US 2005O239845A1

(19) United States

(12) Patent Application Publication (10) Pub. No.: US 2005/0239845A1
Proehl et al. (43) Pub. Date: Oct. 27, 2005
(54) COMBINATION OF PROTON PUMP Related U.S. Application Data
INHIBITOR, BUFFERING AGENT, AND
PROKINETICAGENT (60) Provisional application No. 60/562,820, filed on Apr.
16, 2004.
(75) Inventors: Gerald T. Proehl, San Diego, CA (US);
Warren Hall, Del Mar, CA (US); Kay Publication Classification
Olmstead, San Diego, CA (US); 7
Bonnie Hepburn, Escondido, CA (US) (51) Int. Cl.' ................................................ A61K 31/4439
(52) U.S. Cl. .............................................................. 514/338
Correspondence Address:
WILSON SONS IN GOODRICH & ROSAT (57) ABSTRACT
650 PAGE MILL ROAD
PALO ALTO, CA 94304-1050 (US) Pharmaceutical compositions comprising a proton pump
(73) Assignee: Santarus, Inc. inhibitor, one or more buffering agent and a prokinetic agent
9 are described. Methods are described for treating gastric acid
(21) Appl. No.: 11/107,349 related disorders, using pharmaceutical compositions com
prising a proton pump inhibitor, a buffering agent, and a
(22) Filed: Apr. 15, 2005 prokinetic agent.
US 2005/0239845 A1 Oct. 27, 2005

COMBINATION OF PROTON PUMP INHIBITOR, 0006 Proton pump inhibitors are typically prescribed for
BUFFERING AGENT, AND PROKINETICAGENT Short-term treatment of active duodenal ulcers, gastrointes
tinal ulcers, gastroesophageal reflux disease (GERD), Severe
CROSS REFERENCE TO RELATED erosive esophagitis, poorly responsive Symptomatic GERD,
APPLICATIONS and pathological hyperSecretory conditions Such as
Zollinger Ellison syndrome. These above-listed conditions
0001. This application claims priority to U.S. Provisional commonly arise in healthy or critically ill patients of all
Application Ser. No. 60/562,820 filed Apr. 16, 2004, which ages, and may be accompanied by Significant upper gas
is incorporated herein by reference in its entirety. trointestinal bleeding.
FIELD OF THE INVENTION 0007. It is believed that omeprazole, lansoprazole and
other proton pump inhibiting agents reduce gastrointestinal
0002 The present invention is related to pharmaceutical acid production by inhibiting H/K"-ATPase of the parietal
compositions comprising a proton pump inhibitor, a buffer cell, which is the final common pathway for gastrointestinal
ing agent, and a prokinetic agent. Methods for manufacture acid Secretion. See, e.g., Fellenius et al., Substituted Benz
of the pharmaceutical compositions and use of the pharma imidazoles Inhibit Gastrointestinal Acid Secretion by Block
ceutical compositions in treating disease are disclosed. ing H"/K"-ATPase, Nature, 290: 159-161 (1981); Wallmark
et al., The Relationship Between Gastrointestinal Acid
BACKGROUND OF THE INVENTION Secretion and Gastrointestinal H"/K"-ATPase Activity, J.
Biol. Chem., 260: 13681-13684 (1985); and Fryklund et al.,
0003) Proton Pump Inhibitors Function and Structure of Parietal Cells. After H/K-AT
0004 Proton pump inhibitors (PPIs) are a class of acid Pase Blockade, Am. J. Physiol., 254 (1988).
labile pharmaceutical compounds that block gastric acid 0008 Proton pump inhibitors have the ability to act as
Secretion pathways. Exemplary proton pump inhibitors weak bases which reach parietal cells from the blood and
include, omeprazole (Prilosec(R), lansoprazole (Prevacid(R), diffuse into the Secretory canaliculi. There the drugs become
esomeprazole (Nexium(R), rabeprazole (Aciphex(E), panto protonated and thereby trapped. The protonated compound
prazole (Protonix(E), pariprazole, tenatoprazole, and lemi can then rearrange to form a Sulfenamide which can
noprazole. The drugs of this class SuppreSS gastrointestinal covalently interact with Sulfhydryl groups at critical Sites in
acid secretion by the specific inhibition of the H/K"- the extra cellular (luminal) domain of the membrane-Span
ATPase enzyme System (proton pump) at the Secretory ning H/K-ATPase. See, e.g., Hardman et al., Goodman &
Surface of the gastrointestinal parietal cell. Most proton Gilman's The Pharmacological Basis of Therapeutics, 907
pump inhibitors are Susceptible to acid degradation and, as (9th ed. 1996). As such, proton pump inhibitors are prodrugs
Such, are rapidly destroyed in an acidic pH environment in that must be activated within parietal cells to be effective.
the Stomach. Therefore, proton pump inhibitors are often The Specificity of the effects of proton pump inhibiting
administered as enteric-coated dosage forms in order to agents is also dependent upon: (a) the Selective distribution
permit release of the drug in the duodenum after having of H"/K"-ATPase; (b) the requirement for acidic conditions
passed through the Stomach. If the enteric-coating of these to catalyze generation of the reactive inhibitor; and (c) the
formulated products is disrupted (e.g., during trituration to trapping of the protonated drug and the cationic Sulfenamide
compound a liquid dosage form, or by chewing an enteri within the acidic canaliculi and adjacent to the target
coated granular capsule or tablet), or if a co-administered enzyme.
buffering agent fails to Sufficiently neutralize the gastrointes 0009 Prokinetic Agents
tinal pH, the uncoated drug is exposed to Stomach acid and
may be degraded. 0010 Prokinetic agents may be prescribed in the treate
0005 Omeprazole, a substituted bicyclic aryl-imidazole, ment of Vaious gastrointestinal diseases, Such as gastroe
5-methoxy-2-(4-methoxy-3, 5-dimethyl-2-pyridinyl)m- sophageal reflux disease (GERD), inflammatory bowel dis
ethylsulfinyl)-1H-benzimidazole, is a proton pump inhibi ease, or to treat primary gastrointestinal motility disorders,
tor that inhibits gastrointestinal acid secretion. U.S. Pat. No. Such as diffuse esophageal Spasm or irritable bowel Syn
4,786,505 to Lovgren et al. teaches that a pharmaceutical drome. Motility disorders of the gastrointestinal tract may be
oral Solid dosage form of omeprazole must be protected caused by neural, muscular, or receptor damaage dysfunc
from contact with acidic gastrointestinal juice by an enteric tion. Examples of neural, muscular, and receptor damage or
coating to maintain its pharmaceutical activity and describes dysfunction include (but are not limited to) diabetic gastro
an enteric-coated omeprazole preparation containing one or paresis, Scleroderma, or the carcinoid Syndrome.
more Subcoats between the core material and the enteric 0011 For example, motility disorders can occur, when
coating. Non-enteric coated pharmaceutical compositions the nerves in the gastrointestinal tract are missing, immature,
have also been described, which facilitate immediate release or damaged, e.g., by infections or toxins. Motility disorders
of the pharmaceutically active ingredient into the Stomach can also occur when the nerves are adversely influenced by
and permit Stomach uptake of pharmaceutical agents. Use of chemical Substances from inside the body or outside the
non-enteric coated compositions involves the administration body. Additionally, motility disorders may occur when the
of one or more buffering agents with an acid labile proton GI muscles are diseased—either from a genetic defect (Such
pump inhibitor. The buffering agent is thought to prevent as Some forms of muscular dystrophy) or an acquired
Substantial degradation of the acid labile pharmaceutical disorder (Such as, for example, progressive Systemic Scle
agent in the acidic environment of the Stomach by raising the rosis and amyloidosis). Of course, there are other motility
stomach pH. See, e.g., U.S. Pat. Nos. 5,840,737; 6,489,346; disorcers for which the etiology is not known, Such as
6,645,998; and 6,699,885. irritable bowel Syndrome or functional dyspepsia.
