole None Yes
Lansoprazole Omeprazole Yes Lansoprazole Esomeprazole Yes
Lansoprazole Rabeprazole Yes Lansoprazole Tenatoprazole Yes
Lansoprazole Pantoprazole Yes Rabeprazole Omeprazole No Rabeprazole
Tenatoprazole No Rabeprazole Pantoprazole No Rabeprazole
Esomeprazole No Rabeprazole None Yes Rabeprazole Omeprazole Yes
Rabeprazole Tenatoprazole Yes Rabeprazole Pantoprazole Yes
Rabeprazole Esomeprazole Yes Omeprazole Tenatoprazole No Omeprazole
Pantoprazole No Omeprazole Esomeprazole No Omeprazole Tenatoprazole
Yes Omeprazole Pantoprazole Yes Omeprazole Esomeprazole Yes
Pantoprazole Tenatoprazole No Pantoprazole Esomeprazole No
Pantoprazole Tenatoprazole Yes Pantoprazole Esomeprazole Yes
Tenatoprazole Esomeprazole No Tenatoprazole Esomeprazole Yes
Ilaprazole None Yes Lansoprazole None Yes Rabeprazole None Yes
Pantoprazole None Yes Tenatoprazole None Yes Esomeprazole None
Yes
[0187] The PPIs are listed as the racemate and as the base form.
However, this list is meant to include the enantiomers, based upon
the USAN Handbook, and the salt forms with hydrate (examples
include, but are not limited to, pantoprazole sodium, tenatoprazole
sodium trihydrate, and esomeprazole magnesium). The USAN Handbook,
Chicago, Ill.: US Adopted Names Program (1999).
[0188] In one embodiment disclosed herein provide for a solid
dosage form comprising all or any: omeprazole (60 mg)+lansoprazole
(60 mg)+cimetidine HCl (200 mg)+sodium bicarbonate (1680
mg)+croscarmellose sodium (25 mg)+pregelatinized starch (65
mg)+magnesium stearate (25 mg). Further, aspirin (80 to 325 mg) or
NSAIDs in their normal dosages, such as naproxen (100 to 500 mg)
can be added to the embodiments.
[0189] In another embodiment disclosed herein provide for a solid
dosage form comprising all or any: omeprazole (60 mg)+lansoprazole
(60 mg)+sodium bicarbonate (1200 mg)+calcium carbonate (400
mg)+croscarmellose sodium (25 mg)+pregelatinized starch (65
mg)+magnesium stearate (25 mg). Further, aspirin (80 to 325 mg) or
NSAIDs in their normal dosages, such as naproxen (100 to 500 mg)
can be added to the embodiments.
[0190] Another embodiment disclosed herein provide for a solid
dosage form comprising all or any: omeprazole (60 mg)+lansoprazole
(60 mg)+sodium bicarbonate (1200 mg)+magnesium hydroxide (420
mg)+sodium carboxymethylcellulose (30 mg)+pregelatinized starch (65
mg)+magnesium stearate (25 mg). Further, aspirin (80 to 325 mg) or
NSAIDs in their normal dosages, such as naproxen (100 to 500 mg)
can be added to the embodiments.
[0191] Another embodiment disclosed herein provide for a solid
dosage form comprising all or any: omeprazole (60 mg)+lansoprazole
(60 mg)+sodium bicarbonate (1200 mg)+calcium carbonate (300
mg)+calcium formate (100 mg)+croscarmellose sodium (25
mg)+pregelatinized starch (65 mg)+magnesium stearate (25 mg).
Further, aspirin (80 to 325 mg) or NSAIDs in their normal dosages,
such as naproxen (100 to 500 mg) can be added to the
embodiments.
[0192] Another embodiment disclosed herein provide for a solid
dosage form comprising all or any: omeprazole (60 mg)+lansoprazole
(60 mg)+sodium bicarbonate (1200 mg)+calcium carbonate (300
mg)+calcium formate (100 mg)+sodium carboxymethylcellulose (30
mg)+pregelatinized starch (65 mg)+magnesium stearate (25 mg).
Further, aspirin (80 to 325 mg) or NSAIDs in their normal dosages,
such as naproxen (100 to 500 mg) can be added to the
embodiments.
[0193] Another embodiment disclosed herein provide for a solid
dosage form comprising all or any: omeprazole (70 mg)+lansoprazole
(30 mg)+sodium bicarbonate (1200 mg)+calcium carbonate (300
mg)+calcium formate (100 mg)+croscarmellose sodium (25
mg)+pregelatinized starch (65 mg)+magnesium stearate (25 mg).
Further, aspirin (80 to 325 mg) or NSAIDs in their normal dosages,
such as naproxen (100 to 500 mg) can be added to the
embodiments.
[0194] Another embodiment disclosed herein provide for a solid
dosage form comprising all or any: omeprazole (70 mg)+lansoprazole
(30 mg)+sodium bicarbonate (1200 mg)+calcium carbonate (300
mg)+calcium formate (100 mg)+sodium carboxymethylcellulose (30
mg)+pregelatinized starch (65 mg)+magnesium stearate (25 mg).
Further, aspirin (80 to 325 mg) or NSAIDs in their normal dosages,
such as naproxen (100 to 500 mg) can be added to the
embodiments.
[0195] Another embodiment disclosed herein provide for a solid
dosage form comprising all or any: omeprazole (60 mg)+lansoprazole
(60 mg)+sodium bicarbonate (1000 mg)+calcium carbonate (400
mg)+calcium fonnate (200 mg)+magnesium hydroxide (200
mg)+croscarmellose sodium (25 mg)+pregelatinized starch (65
mg)+magnesium stearate (25 mg). Further, aspirin (80 to 325 mg) or
NSAIDs in their normal dosages, such as naproxen (100 to 500 mg)
can be added to the embodiments.
[0196] Still another embodiment disclosed herein provide for a
solid dosage form comprising all or any: omeprazole (60
mg)+lansoprazole (60 mg)+cimetidine HCl (400 mg)+calcium carbonate
(1200 mg)+magnesium hydroxide (200 mg)+croscarmellose sodium (25
mg)+pregelatinized starch (65 mg)+magnesium stearate (25 mg).
Further, aspirin (80 to 325 mg) or NSAIDs in their normal dosages,
such as naproxen (100 to 500 mg) can be added to each of the
aforementioned embodiments.
[0197] A skilled artisan would appreciate that the foregoing
embodiments in paragraphs [00181]-[00189] would also contemplate
the following ratios of omeprazole to lansoprazole: about 40:40,
about 50:50, about 75:75 and about 80:80.
Example 2
[0198] A study was performed as a cross-over design, with washout
between doses. The subject received the test article after placing
a Bravo pH probe in the stomach and verifying its placement with pH
readings of less than 2. After a baseline evaluation, to ensure
that the pH probe is in the correct place for reading gastric acid
in the stomach, the subject has an intravenous access established
and a baseline blood draw was taken to provide evidence of a lack
of PPI in the blood at baseline. The subject received the one of
three different formulations, and the time of administration was
noted. Blood draws were taken at intervals to characterize the
absorption, distribution and elimination phases of the test
article. From these data the AUC was calculated. Continuous gastric
pH recording was made utilizing the Bravo pH probe and
radiofrequency receiver. Gastric pH values were recorded every 10
seconds. From these data the IGA was determined for the 24 hour
period.