US 2005/0239845 A1 Oct. 27, 2005

0012 Heartburn and constipation are two of the most agent in an amount Sufficient to increase gastric fluid pH to
common Symptoms of motility disorders. Other Symptoms a pH that prevents acid degradation of at least Some of the
include, for example, chronic Vomiting, nausea, cramping, proton pump inhibitor in the gastric fluid, and (c) a thera
bloating, abdominal distention and diarrhea after eating. The peutically effective amount of a 5-HT receptor, are pro
most common motility disturbance is termed “irritable vided herein.
bowel syndrome' which accounts for about 50% of all 0018 Compositions that include (a) a therapeutically
patients. Chronic intestinal pseudo-obstruction is the name effective amount of omeprazole, (b) at least one buffering
given to a group of rare nerve and muscle disorders which agent in an amount Sufficient to increase gastric fluid pH to
Severely affect gastrointestinal motility. Many children and a pH that prevents acid degradation of at least Some of the
adults with chronic intestinal pseudo-obstruction require proton pump inhibitor in the gastric fluid, and (c) a thera
tube feedings or parenteral nutrition. peutically effective amount of a 5-HT, receptor, are pro
0013 Prokinetic agents would be useful in concomitant vided herein.
therapy with proton pump inhibitors to treat patients with 0019 Compositions that include (a) a therapeutically
GERD, erosive esophagitis or functional dyspepsia. PPI and effective amount of omeprazole, (b) at least one buffering
prokinetic agent combinations increase the tone of the lower agent in an amount Sufficient to increase gastric fluid pH to
esophageal Sphincter, decrease the number of transient lower a pH that prevents acid degradation of at least Some of the
eSphageal relaxations, and increase gastric emptying while proton pump inhibitor in the gastric fluid, and (c) a thera
the proton pump inhibitor is administered which decreases peutically effective amount of at least one prokinetic agent
the Volume of gastric juice available for reflux into the Selected from Ondansetron, granisetron, dolanserton,
eSphagus and increases the pH So that refluxed gastric cisapride, norcisapride, loperamide, clonidine, metaclopra
contents are much less injurious to the esophageal mucosa. mide, domperidone, mosapride, itopride, levopride, tiropra
SUMMARY OF THE INVENTION mide, clebopride, dropreidol, promethazine, prochlorpera
0014 Pharmaceutical compositions including (a) a thera Zine, erythromycin ethylsuccinate, erythromycin
peutically effective amount of at least one acid labile proton lactobionate, bethanechol, bethanechol chloride, nor
pump inhibitor, (b) at least one buffering agent in an amount cisapride, and neoStigmine, are provided herein.
Sufficient to increase gastric fluid pH to a pH that prevents 0020 Compositions that include (a) a therapeutically
acid degradation of at least Some of the proton pump effective amount of lanSoprazole, (b) at least one buffering
inhibitor in the gastric fluid, and (c) a therapeutically effec agent in an amount Sufficient to increase gastric fluid pH to
tive amount of at least one prokinetic agent, are provided a pH that prevents acid degradation of at least Some of the
herein. Methods are provided for treating gastric acid related proton pump inhibitor in the gastric fluid, and (c) a thera
disorders in a Subject, using pharmaceutical compositions of peutically effective amount of a 5-HT receptor, are pro
the present invention. vided herein.
0.015 Proton pump inhibitors include, but are not limited 0021 Compositions that include (a) a therapeutically
to, omeprazole, hydroxyomeprazole, esomeprazole, tenato effective amount of lanSoprazole, (b) at least one buffering
prazole, lanSoprazole, pantoprazole, rabeprazole, dontopra agent in an amount Sufficient to increase gastric fluid pH to
Zole, habeprazole, periprazole, ranSoprazole, pariprazole, a pH that prevents acid degradation of at least Some of the
leminoprazole, or a free base, free acid, Salt, hydrate, ester, proton pump inhibitor in the gastric fluid, and (c) a thera
amide, enantiomer, isomer, tautomer, polymorph, or prodrug peutically effective amount of a 5-HT, receptor, are pro
thereof. In one embodiment, the proton pump inhibitor is vided herein.
omeprazole or a free base, free acid, Salt, hydrate, ester,
amide, enantiomer, isomer, tautomer, polymorph, or prodrug 0022 Compositions that include (a) a therapeutically
thereof. Compositions can contain between about 5 mgs to effective amount of lanSoprazole, (b) at least one buffering
about 200 mgs of proton pump inhibitor, Specifically about agent in an amount Sufficient to increase gastric fluid pH to
5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, a pH that prevents acid degradation of at least Some of the
about 40 mg, about 60 mg, or about 80 mg of the proton proton pump inhibitor in the gastric fluid, and (c) a thera
pump inhibitor. In alternative embodiments, compositions peutically effective amount of at least one prokinetic agent
can contain between about 250-3000 mg of proton pump Selected from Ondansetron, granisetron, dolanserton,
inhibitor. cisapride, norcisapride, loperamide, clonidine, metaclopra
mide, domperidone, mosapride, itopride, levopride, tiropra
0016 Prokinetic agents include but are not limited to mide, clebopride, dropreidol, promethazine, prochlorpera
5-HT inhibitors such as 5-HT, inhibitors (e.g., ondasetron, Zine, erythromycin ethylsuccinate, erythromycin
granisetron, and dolanserton) and 5-HT, inhibitors (e.g., lactobionate, bethanechol, bethanechol chloride, nor
cisapride), bulk forming agents such as phylium, polycar cisapride, and neoStigrinine, are provided herein.
bophil, and fiber; intraluminal agents Such as bismuth;
antimotility agents Such as loperamide and clonidine, Saline 0023 Compositions that include (a) a therapeutically
laxatives, and luminally active osmotic agents Such as effective amount of S-omeprazole, (b) at least one buffering
magnesium Sulfate and Sodium phosphate. Other exemplary agent in an amount Sufficient to increase gastric fluid pH to
prokinetic agents include mosapride, metoclopramide, dom a pH that prevents acid degradation of at least Some of the
peridone, clebopride, erythromycin (e.g., erythromycin eth proton pump inhibitor in the gastric fluid, and (c) a thera
ylsuccinate and erythromycin lactobionate), bethanechol peutically effective amount of a 5-HT, receptor, are pro
and bethanechol chloride, norcisapride, and neostigmine. vided herein.
0017 Compositions that include (a) a therapeutically 0024 Compositions that include (a) a therapeutically
effective amount of omeprazole, (b) at least one buffering effective amount of S-omeprazole, (b) at least one buffering
US 2005/0239845 A1 Oct. 27, 2005

agent in an amount Sufficient to increase gastric fluid pH to 0029 Compositions of the invention can be administered
a pH that prevents acid degradation of at least Some of the in an amount to achieve an initial Serum concentration of the
proton pump inhibitor in the gastric fluid, and (c) a thera proton pump inhibitor greater than about 150 ng/ml at any
peutically effective amount of a 5-HT, receptor, are pro time from about 5 mintues to about 30 minutes after admin
vided herein. istration. Compositions of the invention can be administered
in an amount to achieve an initial Serum concentration of the
0025 Compositions that include (a) a therapeutically proton pump inhibitor greater than about 150 ng/ml at any
effective amount of S-omeprazole, (b) at least one buffering time within about 30 minutes after administration.
agent in an amount Sufficient to increase gastric fluid pH to
a pH that prevents acid degradation of at least Some of the 0030 Compositions are provided wherein, upon oral
proton pump inhibitor in the gastric fluid, and (c) a thera administration to the Subject, the composition provides a
peutically effective amount of at least one prokinetic agent pharmacokinetic profile such that at least about 50% of total
Selected from ondansetron, granisetron, dolanserton, area under Serum concentration time curve (AUC) for the
cisapride, norcisapride, loperamide, clonidine, metaclopra proton pump inhibitor occurs within about 2 hours after
mide, domperidone, mosapride, itopride, levopride, tiropra administration of a single dose of the composition to the
mide, clebopride, dropreidol, promethazine, prochlorpera Subject. Compositions are provided wherein, upon oral
Zine, erythromycin ethylSuccinate, erythromycin administration to the Subject, the area under the Serum
lactobionate, bethanechol, bethanechol chloride, nor concentration time curve (AUC) for the proton pump inhibi
cisapride, and neoStigmine, are provided herein. tor in the first 2 hours is at least about 60% of the total area.
Compositions are provided wherein the area under the Serum
0.026 Compositions are provided such that an initial concentration time curve (AUC) for the proton pump inhibi
Serum concentration of the proton pump inhibitor is greater tor in the first 2 hours is at least about 70% of the total area.
than about 100 ng/ml at any time within about 30 minutes
after administering the formulation. Initial Serum concen 0031 Compositions are provided wherein at least about
tration of the proton pump inhibitor can be greater than 50% of total area under the serum concentration time curve
about 100 ng/ml at any time within about 15 minutes. Initial (AUC) for the proton pump inhibitor occurs within about
Serum concentration of the proton pump inhibitor can be 1.75 hours after administration of a single dose of the
greater than about 200 ng/ml at any time within about 1 hour composition to the Subject. Compositions are provided
after administration, greater than about 300 ng/ml at any wherein at least about 50% of total area under the serum
time within about 45 minutes after administration. concentration time curve (AUC) for the proton pump inhibi
tor occurs within about 1.5 hours after administration of a
0.027 Compositions are provided such that a serum con Single dose of the composition to the Subject. Compositions
centration of greater than about 0.1 ug/ml can be maintained are provided wherein at least about 50% of total area under
from at least about 30 minutes to about 1 hour after
administration of the composition. Compositions are pro the Serum concentration time curve (AUC) for the proton
pump inhibitor occurs within about 1 hour after administra
Vided Such that a Serum concentration of proton pump tion of a Single dose of the composition to the Subject.
inhibitor greater than about 100 ng/ml can be maintained
from at least about 15 minutes to about 30 minutes. Com 0032 Compositions are provided wherein, upon oral
positions are provided Such that a Serum concentration of administration to the Subject, the composition provides a
greater than about 100 ng/ml can be maintained from at least pharmacokinetic profile Such that the proton pump inhibitor
about 30 minutes to about 45 minutes. Compositions are reaches a maximum Serum concentration within about 1
provided Such that a Serum concentration of greater than hour after administration of a Single dose of the composition.
about 250 ng/ml can be maintained from at least about 30 Compositions are provided wherein the maximum Serum
minutes to about 1 hour. Compositions are provided Such concentration is reached within about 45 minutes after
that a Serum concentration of greater than about 250 ng/ml administration of the composition. Compositions are pro
can be maintained from at least about 30 minutes to about 45 Vided wherein the maximum Serum concentration is reached
minutes. Compositions are provided Such that a Serum within about 30 minutes after administration of the compo
concentration of greater than about 250 ng/ml can be main Sition.
tained from at least about 15 minutes to about 30 minutes.
0033 Compositions are provided wherein at least some
0028 Compositions of the invention can be administered of the proton pump inhibitor is microencapsulated with a
in an amount to maintain a Serum concentration of the proton material that enhances the shelf-life of the pharmaceutical
pump inhibitor greater than about 150 ng/ml from about 15 composition. Compositions are provided wherein at least
minutes to about 1 hour after administration. Compositions Some of the prokinetic agent is microencapsulated with a
of the invention can be administered in an amount to material that enhances the shelf-life of the pharmaceutical
maintain a Serum concentration of the proton pump inhibitor composition. Compositions are provided wherein Some of
greater than about 150 ng/ml from about 15 minutes to about the proton pump inhibitor and Some of the prokinetic agent
1.5 hours after administration. Compositions of the inven are microencapsulated with a material that enhances the
tion can be administered in an amount to maintain a Serum shelf-life of the pharmaceutical composition. Materials that
concentration of the proton pump inhibitor greater than enhance the shelf-life of the pharmaceutical composition
about 100 ng/ml from about 15 minutes to about 1.5 hours include, but are not limited to, cellulose hydroxypropyl
after administration. Compositions of the invention can be ethers, low-Substituted hydroxypropyl ethers, cellulose
administered in an amount to maintain a Serum concentra hydroxypropyl methyl ethers, methylcellulose polymers,
tion of the proton pump inhibitor greater than about 150 ethylcelluloses and mixtures thereof, polyvinyl alcohol,
ng/ml from about 15 minutes to about 30 minutes after hydroxyethylcelluloses, carboxymethylcelluloses, Salts of
administration. carboxymethylcelluloses, polyvinyl alcohol, polyethylene
US 2005/0239845 A1 Oct. 27, 2005

glycol co-polymers, monoglycerides, triglycerides, polyeth increase gastric fluid pH to a pH that prevents acid degra
ylene glycols, modified food Starch, acrylic polymers, mix dation of at least Some of the proton pump inhibitor in the
tures of acrylic polymers with cellulose ethers, cellulose gastric fluid, and (c) a therapeutically effective amount of at
acetate phthalate, Sepifilms, cyclodextrins; and mixtures least one prokinetic agent, wherein the compositions are free
thereof. The cellulose hydroxypropyl ether can be, but is not of Sucralfate are provided herein.
limited to, Klucel(R) or Nisso HPC. The cellulose hydrox 0038 Compositions are provided that include (a) a thera
ypropyl methyl ether can be, but is not limited to, Seppifilm peutically effective amount of at least one acid labile proton
LC, Pharmacoat(R), Metolose SR, Opadry YS, PrimaFlo, pump inhibitor wherein at least Some of the proton pump
BenecelMP824, or BenecelMP843. The mixture of methyl inhibitor is coated, (b) at least one buffering agent in an
cellulose and hydroxypropyl and methylcellulose polymers amount Sufficient to increase gastric fluid pH to a pH that
can be, but is not limited to, Methocel(R), Benecel-MC, or prevents acid degradation of at least Some of the proton
Metolose(R). The ethylcellulose or mixture thereof can be, pump inhibitor in the gastric fluid, and (c) a therapeutically
but are not limited to, Ethocel(R), BenecelMO43, Celacal, effective amount of at least one prokinetic agent, wherein the
Cumibak N.C., and E461. The polyvinyl alcohol can be, but proton pump inhibitor is useful for treating a gastric acid
is not limited to, Opadry AMB. The acrylic polymers or related disorder.
mixtures thereof include, but are not limited to, EudragitS(R)
EPO, Eudragits(R RD100, and Eudragits(R E100. Other 0039) Compositions are provided that include (a) a thera
materials that enhance the shelf-life of the pharmaceutical peutically effective amount of at least one acid labile proton
composition include, but are not limited to, NatroSol E), pump inhibitor, (b) at least one buffering agent in an amount
Aqualon(R)-CMC, and Kollicoat IRCR. The material that Sufficient to increase gastric fluid pH to a pH that prevents
enhances the Shelf-life of the pharmaceutical composition acid degradation of at least Some of the proton pump
can further include other compatible materials. Such as an inhibitor in the gastric fluid, and (c) a therapeutically effec
antioxidant, a plasticizer, a buffering agent, and mixtures tive amount of at least one prokinetic agent, wherein the
thereof. prokinetic agent is a 5-HT inhibitor. Compositions are
0034 Compositions are provided that include (a) a thera provided herein wherein the 5-HT inhibitor is a 5-HT, or
peutically effective amount of at least one acid labile proton 5-HT, inhibitor.