[0199] The results for three different formulations are summarized
below:
TABLE-US-00004 Formulation 1 80 mg Omeprazole + [**Formulation 2]
[**Formulation 3] 80 mg Lansoprazole + 160 mg Omeprazole + 160 mg
Lansoprazole + 1680 mg NaHCO.sub.3 1680 mg NaHCO.sub.3 1680 mg
NaHCO.sub.3 AUC.sub.0-24 23.7 .mu.g hr/mL 18.1 .mu.g hr/mL 12.4
.mu.g hr/mL AUC > 1 .mu.M.sub.0-24 18.9 .mu.g hr/mL 13.6 .mu.g
hr/mL 9.3 .mu.g hr/mL IGA-24.sub.Day 1 38 mmol h/L 178 mmol h/L 57
mmol h/L
Example 3
[0200] A study was performed as a cross-over design, with washout
between doses. The subject received the test article after placing
a Bravo pH probe in the stomach and verifying its placement with pH
readings of less than 2. After a baseline evaluation, to ensure
that the pH probe is in the correct place for reading gastric acid
in the stomach, the subject has an intravenous access established
and a baseline blood draw was taken to provide evidence of a lack
of PPI in the blood at baseline. The subject received the one of
three different formulations, and the time of administration was
noted. Blood draws were taken at intervals to characterize the
absorption, distribution and elimination phases of the test
article. From these data the AUC was calculated. Continuous gastric
pH recording was made utilizing the Bravo pH probe and
radiofrequency receiver. Gastric pH values were recorded every 10
seconds. From these data the IGA was determined for the 24 hour
period.
[0201] The results for three different formulations are summarized
below:
TABLE-US-00005 Formulation 4 50 mg Omeprazole + Formulation 5
Formulation 6 50 mg Lansoprazole + 100 mg Omeprazole + 100 mg
Lansoprazole + 1680 mg NaHCO.sub.3 1680 mg NaHCO.sub.3 1680 mg
NaHCO.sub.3 AUC.sub.0-24 5.9 .mu.g hr/mL 4.2 .mu.g hr/mL 2.9 .mu.g
hr/mL AUC > 1 .mu.M.sub.0-24 3.1 .mu.g hr/mL 2.2 .mu.g hr/mL 1.8
.mu.g hr/mL IGA-24.sub.Day 1 190 mmol h/L 274 mmol h/L 241 mmol
h/L
Example 4
[0202] A study was performed as a cross-over design, with washout
between doses. The subject received the test article after placing
a Bravo pH probe in the stomach and verifying its placement with pH
readings of less than 2. After a baseline evaluation, to ensure
that the pH probe is in the correct place for reading gastric acid
in the stomach, the subject has an intravenous access established
and a baseline blood draw was taken to provide evidence of a lack
of PPI in the blood at baseline. The subject received the one of
eighteen different formulations, and the time of administration was
noted. Blood draws were taken at intervals to characterize the
absorption, distribution and elimination phases of the test
article. From these data the AUC was calculated. Continuous gastric
pH recording was made utilizing the Bravo pH probe and
radiofrequency receiver. Gastric pH values were recorded every 10
seconds. From these data the IGA was determined for the 24 hour
period
[0203] IR: Immediate-release means that this portion of the
composition is formulated so that delivery begins in the stomach
and there is no enteric coating or timed release coating involved.
The term is intended to refer to any PPI formulation in which all
or part of the PPI is in solution either before administration or
immediately (i.e., within about 30 minutes) after administration.
For example, with an "immediate release" formulation, oral
administration results in immediate release of the agent from the
composition into gastric fluid.
[0204] DR: Delayed release means that release of this component of
the formulation begins at a time other than promptly after
administration. Delayed release formulations includes any
nonimmediate release formulation, including but not limited to,
film-coated formulations, enteric-coated formulations, encapsulated
formulations, sustained release formulations and pulsatile release
formulations. For delayed release formulations, the rate of release
of drug from the dosage form is the rate-limiting step in the
delivery of the drug to the target area.
[0205] The results of the different formulations are summarized
below:
TABLE-US-00006 Formulation 7 Formulation 9 120 mg Omeprazole +
Formulation 8 120 mg Rabeprazole + 200 mg Cimetidine + 40 mg
Omeprazole + 200 mg Cimetidine + 1680 mg NaHCO.sub.3 1680 mg
NaHCO.sub.3 1680 mg NaHCO.sub.3 AUC.sub.0-24 12.9 .mu.g hr/mL 2.6
.mu.g hr/mL 7.1 .mu.g hr/mL Omeprazole Omeprazole Rabeprazole
Half-life (t.sub.1/2) 2.1 hrs 1.1 hrs 0.8 hrs Omeprazole Omeprazole
Rabeprazole IGA-24.sub.Day 1 56 mmol hr/L 202 mmol hr/L 173 mmol
hr/L
TABLE-US-00007 [Formulation 12] Formulation 10 120 mg Omeprazole IR
+ 80 mg Omeprazole IR + 40 mg Tenatoprazole 80 mg Lansoprazole DR +
Formulation 11 IR + 200 mg Cimetidine + 1680 mg NaHCO.sub.3 40 mg
Esomeprazole DR 1680 mg NaHCO.sub.3 AUC.sub.0-24 7.6 .mu.g hr/mL
3.6 .mu.g hr/mL 11.8 .mu.g hr/mL Omeprazole Esomeprazole Omeprazole
14.7 .mu.g hr/mL -- 88.3 .mu.g hr/mL Lansoprazole Tenatoprazole
AUC.sub.0-24 Combined 22.3 .mu.g hr/mL -- -- Lansoprazole Half-life
(t.sub.1/2) 1.6 hrs Omeprazole 1.4 hrs Esomeprazole 1.8 hrs
Omeprazole 2.5 hrs Lansoprazole -- 12.9 hrs Tenatoprazole
IGA-24.sub.Day 1 115 mmol hr/L 316 mmol hr/L 28.4 mmol hr/L
TABLE-US-00008 Formulation 14 Formulation 13 100 mg Pantoprazole IR
+ Formulation 15 120 mg Tentaprazole IR + 60 mg Omeprazole IR + 160
mg Omeprazole IR + 1680 mg NaHCO.sub.3 1680 mg NaHCO.sub.3 1680 mg
NaHCO.sub.3 AUC.sub.0-24 76.9 .mu.g hr/mL 22.6 .mu.g hr/mL 18.1
.mu.g hr/mL Tentaprazole Pantoprazole Omeprazole -- 2.4 .mu.g hr/mL
-- Omeprazole Half-life (t.sub.1/2) 8.6 hrs Tentaprazole 1.5 hrs
Pantoprazole 2.3 hrs Omeprazole -- 0.8 hrs Omeprazole --
IGA-24.sub.Day 1 >400 mmol hr/L >400 mmol hr/L 178 mmol
hr/L
TABLE-US-00009 Formulation 17 Formulation 18 [Formulation 16] 40 mg
Omeprazole IR + 60 mg Lansoprazole IR + 160 mg Lansoprazole IR + 40
mg Tenatoprazole IR + 40 mg Tenatoprazole IR + 1680 mg NaHCO.sub.3
1680 mg NaHCO.sub.3 1680 mg NaHCO.sub.3 AUC.sub.0-24 12.4 .mu.g
hr/mL 2.3 .mu.g hr/mL 2.9 .mu.g hr/mL Lansoprazole Omeprazole