pump inhibitor wherein at least Some of the proton pump 0040 Compositions including (a) a therapeutically effec
inhibitor, (b) at least one buffering agent in an amount tive amount of at least one acid labile proton pump inhibitor,
sufficient to increase gastric fluid pH to a pH that prevents (b) at least one buffering agent in an amount sufficient to
acid degradation of at least Some of the proton pump increase gastric fluid pH to a pH that prevents acid degra
inhibitor in the gastric fluid, (c) a therapeutically effective dation of at least Some of the proton pump inhibitor in the
amount of at least one prokinetic agent, and (d) at least one gastric fluid, and (c) a therapeutically effective amount of at
thickening agent, wherein the dosage form is a powder for least one prokinetic agent, wherein the buffering agent is an
Suspension. In Some embodiments, the powder for Suspen alkaline earth metal Salt or a Group IA metal Selected from
Sion is Substantially uniform or creates a Substantially uni a bicarbonate Salt of a Group LA metal, a carbonate Salt of
form Suspension when mixed. a Group IA metal. The buffering agent can be, but is not
limited to, an amino acid, an alkali metal Salt of an amino
0035 Compositions are provided that include (a) a thera acid, aluminum hydroxide, aluminum hydroxide/magne
peutically effective amount of at least one acid labile proton sium carbonate/calcium carbonate co-precipitate, aluminum
pump inhibitor wherein at least Some of the proton pump magnesium hydroxide, aluminum hydroxide/magnesium
inhibitor is microencapsulated, (b) at least one buffering hydroxide co-precipitate, aluminum hydroxide/sodium
agent in an amount Sufficient to increase gastric fluid pH to bicarbonate coprecipitate, aluminum glycinate, calcium
a pH that prevents acid degradation of at least Some of the acetate, calcium bicarbonate, calcium borate, calcium car
proton pump inhibitor in the gastric fluid, (c) a therapeuti bonate, calcium citrate, calcium gluconate, calcium glycero
cally effective amount of at least one prokinetic agent, and phosphate, calcium hydroxide, calcium lactate, calcium
(d) at least one thickening agent, wherein the dosage form is phthalate, calcium phosphate, calcium Succinate, calcium
a powder for Suspension. In Some embodiments, the powder tartrate, dibasic Sodium phosphate, dipotassium hydrogen
for Suspension is Substantially uniform or creates a Substan phosphate, dipotassium phosphate, disodium hydrogen
tially uniform Suspension when mixed. phosphate, disodium Succinate, dry aluminum hydroxide
0036 Compositions are provided that include (a) a thera gel, L-arginine, magnesium acetate, magnesium aluminate,
peutically effective amount of at least one acid labile proton magnesium borate, magnesium bicarbonate, magnesium
pump inhibitor, (b) at least one buffering agent in an amount carbonate, magnesium citrate, magnesium gluconate, mag
Sufficient to increase gastric fluid pH to a pH that prevents nesium hydroxide, magnesium lactate, magnesium metasili
acid degradation of at least Some of the proton pump cate aluminate, magnesium oxide, magnesium phthalate,
inhibitor in the gastric fluid, (c) a therapeutically effective magnesium phosphate, magnesium Silicate, magnesium Suc
amount of at least one prokinetic agent wherein at least Some cinate, magnesium tartrate, potassium acetate, potassium
of the prokinetic agent is coated, and (d) at least one carbonate, potassium bicarbonate, potassium borate, potas
thickening agent, wherein the dosage form is a powder for sium citrate, potassium metaphosphate, potassium phthalate,
Suspension. In Some embodiments, the powder for Suspen potassium phosphate, potassium polyphosphate, potassium
Sion is Substantially uniform. pyrophosphate, potassium Succinate, potassium tartrate,
Sodium acetate, Sodium bicarbonate, Sodium borate, Sodium
0037 Compositions including (a) a therapeutically effec carbonate, Sodium citrate, Sodium gluconate, Sodium hydro
tive amount of at least one acid labile proton pump inhibitor, gen phosphate, Sodium hydroxide, Sodium lactate, Sodium
(b) at least one buffering agent in an amount Sufficient to phthalate, Sodium phosphate, Sodium polyphosphate,
US 2005/0239845 A1 Oct. 27, 2005

Sodium pyrophosphate, Sodium Sesquicarbonate, Sodium to increase gastric fluid, and (c) a therapeutically effective
Succinate, Sodium tartrate, Sodium tripolyphosphate, Syn amount of at least one prokinetic agent are provided.
thetic hydrotalcite, tetrapotassium pyrophosphate, tetraso
dium pyrophosphate, tripotassium phosphate, triSodium 0046 Compositions including (a) a therapeutically effec
phosphate, trometamol, and mixtures thereof. In particular, tive amount of at least one acid labile proton pump inhibitor,
the buffering agent can be Sodium bicarbonate, Sodium (b) at least one buffering agent in an amount Sufficient to
carbonate, calcium carbonate, magnesium oxide, magne increase gastric fluid pH to a pH that prevents acid degra
sium hydroxide, magnesium carbonate, aluminum hydrox dation of at least Some of the proton pump inhibitor in the
ide, and mixtures thereof. gastric fluid, and (c) a therapeutically effective amount of at
least one prokinetic agent, wherein the composition is in a
0041 Compositions are provided as described herein, dosage form Selected from a powder, a tablet, a bite
where the buffering agent to proton pump inhibitor ratio is disintegration tablet, a chewable tablet, a capsule, an effer
at least 10:1; at least 12:1, at least 15:1; at least 20:1; at least Vescent powder, a rapid-disintegration tablet, or an aqueous
22:1; at least 25:1, at least 30:1; at least 35:1, and at least Suspension produced from powder.
40:1.
0047 Compositions including (a) a therapeutically effec
0.042 Compositions are provided as described herein, tive amount of at least one acid labile proton pump inhibitor,
where the buffering agent is Sodium bicarbonate and is (b) at least one buffering agent in an amount Sufficient to
present in about 0.1 mEq/mg proton pump inhibitor to about increase gastric fluid pH to a pH that prevents acid degra
5 mEq/mg proton pump inhibitor. Compositions are pro dation of at least Some of the proton pump inhibitor in the
Vided as described herein, where the buffering agent is a gastric fluid, and (c) a therapeutically effective amount of at
mixture of Sodium bicarbonate and magnesium hydroxide, least one prokinetic agent, wherein the composition is in the
and each buffering agent is present in about 0.1 mEq/mg form of a tablet and the tablet consists of a first and a second
proton pump inhibitor to about 5 mEq/mg proton pump layer where the first layer comprises at least Some of the
inhibitor. Compositions are provided as described herein, prokinetic agent and the Second layer comprises at least
where the buffering agent is a mixture of Sodium bicarbon Some of the proton pump inhibitor and the buffering agent.
ate, calcium carbonate, and magnesium hydroxide, and each
buffering agent is present in about 0.1 mEq/mg proton pump 0048 Compositions are provided as described herein,
inhibitor to about 5 mEq/mg of the proton pump inhibitor. further including one or more excipients including, but not
limited to, parietal cell activators, erosion facilitators, fla
0.043 Compositions are provided as described herein, Voring agents, Sweetening agents, diffusion facilitators, anti
where the buffering agent is present in an amount of about oxidants and carrier materials Selected from binders, Sus
0.1 mEq/mg to about 5 mEq/mg of the proton pump inhibi pending agents, disintegration agents, filling agents,
tor, or about 0.25 mEq/mg to about 3 mEq/mg of the proton Surfactants, Solubilizers, Stabilizers, lubricants, wetting
pump inhibitor, or about 0.3 mEq/mg to about 2.5 mEq/mg agents, diluents, anti-adherents, and antifoaming agents.
of the proton pump inhibitor, or about 0.4 mEq/mg to about
2.0 mEq/mg of the proton pump inhibitor, or about 0.5 0049 Methods are provided for treating a gastric acid
mEq/mg to about 1.5 mEq/mg of the proton pump inhibitor. related disorder by administering to the Subject a pharma
Compositions are provided as described herein, where the ceutical composition including (a) a therapeutically effective
buffering agent is present in an amount of at least 0.25 amount of at least one acid labile proton pump inhibitor, (b)
mEq/mg to about 2.5 mEq/mg of the proton pump inhibitor, at least one buffering agent in an amount Sufficient to
or at least about 0.4 mEq/mg of the proton pump inhibitor. increase gastric fluid pH to a pH that prevents acid degra
Compositions are provided as described herein, where the dation of at least Some of the proton pump inhibitor in the
composition includes about 200 to 3000 mg of buffering gastric fluid, and (c) a therapeutically effective amount of at
agent, or about 500 to about 2500 mg of buffering agent, or least one prokinetic agent, wherein the proton pump inhibi
about 1000 to about 2000 mg of buffering agent, or about tor treats the gastric acid related disorder. Methods are
1500 to about 2000 mg of buffering agent. provided wherein the composition as described herein is
0044) Compositions including (a) a therapeutically effec formulated for stomach delivery of at least some of the
proton pump inhibitor. Methods are provided wherein the
tive amount of at least one acid labile proton pump inhibitor, composition as described herein is formulated for duodenal
(b) at least one buffering agent in an amount Sufficient to delivery of some of the proton pump inhibitor.
increase gastric fluid pH to a pH that prevents acid degra
dation of at least Some of the proton pump inhibitor in the 0050 Methods are provided for treating a gastric acid
gastric fluid, and (c) a therapeutically effective amount of at related disorder by administering to a horse a pharmaceuti
least one prokinetic agent are provided, wherein at least cal composition including (a) a therapeutically effective
Some of the prokinetic agent is coated. Sutiable coatings amount of at least one acid labile proton pump inhibitor, (b)
include, but are not limited to, gastric resistant coatings Such at least one buffering agent in an amount Sufficient to
as enteric coatings, controlled-release coatings, enzymatic increase gastric fluid pH to a pH that prevents acid degra
controlled coatings, film coatings, Sustained-release coat dation of at least Some of the proton pump inhibitor in the
ings, immediate-release coatings, and delayed-release coat gastric fluid, and (c) a therapeutically effective amount of at
IngS. least one prokinetic agent.
0045 Compositions including (a) a therapeutically effe 0051 Methods are provided for treating a gastric acid
cive amount of at least one acid labile proton pump inhibitor, related disorder including, but not limited to duodenal ulcer
(b) at least one buffering agent Selected from Sodium bicar disease, gastric ulcer disease, gastroesophageal reflux dis
bonate, calcium carbonate, and magnesium hydroxide, ease, erosive esophagitis, poorly responsive Symptomatic
wherein the buffering agent is present in an amount Sufficient gastroesophageal reflux disease, pathological gastrointesti
US 2005/0239845 A1 Oct. 27, 2005

nal hyperSecretory disease, Zollinger Ellison Syndrome, terms used herein will become apparent from the context of
heartburn, esophageal disorder, and acid dyspepsia. Method this Specification in View of common usage of various terms
are provided wherein the proton pump inhibitor treats an and the explicit definitions of other terms provided in the
episode of gastric acid related disorder. Methods are pro glossary below or in the ensuing description.
Vided wherein the pharmaceutical composition prevents or 0060 AS used herein, the terms “comprising,”“includ
treats an NSAID induced gastric acid related disorder. ing, and “Such as are used in their open, non-limiting
0.052 Methods are provided for treating a gastric acid SCSC.
related disorder by administering to a Subject a pharmaceu 0061 The term “about” is used synonymously with the
tical composition including (a) a therapeutically effective term “approximately.” Illustratively, the use of the term
amount of at least one acid labile proton pump inhibitor, (b) “about” indicates that values slightly outside the cited val
at least one buffering agent in an amount Sufficient to ues, i.e., plus or minus 0.1% to 10%, which are also effective
increase gastric fluid pH to a pH that prevents acid degra and Safe. Such dosages are thus encompassed by the Scope
dation of at least Some of the proton pump inhibitor in the of the claims reciting the terms “about' and "approxi
gastric fluid, and (c) a therapeutically effective amount of at mately.”
least one prokinetic agent, wherein the composition is in a
dosage form including, but not limited to, a powder, a 0062) The phrase “acid-labile pharmaceutical agent”
powder for Suspension, a tablet, a caplet, a bite-disintegra refers to any pharmacologically active drug Subject to acid
tion tablet, a chewable tablet, a capsule, an effervescent catalyzed degradation.
powder, a rapid-disintegration tablet, or an aqueous Suspen 0063 “Anti-adherents,”“glidants,” or “anti-adhesion”
Sion produced from powder. agents prevent components of the formulation from aggre
0.053 Methods are provided wherein the composition gating or Sticking and improve flow characteristics of a
further comprises one or more excipients including, but not material. Such compounds include, e.g., colloidal Silicon
limited to, parietal cell activators, erosion facilitators, fla dioxide Such as Cab-O-Silf; tribasic calcium phosphate, talc,
Voring agents, Sweetening agents, diffusion facilitators, anti corn Starch, DL-leucine, Sodium lauryl Sulfate, magnesium
oxidants and carrier materials Selected from binders, Sus Stearate, calcium Stearate, Sodium Stearate, kaolin, and
pending agents, disintegration agents, filling agents, micronized amorphous silicon dioxide (Syloid(R)and the
Surfactants, Solubilizers, Stabilizers, lubricants, wetting like.
agents, diluents, anti-adherents, and antifoaming agents. 0.064 " Antifoaming agents’ reduce foaming during pro
DETAILED DESCRIPTION OF THE cessing which can result in coagulation of aqueous disper
INVENTION Sions, bubbles in the finished film, or generally impair
processing. Exemplary anti-foaming agents include Silicon
0.054 The present invention is directed to pharmaceutical emulsions or Sorbitan Sesquoleate.
compositions comprising a proton pump inhibitor, a buffer
ing agent, and a prokinetic agent, wherein the compositions 0065 “Antioxidants” include, e.g., butylated hydroxy
are useful for the treatment of a disease, condition or toluene (BHT), sodium ascorbate, and tocopherol.
disorder, wherein treatment includes treating the Symptoms 0066 “Binders' impart cohesive qualities and include,
of the disease, condition or disorder. Methods of treatment e.g., alginic acid and Salts thereof; cellulose derivatives Such
using the pharmaceutical compositions of the present inven as carboxymethylcellulose, methylcellulose (e.g., Metho
tion are also described. cel(R), hydroxypropylmethylcellulose, hydroxyethylcellu
0055. It has been discovered that pharmaceutical compo lose, hydroxypropylcellulose (e.g., Klucel(R), ethylcellulose
Sitions comprising (1) an acid labile proton pump inhibitor, (e.g., Ethocele), and microcrystalline cellulose (e.g.,
together with (2) one or more buffering agents, and (3) a Avicelf); microcrystalline dextrose; amylose; magnesium
prokinetic agent, provide improved relief from gastric acid aluminum Silicate; polysaccharide acids, bentonites, gelatin;
related disorders. polyvinylpyrrollidone/vinyl acetate copolymer; crospovi
done; poVidone; Starch; pregelatinized Starch; tragacanth,
0056. It has been discovered that pharmaceutical compo dextrin, a Sugar, Such as Sucrose (e.g., DipacE), glucose,
Sitions comprising (1) an acid labile proton pump inhibitor dextrose, molasses, mannitol, Sorbitol, xylitol (e.g., Xyl
which is microencapsulated with a material that enhances itab(E), and lactose; a natural or Synthetic gum Such as
the shelf-life of the pharmaceutical composition, together acacia, tragacanth, ghatti gum, mucilage of isapol husks,
with (2) one or more buffering agents, and (3) a prokinetic polyvinylpyrrollidone (e.g., Polyvidone(RCL, Kollidon(R)
agent, provide Superior performance by enhancing Shelf-life CL, Polyplasdone(R) XL-10), larch arabogalactan, Veegum(R),
Stability of the pharmaceutical composition during manu polyethylene glycol, waxes, Sodium alginate, and the like.
facturing and Storage.