Lansoprazole -- 56.3 .mu.g hr/mL 48.4 .mu.g hr/mL Tenatoprazole
Tenatoprazole Half-life (t.sub.1/2) 2.4 hrs Lansoprazole 0.9 hrs
Omeprazole 1.6 hrs Lansoprazole -- 10.6 hrs Tenatoprazole 7.9 hrs
Tenatoprazole IGA-24.sub.Day 1 57 mmol hr/L >400 mmol hr/L
>400 mmol hr/L
TABLE-US-00010 Formulation 19 Formulation 20 40 mg Esomeprazole DR
+ 60 mg Omeprazole IR + Formulation 21 60 mg Lansoprazole IR + 60
mg Pantoprazole IR + 120 mg Lansoprazole IR + 1680 mg NaHCO.sub.3
1680 mg NaHCO.sub.3 1680 mg NaHCO.sub.3 AUC.sub.0-24 2.7 .mu.g
hr/mL 3.8 .mu.g hr/mL 2.7 .mu.g hr/mL Esomeprazole Omeprazole
Lansoprazole 4.0 .mu.g hr/mL 8.9 .mu.g hr/mL -- Lansoprazole
Pantoprazole Half-life (t.sub.1/2) 1.1 hrs Esomeprazole 1.7 hrs
Omeprazole 2.4 hrs Lansoprazole 2.6 hrs Lansoprazole 1.1 hrs
Pantoprazole -- IGA-24.sub.Day 1 >400 mmol hr/L 109 mmol hr/L
>400 mmol hr/L
TABLE-US-00011 Formulation 22 Formulation 23 120 mg Pantoprazole IR
+ 120 mg Omeprazole IR + 1680 mg NaHCO.sub.3 1680 mg NaHCO.sub.3
AUC.sub.0-24 9.2 .mu.g hr/mL 9.6 .mu.g hr/mL Pantoprazole
Omeprazole Half-life (t.sub.1/2) 0.9 hrs Pantoprazole 1.9 hrs
Omeprazole IGA-24.sub.Day 1 >400 mmol hr/L >400 mmol hr/L
Example 5
[0206] Overview: A prospective, randomized study can be conducted
to evaluate the regression of Barrett's esophagus, in patients
diagnosed with Barrett's esophagus, following treatment with
Nexium.RTM. (esomeprazole) as compared to test article. Patients
with Barrett's esophagus, with or without low grade dysplasia, can
be randomized to receive Nexium.RTM. 40 mg once daily or the test
article once daily.
[0207] Introduction. Barrett's esophagus is related to acid reflux
into the esophagus. In general, it is thought that chronic acid
reflux leads to Barrett's which leads to low and then high grade
dysplasia which leads to adenocarcinoma of the esophagus. J W van
Sandick, "Impact of endoscopic biopsy surveillance of Barrett's
oesophagus on pathological stage and clinical outcome of Barrett's
carcinoma", GUT, Vol. 43, pp. 216-222 (1998). The incidence of all
of these conditions is increasing in the U.S. Adenocarcinoma of the
esophagus is the most rapidly growing cancer. Patients with
Barrett's esophagus are currently managed by repeat endoscopic
surveillance with biopsy/pathological evaluation. If changes in
pathology of biopsied areas are noted to involve low or high grade
dysplasia, patients are monitored more frequently (low grade
dysplasia) or evaluated for other procedures such as ablation,
mucosal resection or esophagectomy (high grade dysplasia). If
carcinoma is noted, then esophagectomy is often recommended.
Currently, there is no medical treatment to reverse Barrett's
esophagus to normal squamous esophageal mucosa. In a review of
prospective studies of the treatment of BE with proton pump
inhibitors (PPIs) (with or without surgery), only 3 of 123 patients
had complete apparent reversal of BE. Sampliner, R., "Reduction of
Acid Exposure and Regression of Barrett's Esophagus", Digestive
Diseases, Vol. 18(4), pp. 203-207 (2001).
[0208] Nighttime acid break-through (pH below 4 for more than 60
consecutive minutes in patients on twice daily PPI therapy) occurs
in over 70% of patients. Thompson, CA., "First federal comparative
effectiveness review examines GI disorder", Am J Health-Syst Pharm,
Vol. 63, pg. 302 (2006). The addition of an H2 blocker at bedtime
has been suggested as a method to control nocturnal acid
breakthrough, however, this has been shown to be effective for only
one week, then tolerance develops and the nighttime effects of the
H2 blocker are eliminated. Janiak P, `Clinical trial: the effects
of adding ranitidine at night to twice daily omeprazole therapy on
nocturnal acid breakthrough and acid reflux in patients with
systemic sclerosis--a randomized controlled, cross-over trial",
Alimentary Pharmacology Therapeutics, Vol. 26, pp. 1259-1265
(2007). Esomeprazole (Nexium.RTM.) 40 mg is a potent inhibitor of
proton pumps and is widely used for acid-related disorders. The
test article can be a PPI combination developed at the University
of Missouri to maximize the AUC (area under the serum concentration
vs time curve) of PPI and is capable of producing and maintaining
pH values at >4 for 24 hours per day after Day 1 of
treatment.
[0209] Methods
[0210] Null Hypothesis: There will be no difference in the rate of
reversal of patients with Barrett's whether they receive
Nexium.RTM. 40 mg once daily or test article once daily.
[0211] Alternative Hypothesis: There will be a difference in the
rate of reversal of patients with Barrett's whether they receive
Nexium.RTM. 40 mg once daily or test article once daily.
[0212] Sample size. Data from the literature suggest a 2.4%
incidence of complete reversal of Barrett's after 24 months of
treatment with PPI. Based upon the achievement of complete control
of pH with pH values maintained above 4 for 24 hours per day, a
reversal rate of 50% can be expected in the test article arm. Based
upon these assumptions, a sample size of 10 subjects per arm will
be needed to detect a difference if one assumes a Type I error rate
of 5% and a Type II error rate of 20%.
[0213] Patients can be evaluated every 3 months by endoscopy-guided
biopsy. Pathology results will be compared at 3 months 6 months and
9 months for signs of reversal of Barrett's or reversal of
dysplastic lesions. Partial reversal and complete reversal can be
compared. Biopsy protocols using acetic acid test for standard,
non-magnifying endoscopic detection of biopsy areas and jumbo
forceps/4-quadrant biopsies every 1 cm can be employed.
Vazquez-Iglesias, J L., "Acetic acid allows effective selection of
areas for obtaining biopsy samples in Barrett's esophagus",
European Journal of Gastroenterology & Hepatology. Vol. 19(3),
pp. 187-193 (2007).
[0214] Test article can comprise: omeprazole powder (80
mg)+lansoprazole powder (80 mg)+sodium bicarbonate (1680
mg)+croscarmellose sodium (25 mg)+pregelatinized starch (65
mg)+magnesium stearate (25 mg).