0057. It has been discovered that pharmaceutical compo 0067 “Bioavailability” refers to the extent to which an
Sitions comprising (1) an acid labile proton pump inhibitor, active moiety, e.g., drug, prodrug, or metabolite, is absorbed
together with (2) one or more buffering agents, and (3) a into the general circulation and becomes available at the Site
prokinetic agent which is coated provide Superior perfor of drug action in the body.
mance by enhancing shelf-life Stability of the pharmaceuti 0068 “Carrier materials” include any commonly used
cal composition during manufacture and Storage. excipients in pharmaceutics and should be Selected on the
0.058 Glossary of Terms basis of compatibility with the proton pump inhibitor and the
release profile properties of the desired dosage form. Exem
0059) To more readily facilitate an understanding of the plary carrier materials include, e.g., binders, Suspending
invention and its preferred embodiments, the meanings of agents, disintegration agents, filling agents, Surfactants,
US 2005/0239845 A1 Oct. 27, 2005

Solubilizers, Stabilizers, lubricants, wetting agents, diluents, Sol E), cross-linked carboxymethylcellulose, or cross-linked
and the like. "Pharmaceutically compatible carrier materi croScarmelloSe; a cross-linked Starch Such as Sodium Starch
als' may comprise, e.g., acacia, gelatin, colloidal Silicon glycolate; a cross-linked polymer Such as croSpoVidone; a
dioxide, calcium glycerophosphate, calcium lactate, malto croSS-linked polyvinylpyrrollidone; alginate Such as alginic
dextrin, glycerine, magnesium Silicate, Sodium caseinate, acid or a Salt of alginic acid Such as Sodium alginate, a clay
Soy lecithin, Sodium chloride, tricalcium phosphate, dipo Such as Veegum(E) HV (magnesium aluminum silicate); a
tassium phosphate, Sodium Stearoyl lactylate, carrageenan, gum Such as agar, guar, locust bean, Karaya, pectin, or
monoglyceride, diglyceride, pregelatinized Starch, and the tragacanth; Sodium Starch glycolate; bentonite; a natural
like. See, e.g., Remington. The Science and Practice of Sponge; a Surfactant; a resin Such as a cation-exchange resin;
Pharmacy, Nineteenth Ed (Easton, Pa.; Mack Publishing citrus pulp; Sodium lauryl Sulfate, Sodium lauryl Sulfate in
Company, 1995); Hoover, John E., Remington's Pharma combination Starch; and the like.
ceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; 0075) “Drug absorption” or “absorption” refers to the
Liberman, H. A. and Lachman, L., Eds., Pharmaceutical process of movement from the Site of administration of a
Dosage Forms, Marcel Decker, New York, N.Y., 1980; and drug toward the Systemic circulation, e.g., into the blood
Pharmaceutical Dosage Forms and Drug Delivery Systems, Stream of a Subject.
Seventh Ed. (Lippincott Williams & Wilkins 1999). 0076 An “enteric coating” is a substance that remains
0069. “Character notes” include, e.g., aromatics, basis Substantially intact in the Stomach but dissolves and releases
tastes, and feeling factors. The intensity of the character note the drug once the Small intestine is reached. Generally, the
can be Scaled from 0-none, 1-slight, 2-moderate, or 3-strong. enteric coating comprises a polymeric material that prevents
0070 A“derivative” is a compound that is produced from release in the low pH environment of the stomach but that
ionizes at a slightly higer pH, typically a pH of 4 or 5, and
another compound of Similar structure by the replacement of thus dissolves Sufficiently in the Small intestines to gradually
Substitution of an atom, molecule or group by another release the active agent therein.
Suitable atom, molecule or group. For example, one or more
hydrogen atom of a compound may be Substituted by one or 0077 “Erosion facilitators' include materials that control
more alkyl, acyl, amino, hydroxyl, halo, haloalkyl, aryl, the erosion of a particular material in gastrointestinal fluid.
heteroaryl, cycloaolkyl, heterocycloalkyl, or heteroalkyl Erosion facilitators are generally known to those of ordinary
group to produce a derivative of that compound. skill in the art. Exemplary erosion facilitators include, e.g.,
hydrophilic polymers, electrolytes, proteins, peptides, and
0071 “Diffusion facilitators" and “dispersing agents' amino acids.
include materials that control the diffusion of an aqueous 0078 "Filling agents” include compounds such as lac
fluid through a coating. Exemplary diffusion facilitatorS/ tose, calcium carbonate, calcium phosphate, dibasic calcium
dispersing agents include, e.g., hydrophilic polymers, elec phosphate, calcium Sulfate, microcrystalline cellulose, cel
trolytes, Tween(F) 60 or 80, PEG and the like. Combinations lulose powder, dextrose; dextrates, dextran, Starches, prege
of one or more erosion facilitator with one or more diffusion latinized Starch, Sucrose, Xylitol, lactitol, mannitol, Sorbitol,
facilitator can also be used in the present invention. Sodium chloride, polyethylene glycol, and the like.
0.072 “Diluents” increase bulk of the composition to 0079. “Flavoring agents” or “sweeteners' useful in the
facilitate compression. Such compounds include e.g., lac pharmaceutical compositions of the present invention
tose, Starch; mannitol, Sorbitol; dextrose; microcrystalline include, e.g., acacia Syrup, aceSulfame K, alitame, anise,
cellulose Such as AVicelf), dibasic calcium phosphate, dical apple, aspartame, banana, Bavarian cream, berry, black
cium phosphate dihydrate; tricalcium phosphate, calcium currant, butterScotch, calcium citrate, camphor, caramel,
phosphate, anhydrous lactose; Spray-dried lactose; pregelat cherry, cherry cream, chocolate, cinnamon, bubble gum,
inzed Starch; compressible Sugar, Such as Di-PacE) (Amstar); citrus, citrus punch, citrus cream, cotton candy, cocoa, cola,
mannitol, hydroxypropylmethylSellulose, Sucrose-based cool cherry, cool citrus, cyclamate, cylamate, dextrose,
diluents, confectioner's Sugar, monobasic calcium Sulfate eucalyptus, eugenol, fructose, fruit punch, ginger, glycyr
monohydrate; calcium Sulfate dihydrate; calcium lactate rhetinate, glycyrrhiza (licorice) Syrup, grape, grapefruit,
trihydrate; dextrates, hydrolyzed cereal Solids, amylose; honey, isomalt, lemon, lime, lemon cream, monoammonium
powdered cellulose, calcium carbonate, glycine; kaolin; glyrrhizinate (MagnaSweetB), maltol, mannitol, maple,
mannitol, Sodium chloride; inoSitol, bentonite, and the like. marshmallow, menthol, mint cream, mixed berry, neohes
peridine DC, neotame, orange, pear, peach, peppermint,
0073. The term “disintegrate” includes both the dissolu peppermint cream, ProSweet (E) Powder, raspberry, root beer,
tion and dispersion of the dosage form when contacted with rum, Saccharin, Safrole, Sorbitol, Spearmint, Spearmint
gastrointestinal fluid. cream, Strawberry, Strawberry cream, Stevia, Sucralose,
0.074 “Disintegration agents' facilitate the breakup or Sucrose, Sodium Saccharin, Saccharin, aspartame,
disintegration of a Substance. Examples of disintegration aceSulfame potassium, mannitol, talin, Sylitol, Sucralose,
agents include a Starch, e.g., a natural Starch Such as corn Sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti
Starch or potato Starch, a pregelatinized Starch Such as fruitti, Vanilla, walnut, watermelon, wild cherry, winter
National 1551 or Amijelf), or sodium starch glycolate such green, Xylitol, or any combination of these flavoring ingre
as Promogel(R) or ExplotabCE); a cellulose such as a wood dients, e.g., anise-menthol, cherry-anise, cinnamon-Orange,
product, methylcrystalline cellulose, e.g., Avice1(R), AVicel(R) cherry-cinnamon, chocolate-mint, honey-lemon, lemon
PH101, Avice1(R) PH102, Avice1(R) PH105, Elcema(E) P100, lime, lemon-mint, menthol-eucalyptus, orange-cream,
Emcocel(R), Vivacel(R), Ming Tia(E), and Solka-FloccE), meth Vanilla-mint, and mixtures thereof.