Example 6
[0215] Overview: A double-blind, randomized study may be performed
to compare 80 mg omeprazole plus 80 mg lansoprazole with
Zegrid.RTM. 40 mg in normal, healthy adults. The study can include
a cross-over design with washout between doses. Participants need
to fast starting midnight of the day of visit (Day 1). The
participant can receive a Bravo pH probe into their stomach and
verifying its placement with pH readings of less than 2. The
participant can also have an intravenous access established. Prior
to PPI administration, participant can be given breakfast, after
which a 5 mL pre-dose blood sample can be collected. After the dose
of one of the study drugs, 4 mL blood collections can be taken at
5, 15, 60, 45, 60, 75, 135, 195, 315, and 375 minutes. At the noon
hour, the participant can be given lunch. The IV can be removed
after the 375 minute blood draw, but the participant can keep the
Bravo pH probe in their stomach for a total of 24 hours.
Participant can be allowed to eat after the 375 minute blood draw.
There can be a 7-day washout period. Afterwards (Day 8), the other
study drug can be tested following the same protocol as described
above.
[0216] The study can measure the level of IGA, the pharmacokinetics
of the drug, such as elimination half-life (t.sub.1/2), AUC and
maximum concentration (C.sub.max), and the level of Grastrin-17 in
the participant's bloodstream. Each of the parameters can aid in
the determination of the efficacy of the study drugs. Gastrin
concentrations directly relate to the activity of the parietal
cells, which are responsible for acid production in the stomach.
The PPI inhibits the proton pump and prevents the production of
acid. Therefore, the gastrin results, in conjunction with the pH,
can help determine the effectiveness of the PPI at suppressing acid
production.
[0217] Protocol
[0218] Schedule of Events
[0219] This study will have two treatment periods, one for each
study medication treatment arm. The participant will be randomized
to one treatment arm. After completion and washout, they will be
placed on the other treatment arm.
[0220] Study Day Minus : Participant will sign the informed consent
and HIPAA forms. All study procedures will be explained and all
questions will be answered. The participant will be informed they
need to be fasting starting at midnight on Study Day 1. At this
visit, their concomitant medications will be recorded, as well as
relevant medical/surgical history. The inclusion/exclusion criteria
will be evaluated. If the participant needs to complete a washout
period, their Study Day 1 will be scheduled to provide the needed
washout time. Study Day 1 will also be scheduled according to their
personal schedule and such that all visit days will fall on Monday
through Friday.
[0221] Study Day 1: Participant will need to be fasting starting
midnight the day of the visit. Concomitant medications will be
reviewed and they must meet all inclusion and no exclusion
criteria. They will be provided a breakfast and a lunch meal and
allowed to drink only water before and during the visit. For
females of child-bearing potential, a urine sample will be
collected for a urine pregnancy test. A 20 gauge IV catheter will
be inserted into their hand or arm for approximately eleven 4 mL
blood collections. The participant will swallow, with water, a
tethered swallowable Bravo pH probe into their stomach under
appropriate supervision. The string will have a bead attached, at
the participant's lip, to mark placement of the string in order to
keep the probe suspended in the stomach. The string will be secured
to the participant's cheek and neck with two tegaderms. After
successfully swallowing the Bravo pH probe, and before medication
is taken, the participant will be given a McDonald's Egg McMuffin
to eat for breakfast. While data from the probe is being collected
they will keep the pH probe receiver within five feet of themselves
at all times. A 5 mL pre-dose blood sample will be collected. The
participant will take the dose of study drug. There will be 4 mL
blood collections at 5, 15, 30, 45, 60, 75, 135, 195, 315, and 375
minutes after the dose. At the noon hour, the participant will be
given a McDonald's cheeseburger and medium french fries for the
noon meal. The IV will be removed after the 375 minute blood draw
and the participant will keep the Bravo pH probe in their stomach
for a total of 24 hours. They will be allowed to eat again after
the 375 minute blood draw.
[0222] Study Day 2: The participant will return for collection of
the pH probe receiver and recorded data. The participant will have
two options for removal of the probe. The string may be cut below
the point the bead is attached so the probe and string will pass
through the digestive system. The probe may also be withdrawn from
the stomach by appropriate staff. If resistance is met, the string
will be cut below the bead and appropriate personnel will be
notified.
[0223] Study Day 8: The participant will enter the second treatment
period and will take the second arm of study medication.
Participant will need to be fasting starting midnight the day of
the visit. They will be provided a breakfast and a lunch meal and
allowed to drink only water before and during the visit. For
females of child-bearing potential, a urine sample will be
collected for a urine pregnancy test. A 20 gauge IV catheter will
be inserted into their hand or arm for approximately eleven 4 mL
blood collections. The participant will swallow, with water, a
tethered swallowable Bravo pH probe into their stomach under the
appropriate supervision. The string will have a bead attached, at
the patient's lip, to mark placement of the string to keep the
probe suspended in the stomach. The string will be secured to the
participant's cheek and neck with two tegaderms. After successfully
swallowing the Bravo pH probe, and before medication is taken, the
participant will be given a McDonald's Egg McMuffin to eat for
breakfast. While data from the probe is being collected they will
keep the pH probe receiver within five feet of themselves at all
times. A 5 mL pre-dose blood sample will be collected. The
participant will take the dose of study drug and blood will be
collected at 5, 15, 30, 45, 60, 75, 135, 195, 315, and 375 minutes
after the dose. At the noon hour, the participant will be given a
McDonald's cheeseburger and medium french fries for the noon meal.
The IV will be removed after the 375 minute blood draw and the
participant will keep the Bravo pH probe in their stomach for a
total of 24 hours. They will be allowed to eat again after the 375
minute blood draw.
[0224] Study Day 9: The participant will return for collection of
the pH probe receiver and recorded data. The participant will have
two options for removal of the probe. The string may be cut below
the point the bead is attached so the probe and string will pass
through the digestive system. The probe may also be withdrawn from
the stomach by appropriate personnel. If resistance is met, the
string will be cut below the bead and appropriate personnel will be
notified. The participant will receive a compensation check.
[0225] Abbreviations [0226] AE=Adverse Event [0227] AUC=Area Under
the Curve [0228] b.i.d.=Twice daily [0229] CRF=Case Report Form
[0230] FDA=Food and Drug Administration [0231]
GERD=Gastroesophageal Reflux Disease [0232] IDS=Investigational
Drug Services [0233] IRB=Institutional Review Board [0234]
mg=milligrams [0235] mL=milliliters [0236] NSAID=Non-Steroidal
Anti-Inflammatory Drug [0237] PPI=Proton Pump Inhibitor [0238]
SAE=Serious Adverse Event [0239] t.i.d.=Three Times per Day [0240]
UMHC=University of Missouri Health Care [0241]
ZES=Zollinger-Ellison syndrome
[0242] Background Information
[0243] Omeprazole (the active ingredient in Zegerid and Prilosec)
and Lansoprazole (the active ingredient in Prevacid) are two
FDA-approved drugs that are commonly used to treat a wide variety
of gastric acid-related disorders, including gastric and duodenal
ulcers, gastroesophageal reflux disease (GERD), and
Zollinger-Ellison Syndrome (7ES). They belong to a class of
antisecretory compounds called the substituted benzimidazoles and
act by inhibiting the proton pumps in the parietal cells (hence the
term "Proton Pump Inhibitor," abbreviated as "PPI"), thereby
blocking the final step of gastric acid production. In clinical
studies, the mean plasma elimination half-life in healthy adults
has been found to be about 1.5 hours for lansoprazole.sup.1 and
less than 1 hour for omeprazole.sup.2. The acid inhibitory
effect--which was measured by the decrease in basal acid output,
increase in mean gastric pH, and percent time the gastric pH was
greater than 3 and 4--lasted more than 24 hours on the fifth day of
treatment with a 30 mg dose of lansoprazole or with a 40 mg dose of
omeprazole according to the package inserts for Prevacid and
Prilosec, respectively. The drugs also significantly reduced
meal-stimulated gastric acid output and secretion volume as well as
pentagastrin-stimulated acid output on the fifth day. On the first
few days of treatment, however, efficacy is usually low and acid
inhibition rarely lasts for longer than 2-3 hours.sup.3,4.