ylcellulose, croScarmellose, or a cross-linked cellulose, Such 0080) “Gastrointestinal fluid” is the fluid of stomach
as cross-linked Sodium carboxymethylcellulose (Ac-Di Secretions of a Subject or the Saliva of a Subject after oral
US 2005/0239845 A1 Oct. 27, 2005

administration of a composition of the present invention, or under the Serum concentration time curve (AUC) may vary
the equivalent thereof. An "equivalent of Stomach Secretion' from subject to subject. Due to this variability, the amount
includes, e.g., an in Vitro fluid having Similar content and/or necessary to constitute "a therapeutically effective amount”
pH as Stomach Secretions Such as a 1% Sodium dodecyl of proton pump inhibitor, prokinetic agent, or other thera
Sulfate Solution or 0.1N HCl Solution in water. peutic agent, may vary from Subject to Subject. It is under
0081) “Half-life” refers to the time required for the stood that when mean plasma concentrations are disclosed
plasma drug concentration or the amount in the body to for a population of Subjects, these mean values may include
Substantial variation.
decrease by 50% from its maximum concentration.
0082 “Lubricants” are compounds which prevent, 0088 “Plasticizers” are compounds used to soften the
reduce or inhibit adhesion or friction of materials. Exem microencapsulation material or film coatings to make them
plary lubricants include, e.g., Stearic acid, calcium hydrox leSS brittle. Suitable plasticizers include, e.g., polyethylene
ide; talc, Sodium Stearyl fumerate; a hydrocarbon Such as glycols such as PEG 300, PEG 400, PEG 600, PEG 1450,
mineral oil, or hydrogenated vegetable oil Such as hydroge PEG 3350, and PEG 800, stearic acid, propylene glycol,
nated soybean oil (Sterotex(R); higher fatty acids and their oleic acid, and triacetin.
alkali-metal and alkaline earth metal Salts, Such as alumi 0089) “Prevent” or “prevention” when used in the context
num, calcium, magnesium, Zinc, Stearic acid, Sodium Stear of a gastric acid related disorder means no gastrointestinal
ates, glycerol, talc, waxes, StearowetCE, boric acid, Sodium disorder or disease development if none had occurred, or no
benzoate, Sodium acetate, Sodium chloride, leucine, a poly further gastrointestinal disorder or disease development if
ethylene glycol or a methoxypolyethylene glycol Such as there had already been development of the gastrointestinal
CarbowaxTM, Sodium oleate, glyceryl behenate, polyethyl disorder or disease. Also considered is the ability of one to
ene glycol, magnesium or Sodium lauryl Sulfate, colloidal prevent Some or all of the Symptoms associated with the
silica such as Syloid TM, Carb-O-Sile), a starch such as corn gastrointestinal disorder or disease.
Starch, Silicone oil, a Surfactant, and the like.
0090 A“prodrug” refers to a drug or compound in which
0.083. A “measurable serum concentration” or “measur the pharmacological action results from conversion by meta
able plasma concentration” describes the blood Serum or bolic processes within the body. Prodrugs are generally drug
blood plasma concentration, typically measured in mg, ug, precursors that, following administration to a Subject and
or ng of therapeutic agent per ml, dl, or 1 of blood Serum, of Subsequent absorption, are converted to an active, or a more
a therapeutic agent that is absorbed into the bloodstream active Species via Some process, Such as conversion by a
after administration. One of ordinary skill in the art would metabolic pathway. Some prodrugs have a chemical group
be able to measure the Serum concentration or plasma present on the prodrug which renders it leSS active and/or
concentration of a proton pump inhibitor or a prokinetic conferS Solubility or Some other property to the drug. Once
agent. See, e.g., Gonzalez H. et al., J. Chromatogr. B. Analyt. the chemical group has been cleaved and/or modified from
Technol. Biomed. Life Sci., vol. 780, pp. 459-65, (Nov. 25, the prodrug the active drug is generated. Prodrugs may be
2002). designed as reversible drug derivatives, for use as modifiers
0084) “Parietal cell activators” or “activators” stimulate to enhance drug transport to Site-specific tissues. The design
the parietal cells and enhance the pharmaceutical activity of of prodrugs to date has been to increase the effective water
the proton pump inhibitor. Parietal cell activators include, Solubility of the therapeutic compound for targeting to
e.g., chocolate; alkaline Substances Such as Sodium bicar regions where water is the principal Solvent. See, e.g.,
bonate, calcium Such as calcium carbonate, calcium glucon Fedorak et al., Am. J Physiol, 269:G210-218 (1995);
ate, calcium hydroxide, calcium acetate and calcium glyc McLoed et al., Gastroenterol., 106:405-413 (1994); Hoch
erophosphate; peppermint oil; Spearmint oil; coffee, tea and haus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and
colas (even if decaffeinated); caffeine; theophylline; theo H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J.
bromine; amino acids (particularly aromatic amino acids Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula
Such as phenylalanine and tryptophan); and combinations et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V.
thereof. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the
0085 “Pharmacodynamics” refers to the factors which A.C.S. Symposium Series; and Edward B. Roche, Bior
determine the biologic response observed relative to the eversible Carriers in Drug Design, American Pharmaceu
concentration of drug at a site of action. tical Association and Pergamon Press, 1987.