[0244] Lansoprazole has been shown in many studies to be
extensively metabolized in the liver in approximately equal amounts
by both the 2C19 and 3A4 isoforms of the Cytochrome P450
enzyme.sup.5, while omeprazole is metabolized mostly by the 2C19
isoform.sup.6. Following a single oral dose, most of the PPI
detected in the urine is in the inactive metabolized form.sup.7.
Elimination rates have been found to be faster in pediatric
patients and slower in geriatric patients and dosing adjustments
for these populations have been suggested in various past
studies.sup.8. No differences in PPI pharmacokinetics and
intragastric pH between males and females have been
reported.sup.3,4. Patients with renal insufficiency had a shortened
elimination half-life and a decreased total AUC.sup.9,10, while
patients with hepatic diseases had significantly extended
elimination half-lives and increased total AUC.sup.10,11. Over
10,000 patients have been treated with both PPIs in Phase 2 and 3
clinical trials and each drug is regularly used in clinical
settings to control various acid-related disorders.
[0245] Because of the high specificity of PPIs, side effects are
usually rare and mild. Omeprazole and lansoprazole are both
pro-drugs that are only converted to their active form at pH of
below 2 and since the only physiological location that satisfies
this requirement is the parietal cell canalicular space; the
effects of the drugs are limited only to this area. Adverse effects
as reported by the package inserts for each drug are outlined
below:
TABLE-US-00012 TABLE 1 Adverse effects (in terms of % of patients)
that were found in at least 1% of patients taking either drug in
clinical trials.sup.3, 4. Zegerid .TM. package insert Prevacid
.RTM. package insert Omeprazole Placebo Lansoprazole Placebo Effect
(n = 2631) (n = 120) (n = 2768) (n = 1023) Abdominal 5.2 3.3 2.1
1.2 pain Asthenia 1.3 0.8 <1 N/R Constipation 1.5 0.8 1.0 0.4
Diarrhea 3.7 2.5 3.8 2.3 Headache 2.9 2.5 <1 <1
[0246] Oral administration of PPI drugs is typical. The hypothesis
that will be tested in this study is that there is no difference in
24-hour integrated gastric acidity between subjects receiving a
single 40 mg dose of Zegerid and subjects receiving a single dose
of 80 mg omeprazole plus 80 mg lansoprazole in an immediate-release
formulation; the alternate hypothesis is that there is a difference
in 24-hour integrated gastric acidity subjects receiving a single
40 mg dose of Zegerid and subjects receiving a single dose of 80 mg
omeprazole plus 80 mg lansoprazole in an immediate-release
formulation. Therefore, by design, a single dose will be given.
[0247] Population to be Studied
[0248] Normal, healthy adults between the ages of 18 and 60 that
volunteer for participation.
REFERENCES
[0249] References to literature and data that are relevant to the
trial and that provide background for the trial: [0250] 1. Karol,
M. D., Pharmacokinetics of lansoprazole in hemodialysis patients.
[0251] 2. Cederberg, C., Omeprazole: pharmacokinetics and
metabolism in man. [0252] 3. Prilosec delayed-release capsules. In
AstraZeneca: Wilmington, Del., 2002. [0253] 4. Prevacid
delayed-release capsules. In TAP Pharmaceuticals: Lake Forest,
Ill., 2003. [0254] 5. Pichard, L.; Curi-Pedrosa, R.; Bonfils, C.;
Jacqz-Aigrain, E.; Domergue, J.;
[0255] Joyeux, H., Oxidative metabolism of lansoprazole by human
liver cytochromes P450. Molecular Pharmacology 1995, 47, (2),
410-8. [0256] 6. Yamazaki, H.; Inoue, K.; Shaw, P. M.; Checovich,
W. J.; Guengerich, F. P.; Shimada, T., Different contributions of
cytochrome P450 2C19 and 3A4 in the oxidation of omeprazole by
human liver microsomes: effects of contents of these two forms in
individual human samples. Journal of Pharmacology and Experimental
Therapeutics 1997, 283, (2), 434-42. [0257] 7. Sohn, D. R.;
Kobayashi, K.; Chiba, K.; Lee, K. H.; Shin, S. G.; Ishizaki, T.,
Disposition kinetics and metabolism of omeprazole in extensive and
poor metabolizers of S-mephenytoin 4'-hydroxylation recruited from
an Oriental population. Journal of Pharmacology and Experimental
Therapeutics 1992, 262, (3), 1195-202. [0258] 8. Phillips J O, B.
J., Siddiqi S H, Bothwell M, Pediatric patients have shorter
lansoprazole half-life than previously reported. American Journal
of Gastroenterology 2007, 102, (s2), S548. [0259] 9. Naesdal, J.;
Andersson, T.; Bodemar, G.; Larsson, R.; Reg{dot over (a)}rdh, C.
G.; Sk{dot over (a)}berg, I., Pharmacokinetics of [14C]omeprazole
in patients with impaired renal function. Clinical Pharmacology
& Therapeutics 1986, 40, (3), 344-51. [0260] 10.
Delhotal-Landes, B.; Flouvat, B.; Duchier, J.; Molinie, P.;
Dellatolas, F.; Lemaire, M., Pharmacokinetics of lansoprazole in
patients with renal or liver disease of varying severity. European
Journal of Clinical Pharmacology 1993, 45, (4), 367-71. [0261] 11.
Yin, O. Q. P.; Brian, T.; Albert, H. L. C.; Mary, M. Y. W.; Moses,
S. S. C., Omeprazole as a CYP2C 19 marker in Chinese subjects:
assessment of its gene-dose effect and intrasubject variability.
The Journal of Clinical Pharmacology 2004, 44, (6), 582-9.
[0262] Trial Objectives and Purpose
[0263] Hypothesis. The hypothesis that will be tested in this study
is; that there is no difference in 24-hour integrated gastric
acidity between subjects receiving a single 40 mg dose of Zegerid
and subjects receiving a single dose of 80 mg omeprazole plus 80 mg
lansoprazole in an immediate-release formulation; the alternate
hypothesis will be that there is a difference in 24-hour integrated
gastric acidity subjects receiving a single 40 mg dose of Zegerid
and subjects receiving a single dose of 80 mg omeprazole plus 80 mg
lansoprazole in an immediate-release formulation.
[0264] Trial Design
[0265] Primary endpoint. The primary endpoint will be the
integrated gastric acidity over 24 hours. pH probe data will be
transformed into integrated gastric acidity using the AcidipHy
software.
[0266] This trial is a double-blind, single site trial.
[0267] Measures taken to avoid/minimize bias. The study medication
will be double-blind. A single dose of one of the study medication
arms will be given for each treatment period for a total of two
doses of study medication.
[0268] Length of participation. The participant will participate in
the trial for a minimum of 10 days. Required washout before Study
Day 1 will cause the length of participation to vary slightly among
participants. The Study Day Minus visit will last about half an
hour. The Day 1 visit will last approximately 24 hours because the
participant will keep the probe in their stomach for 24 hours. The
Day 2 visit will last 30 minutes. There will then be a 7-day
washout period between study drugs. The Day 8 visit will last
approximately 24 hours because the participant will keep the probe
in their stomach for 24 hours, and the Day 9 and final visit will
last 30 minutes.
[0269] Storage of Investigational Products. The investigational
products will be dispensed only by the pharmacist in charge of
investigational drug trials. Bravo pH probes, tethering equipment
and blood draw supplies will be stored at the study site.
[0270] Dispensing Investigational Products. The investigational
products will be dispensed in a 50 mL centrifuge tube. Before the
study drug is consumed by the participant, 30 mL of water will be
added and mixed.
[0271] Randomization Codes. Maintenance of trial treatment
randomization codes and procedures for breaking codes is as
follows: the blind may be broken in the case of a serious adverse
event. The IDS pharmacist in charge of the study drug and in charge
of randomizing the participant will have a participant list and
information on what study medication they are taking. The
participant will be given a card to carry with them stating that
they are enrolled in a clinical trial, brief details of the trial
and who to call in case of an emergency.
[0272] Data to be recorded on the CRF. Participant initials, sex,
date of birth, ethnicity, pregnancy and lactation status,
inclusion/exclusion criteria, concomitant medications, relevant
medical history, blood test data, pH probe data, time of blood
collections and the time of consumption of the study medication,
any use of a prohibited medication and adverse events.
[0273] Methods
[0274] Study drug form. The study drugs will be in the form of a
suspension consisting of powder for oral administration mixed with
30 mL of water.
[0275] Methods used to identify and recruit participants. Word of
mouth.
[0276] Methods used to avoid inadvertent coercion in the
recruitment process. Potential participants will receive written
informed consent information. The participants will be assured that
they have the right to not participate.
[0277] Bravo pH probe. The Bravo pH probe will be deployed from its
delivery system so that the probe is separate from the delivery
mechanism before it is swallowed by the patient. A 0.1 mm diameter
polyester braided tethering string will be tied securely around the
pin at the top of the probe in order to secure the string to the
probe. A bead will be attached to the string at the patient's lip
to mark placement. Two tegaderms will be used to secure the string
to the participant's cheek.
[0278] Pregnancy and lactation screening. Female participants of
child-bearing potential will be administered a urine pregnancy
test. They will be verbally asked if they are lactating.
[0279] Consent and Assent Processes and Documents
[0280] Type of Consent Process: Written
[0281] Description of the consent process. The study will be
explained in full detail. The participant will be allowed time to
read the consent. All questions will be answered. After verbal
assent is made, the participant will sign the consent. The original
will be kept with the study documents and the subject will be given
a copy.
[0282] Voluntary Participation. A participant may decide to
participate in this study or not to participate. If the participant
chooses not to participate, he or she may leave the study at any
time. The participant's decision will not affect the care the
participant will receive from any medical care provider or medical
benefits to which the participant is entitled. If the participant
decides to withdraw from the study at a later date, we will keep
the information we have collected up to that point but will not ask
the participant for any more information. We will continue to use
the data and specimens the participant provided up to that time
unless we get a signed written request from the participant asking
us not to do so. The investigator(s) conducting the study may also
decide to withdraw the participant from the study without his or
her consent if it is determined that the participant is not
actually eligible or is no longer able to complete the requirements
of the study.
[0283] Blood Collection
[0284] All IV insertions will be performed by a registered nurse or
by a licensed practical nurse who is certified to start IVs. The
goal of the blood collection is to characterize the
pharmacokinetics of omeprazole and lansoprazole in the subjects and
to determine the levels of Gastrin-17 over the course of the
collection period. An occasional blood sample may be collected
slightly outside of the scheduled time. The characterization of
pharmacokinetics can accommodate different times if the actual time
of blood collection is recorded. The scheduled and actual time of
the blood collection will be recorded on the CRF. If the IV becomes
occluded and another cannot be started in time for the next
scheduled blood draw, a butterfly needle will be used to obtain the
needed blood sample. Every effort will be made to adhere to the
blood draw schedule. Over the course of two treatment periods
twenty 4-mL blood samples and two 5 mL blood samples will be
collected, for a total of 90 mL of blood. After each blood
collection approximately 3-5 mL of 0.9% Sodium Chloride will be
flushed through the participant's IV catheter to prevent blockage
in the IV cannula.
[0285] Banking. Blood will not be banked (kept indefinitely), for
use in other research not related to this project.
[0286] Selection and Withdrawal of Subjects
[0287] Inclusion Criteria [0288] 1. Adult between 18 and 60 years
of age. [0289] 2. If a female is of child-bearing potential, they
must be using an acceptable form of birth control: oral
contraceptive, intra-uterine device, contraceptive patch,
injection, or vaginal ring, double-barrier method i.e. condoms and
spermicide, tubal ligation, abstinence, or male partner with a
vasectomy. [0290] 3. Ability to swallow a multi-vitamin sized pill
with water, without difficulty. [0291] 4. Willing and able to
comply with all study procedures.
[0292] Exclusion Criteria [0293] 1. Concomitant use of any
medication used to treat acid reflux. [0294] 2. Use of an
investigational drug with in 30 days prior to enrollment. [0295] 3.
Chronic PPI use. [0296] 4. PPI use 7 days prior to enrollment.
[0297] 5. H2 receptor antagonist use for 8 hours prior to
enrollment. [0298] 6. Antacid use 4 hours prior to enrollment.
[0299] 7. Pregnant or lactating female. [0300] 8. Dysphagia, or a
feeling that food gets "stuck". [0301] 9. Diabetes. [0302] 10.
Liver disease. [0303] 11. Allergies to any study medication [0304]
12. Allergies to cheese. [0305] 13. Use of any drug/herbal
supplement in the five days or ten half-lives prior to Study Day 1
and Study Day 8 (whichever is longer) that is partially or
completely metabolized by Cytochrome P450 2C 19 or 3A4. [0306] 14.
Use of any drug/herbal supplement in the past five days or ten
half-lives (whichever is longer) that affects gastrin
production.
[0307] Withdrawal/Early Termination Criteria [0308] 1. Participant
withdraws consent. [0309] 2. Vomiting from probe placement that
produces severe fluid losses (greater than 1.5 Liters) [0310] 3.
Participant experiences a serious adverse event.
[0311] Treatment of Subjects
[0312] Concomitant medications. Concomitant use of the following
will be prohibited: Any medication used to treat acid reflux will
not be permitted during the study. The use of any drug/herbal
supplement in the five days or ten half-lives before Study Day 1
and Study Day 8, (whichever is longer) that is partially or
completely metabolized by Cytochrome P450 2C19 or 3A4. The use of
any drug/herbal supplement in the five days or ten half-lives
before Study Day 1 and Study Day 8, (whichever is longer) that
affects gastrin production.
[0313] Treatments to be administered. Omeprazole 80 mg plus
lansoprazole 80 mg power will be administered orally in the form of
a suspension in 30 mL of water. It will be given once on Study day
1 or 8. Zegerid 40 mg powder will be also be administered orally as
a suspension in 30 mL of water. It will be given once on Study day
1 or 8.
[0314] Treatment compliance. The procedure for monitoring treatment
compliance will consist of the study staff observing the
participant taking the study medication. The participant will be
questioned by study staff on the use of prohibited medications.
[0315] Evaluation of Benefits and Risks/Discomforts/Adverse
Events
[0316] Definition of adverse events. An adverse event is any
untoward medical occurrence in a subject administered a
pharmaceutical product. The AE does not necessarily have a causal
relationship with the treatment. An AE can be any unfavorable and
unintended sign, symptom, or disease temporarily associated with
the use of a pharmaceutical product. A pre-existing condition is
only considered an AE if there is an increase in frequency or
severity or a change in nature or as a consequence of use of a
medication in a clinical trial. Any AE with an onset date after
consent and through study completion will be recorded in the CRF on
the appropriate page.
[0317] An AE does not include: [0318] Medical or surgical
procedures; the condition that leads to the procedure is the AE
[0319] Pre-existing diseases or conditions present prior to
consent. [0320] Situations where an untoward medical occurrence has
not occurred (e.g., hospitalization for elective surgery, social
and/or convenience admissions)
[0321] Assessment of AEs. All AEs will be assessed by the
investigators and recorded on the appropriate CRF page. Data
recorded will include onset, resolution and outcome, severity,
relationship to the study medication, and action taken.
[0322] Procedures for recording and reporting adverse events. AEs
and SAEs will be reported to the IRB per the IRB policy. AEs and
SAEs will be recorded in the Case Report Form binder.
[0323] Reasonably foreseeable risks and discomforts to the
subjects. Study's foreseeable risks and discomforts of adverse
events related to omeprazole contained in Zegerid are uncommon and
mild. Adverse Events related to omeprazole and side effects related
to lansoprazole and omeprazole are abdominal pain, asthenia,
constipation, diarrhea and headache. Vomiting and/or gagging,
coughing and aspiration of fluid into the lungs are possible
adverse events of swallowing and withdrawing the Bravo pH probe.
Possible adverse events of the tether are sore throat, superficial
trauma to the oropharynx, intolerance and nausea. Possible adverse
events of the tape used to secure the tether are skin rash and
superficial skin trauma.
[0324] Procedures used to prevent and/or minimize any potential
risks and discomfort. Participants will be monitored throughout the
clinical phase of this study by study staff as follows: [0325]
Participants will be monitored for signs and symptoms of allergic
reaction to the test articles. [0326] Participants will be
monitored for signs and symptoms of potential risks and discomfort
potentially related to blood collection and the swallowing of the
probe. [0327] Procedures/tests will be performed and explained by
experienced staff. [0328] The tethering string will be used to
reduce the risk of aspiration.
[0329] Appropriate personnel will be present when the participant
swallows the Bravo pH probe and at withdraw the probe.
Alternatively, the participant may choose to have the string cut.
If resistance is met when withdrawing the probe, the string will be
cut and appropriate personnel will be notified.
[0330] Potential benefits of participation for the subject. There
may or may not be direct medical benefit to the participant. A
participant may expect to benefit from taking part in this research
to the extent that he/she is contributing to medical knowledge. We
hope the information learned from this study will benefit other
patients who require immediate control of acid secretion in the
future.
[0331] The risk/benefit relationship for the participant in this
project. The risk relative to benefit is minimal for two reasons:
(1) PPI drugs are very specific in their mechanism of action as
they are Pro-drugs that are only converted to their active form at
a pH below 2. Since the only physiological location that satisfies
this requirement is the parietal cell canalicular space, the
effects of the drug are limited only to this area and (2) The
subjects receive one dose of each drug separated by at least one
week; therefore there is no chronic exposure risk. The possible
benefit of taking part in this study is improving treatment for
patients requiring immediate control of acid secretion.
[0332] Pregnancy
[0333] Pregnancy test administration. A urine pregnancy test will
be administered to women of childbearing potential prior to
acceptance into study and prior to the second dose of study drug in
the second treatment period. Those testing positive will be
excluded from the study. Lansoprazole is in pregnancy category B
and Omeprazole and Zegerid are in category C. In studies of rats,
lansoprazole or its metabolites were found to be excreted in breast
milk. It is not known if Omeprazole is excreted into breast
milk.
[0334] Birth control for women of child-bearing potential.
Acceptable methods of birth control will be: [0335] Oral
contraceptive [0336] Intra-uterine device [0337] Contraceptive
injection, patch, or vaginal ring [0338] Double-barrier method;
i.e. condom and spermicide [0339] Tubal ligation [0340] Male
partner with a vasectomy [0341] Abstinence
[0342] Assessment of Efficacy
[0343] Specification of the efficacy parameters. The pH probe data
will be used to determine integrated gastric acidity, an accepted
measure of PPI efficacy, using the AcidipHy software.
[0344] Methods and timing for assessing, recording, and analyzing
safety parameters. The goal of the blood draws is to characterize
the pharmacokinetics of omeprazole and lansoprazole and the levels
of Gastrin-17 in the participant's bloodstream. The concentration
of omeprazole and lansoprazole in the participant's plasma will be
determined and plotted on a concentration vs. time graph, which
allows the determination of important pharmacokinetic parameters
like elimination half-life (t.sub.1/2), area under the curve of
drug concentration (AUC), and maximum concentration (C.sub.max).
These parameters will give a good approximation of how much of the
drug is in the participant's bloodstream and how long it stays
there; therefore, an analysis can be made of when (and to what
extent) the drug is most active in the participant.
[0345] The gastrin-17 assay will be conducted with each blood
sample to determine the response of gastrin to the drug and to
meals. Elevated gastrin concentrations are an indicator of
increased activity of the parietal cells, which are the cells
responsible for acid production in the stomach. The concentration
of gastrin will be plotted on a separate graph with respect to time
and will give an improved idea of how much stomach acid would
normally be produced at any given time. The PPI inhibits the proton
pumps and prevents the production of the acid, so the gastrin
results (when combined with the pH) will help determine how
effective the PPI is at suppressing the acid production.
[0346] It will be acceptable for blood draws to extend outside of
scheduled times since characterization of pharmacokinetics can
accommodate different times than scheduled if accurate time of
blood draw is noted. Every effort will be made to adhere to the
blood draw schedule.
[0347] Statistics
[0348] Statistical method. Statistical method to be used to analyze
and compare data will be Student's T-test for paired data.
[0349] Power analysis. A 50% reduction in integrated acidity is
expected on Day 1 when comparing: a single dose of Zegerid 40 mg to
a single dose of omeprazole 80 mg plus lansoprazole 80 mg. The
Power calculation results in a sample size per arm of 13 subjects,
therefore a minimum of 26 subjects will be required for the full
study. Enrollment of a total of 30 subjects will allow for
drop-outs, of which 10% is expected. The calculation is based upon
this formula
TABLE-US-00013 n = S 1 .times. ( 100 - S 1 ) + S 2 .times. ( 100 -
S 2 ) ( S 2 - S 1 ) 2 .times. f ( .alpha. , .beta. ) ##EQU00002##
.beta.(Type II error) 0.05 0.1 0.2 0.5 .alpha. 0.1 10.8 8.6 6.2 2.7
(Type I error) 0.05 13 10.5 7.9 3.8 0.02 15.8 13 10 5.4 0.01 17.8
14.9 11.7 6.6 Use the table above to calculate the f(.alpha.,
.beta.). Choose an .alpha. and .beta. then cross reference.
[0350] Level of significance. Level of significance to be used is
p<0.05 alpha p<0.2 beta.
[0351] Procedure for accounting for missing or unused data. How and
why the data was lost will be recorded. A calculation of
pharmacokinetic parameters and integrated gastric acidity can
proceed with some loss of data.
[0352] Participants to be included. The participants to be included
in the analyses are healthy volunteers that complete the trial.
[0353] Study Costs
[0354] Costs that will not be paid by participants or their
insurance providers
[0355] Study costs are limited to:
[0356] All supplies needed for blood collection and all tests
performed on the blood.
[0357] Study medications.
[0358] Bravo pH probe and associated monitor.
[0359] Breakfast and lunch meals.
[0360] Cost that will be paid by participants or their insurance
providers. The participant will be required to pay for their
transportation and parking and other travel costs. The use of other
medications to help control side effects could result in added
costs that may or may not be covered by participants' medical
insurance. Upon completion of the trial, the participant will be
paid up to the amount of $500. For the Study Day Minus visit they
will receive $20. For each of the Study Days 1, 2, 8 and 9 visits
they will receive $120. To receive the $120 at Study Days 1 and 8
the participant is required to make an effort to swallow the Bravo
pH probe and if swallowed, to keep the probe in their stomach and
to allow at least two attempts for insertion of an IV for blood
draws. On Study Days 2 and 9 they are required to successfully
complete the study procedures of the previous visits and to return
the Bravo pH probe monitor. If the participant experiences and
adverse event and cannot continue in the study they will receive
compensation up through the visit day they experienced that adverse
event.
[0361] Direct Access to Source/Data Documents
[0362] The investigator(s)/institution will permit trial-related
monitoring, audits, IRB/IEC review, and regulatory inspection(s) by
providing direct access to source data/documents. The FDA may also
perform trial-related audits and will have direct access to all
source data/documents.
[0363] Quality Control and Quality Assurance
[0364] Study medications will be purchased from the manufacturer
and will be dispensed by appropriate personnel.
[0365] Compliance Statement. This trial will be compliant with Good
Clinical Practice and will meet all Institutional Review Board
requirements.
[0366] Data Safety Monitoring Plan. Study data will be reviewed
after each group of participants, including a review of AEs for
trends. The study staff will review the data and monitor the
patients throughout the study and alert appropriate personnel if an
adverse event is suspected. All adverse events will be reviewed by
appropriate personnel. Appropriate personnel will be present when
the participant swallows the Bravo pH probe and at withdraw the
probe. If resistance is met, the string will be cut and appropriate
personnel notified. Appropriate personnel will remain on call if
complications arise while the participant is in an exam room. 911
will be used as back-up if they are unavailable. A crash cart will
be available. Blood testing data will be analyzed. Test results and
data files will be shared among those registered with the IRB as
working on this study. All participant data and test results will
be kept securely maintained at all times.
[0367] All references, including publications, patent applications,
and patents, cited herein are hereby incorporated by reference to
the same extent as if each reference there individually and
specifically indicated to be incorporated by reference and were set
forth in its entirety herein.
[0368] The use of the terms "a" and "an" and "the" and similar
referents in the context of this disclosure (especially in the
context of the following claims) are to be construed to cover both
the singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. All methods described herein can
be performed in any suitable order unless otherwise indicated
herein or otherwise clearly contradicted by context. The use of any
and all examples, or exemplary language (e.g., such as, preferred,
preferably, particularly) provided herein, is intended merely to
further illustrate the content of the disclosure and does not pose
a limitation on the scope of the claims. No language in the
specification should be construed as indicating any non-claimed
element as essential to the practice of the claimed invention.
[0369] Alternative embodiments of the claimed invention are
described herein, including the best mode known to the inventors
for carrying out the claimed invention. Of these, variations of the
disclosed embodiments will become apparent to those of ordinary
skill in the art upon reading the foregoing disclosure. The
inventors expect skilled artisans to employ such variations as
appropriate, and the inventors intend for the claimed invention to
be practiced otherwise than as specifically described herein.
[0370] Accordingly, the claimed invention includes all
modifications and equivalents of the subject matter recited in the
claims appended hereto as permitted by applicable law. Moreover,
any combination of the above-described elements in all possible
variations thereof is encompassed by the claimed invention unless
otherwise indicated herein or otherwise clearly contradicted by
context.
[0371] The use of individual numerical values are stated as
approximations as though the values were preceded by the word
"about" or "approximately." Similarly, the numerical values in the
various ranges specified in this application, unless expressly
indicated otherwise, are stated as approximations as though the
minimum and maximum values within the stated ranges were both
preceded by the word "about" or "approximately." In this manner,
variations above and below the stated ranges can be used to achieve
substantially the same results as values within the ranges. As used
herein, the terms "about" and "approximately" when referring to a
numerical value shall have their plain and ordinary meanings to a
person of ordinary skill in the art to which the disclosed subject
matter is most closely related or the art relevant to the range or
element at issue. The amount of broadening from the strict
numerical boundary depends upon many factors. For example, some of
the factors which may be considered include the criticality of the
element and/or the effect a given amount of variation will have on
the performance of the claimed subject matter, as well as other
considerations known to those of skill in the art. As used herein,
the use of differing amounts of significant digits for different
numerical values is not meant to limit how the use of the words
"about" or "approximately" will serve to broaden a particular
numerical value. Thus, as a general matter, "about" or
"approximately" broaden the numerical value. Also, the disclosure
of ranges is intended as a continuous range including every value
between the minimum and maximum values plus the broadening of the
range afforded by the use of the term "about" or "approximately."
Thus, recitation of ranges of values herein are merely intended to
serve as a shorthand method of referring individually to each
separate value falling within the range, unless otherwise indicated
herein, and each separate value is incorporated into the
specification as if it there individually recited herein.
[0372] It is to be understood that any ranges, ratios and ranges of
ratios that can be formed by, or derived from, any of the data
disclosed herein represent further embodiments of the present
disclosure and are included as part of the disclosure as though
they were explicitly set forth. This includes ranges that can be
formed that do or do not include a finite upper and/or lower
boundary. Accordingly, a person of ordinary skill in the art most
closely related to a particular range, ratio or range of ratios
will appreciate that such values are unambiguously derivable from
the data presented herein.
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