0086) “Pharmacokinetics” refers to the factors which 0091) “Serum concentration” refers to the concentration
determine the attainment and maintenance of the appropriate of a Substance Such as a therapeutic agent, in blood plasma
concentration of drug at a site of action. or blood serum of a subject. It is understood that the serum
concentration of a therapeutic agent may vary many-fold
0.087 “Plasma concentration” refers to the concentration between Subjects, due to variability with respect to metabo
of a Substance in blood plasma or blood Serum of a Subject. lism of therapeutic agents. In accordance with one aspect of
It is understood that the plasma concentration of a thera the present invention, the Serum concentration of a proton
peutic agent may vary many-fold between Subjects, due to pump inhibitors and/or prokinetic agent may vary from
variability with respect to metabolism of therapeutic agents. Subject to Subject. Likewise, values Such as maximum Serum
In accordance with one aspect of the present invention, the concentraton (C) or time to reach maximum serum
plasma concentration of a proton pump inhibitors and/or concentration (T,), or total area under the serum concen
prokinetic agent may vary from Subject to Subject. Likewise, tration time curve (AUC) may vary from subject to subject.
values Such as maximum plasma concentraton (C) or Due to this variability, the amount necessary to constitute “a
time to reach maximum serum concentration (T,), or area therapeutically effective amount of proton pump inhibitor,
US 2005/0239845 A1 Oct. 27, 2005

prokinetic agent, or other therapeutic agent, may vary from 0.098 “Total intensity of flavor” is the overall immediate
Subject to Subject. It is understood that when mean Serum impression of the Strength of the flavor including aromatics,
concentrations are disclosed for a population of Subjects, basic tastes and mouth feel Sensations.
these mean values may include Substantial variation. 0099. “Treat” or “treatment” as used in the context of a
0092 “Solubilizers” include compounds such as citric gastric acid related disorder refers to any treatment of a
acid, Succinic acid, fumaric acid, malic acid, tartaric acid, disorder or disease associated with a gastrointestinal disor
maleic acid, glutaric acid, Sodium bicarbonate, Sodium car der, Such as preventing the disorder or disease from occur
bonate and the like. ring in a Subject which may be predisposed to the disorder
or disease, but has not yet been diagnosed as having the
0.093 “Stabilizers” include compounds such as any anti disorder or disease; inhibiting the disorder or disease, e.g.,
oxidation agents, buffers, acids, and the like. arresting the development of the disorder or disease, reliev
0094) “Suspending agents” or “thickening agents' ing the disorder or disease, causing regression of the disor
include compounds Such as polyvinylpyrrollidone, e.g., poly der or disease, relieving a condition caused by the disease or
vinylpyrrolidone K12, polyvinylpyrrollidone K17, polyvi disorder, or Stopping the Symptoms of the disease or disor
nylpyrrolidone K25, or polyvinylpyrrolidone K30; polyeth der. “Treat' or “treatment” as used in the context of a
ylene glycol, e.g., the polyethylene glycol can have a prokinetic agent refers to any treatment of a disorder or
molecular weight of about 300 to about 6000, or about 3350 disease associated with a gastrointestinal disorder, Such as
to about 4000, or about 7000 to about 5400; Sodium car preventing the disorder or disease from occurring in a
boxymethylcellulose; methylcellulose, hydroxy-propylm Subject which may be predisposed to the disorder or disease,
ethylcellulose; polysorbate-80, hydroxyethylcellulose; but has not yet been diagnosed as having the disorder or
Sodium alginate, gums, Such as, e.g., gum tragacanth and disease; inhibiting the disorder or disease, e.g., arresting the
gum acacia, guar gum, Xanthans, including Xanthan gum, development of the disorder or disease, relieving the disor
Sugars, cellulosics, Such as, e.g., Sodium carboxymethylcel der or disease, causing regression of the disorder or disease,
lulose, methylcellulose, Sodium carboxymethylcellulose, relieving a condition caused by the disease or disorder, or
hydroxypropylmethylcellulose, hydroxyethylcellulose; Stopping the Symptoms of the disease or disorder. Thus, as
polySorbate-80; Sodium alginate; polyethoxylated Sorbitan used herein, the term “treat' is used synonymously with the
monolaurate; polyethoxylated Sorbitan monolaurate; povi term “prevent.”
done and the like. 0100 “Wetting agents” include compounds such as oleic
0.095 "Surfactants' include compounds such as sodium acid, glyceryl monoStearate, Sorbitan monooleate, Sorbitan
lauryl Sulfate, Sorbitan monooleate, polyoxyethylene Sorbi monolaurate, triethanolamine oleate, polyoxyethylene Sor
tan monooleate, polySorbates, polaxomers, bile Salts, glyc bitan monooleate, polyoxyethylene Sorbitan monolaurate,
eryl monoStearate, copolymers of ethylene oxide and pro Sodium oleate, Sodium lauryl Sulfate, and the like.
pylene oxide, e.g., Pluronic(R) (BASF); and the like. 0101 Combination Therapy
0096. A “therapeutically effective amount” or “effective 0102 Compositions and methods for combination
amount' is that amount of a pharmaceutical agent to achieve therapy are provided herein. In accordance with one aspect,
a pharmacological effect. The term “therapeutically effective the pharmaceutical compositions disclosed herein are used
amount' includes, for example, a prophylactically effective to treat a gastric acid related disorder. In one embodiment,
amount. An “effective amount” of a proton pump inhibitor pharmaceutical compositions disclosed herein are used treat
is an amount effective to achieve a desired pharmacologic a Subject Suffering from a gastric acid related disorder.
effect or therapeutic improvement without undue adverse 0.103 Combination therapies contemplated by the present
Side effects. For example, an effective amount of a proton invention can be used as part of a specific treatment regimen
pump inhibitor refers to an amount of proton pump inhibitor intended to provide a beneficial effect from the co-action of
that reduces acid Secretion, or raises gastrointestinal fluid the proton pump inhibitor and the prokinetic agent.
pH, or reduces gastrointestinal bleeding, or reduces the need
for blood transfusion, or improves Survival rate, or provides 0104. It is understood that the dosage regimen to treat,
for a more rapid recovery from a gastric acid related prevent, or ameliorate the condition(s) for which relief is
disorder. An "effective amount of a prokinetic agent is an Sought, can be modified in accordance with a variety of
amount effective to achieve a desired pharmacological effect factors. These factors include the type of gastric acid dis
on the Subject's condition, without undue adverse side order from which the Subject Suffers, the proton pump
effects. The effective amount of a pharmaceutical agent will inhibitor being administered, the prokinetic agent being
be selected by those skilled in the art depending on the administered, as well as the age, weight, Sex, diet, and
particular patient and the disease level. It is understood that medical condition of the Subject. Thus, the dosage regimen
“an effect amount” or “a therapeutically effective amount” actually employed can vary widely and therefore can deviate
can vary from Subject to Subject, due to variation in metabo from the dosage regimens Set forth herein.
lism of therapeutic agents Such as proton pump inbhibitors
and/or prokinetic agents, age, Weight, general condition of 0105. In accordance with one aspect, compositions and
the Subject, the condition being treated, the Severity of the methods of the present invention are designed to produce
condition being treated, and the judgment of the prescribing release of the proton pump inhibitor to the Site of delivery,
physician. while Substantially preventing or inhibiting acid degradation
of the proton pump inhibitor. The present invention includes
0097. “Total intensity of aroma” is the overall immediate compositions and methods for treating, preventing, revers
impression of the Strength of the aroma and includes both ing, halting or slowing the progression of a gastric acid
aromatics and nose feel Sensations. related disorder once it becomes clinically evident, or treat
US 2005/0239845 A1 Oct. 27, 2005

ing the Symptoms associated with or related to the gastric kinetic profile of the pharmaceutical agent. Circadian varia
acid related disorder, by administering to the Subject a tion of the target molecule concentration may also determine
composition of the present invention. The Subject may the optimal dose interval.
already have a gastric acid related disorder at the time of 0109 Proton Pump Inhibitors
administration, or be at risk of developing a gastric acid
related disorder. The Symptoms or conditions of a gastric 0110. The terms “proton pump inhibitor,”“PPI,” and
acid related disorder in a Subject can be determined by one “proton pump inhibiting agent' can be used interchangeably
skilled in the art and are described in Standard textbooks. to describe any acid labile pharmaceutical agent possessing
The method comprises the oral administration of an effective pharmacological activity as an inhibitor of H/K-ATPase. A
amount of one or more compositions of the present inven proton pump inhibitor may, if desired, be in the form of free
tion to a Subject in need thereof. Gastric acid related base, free acid, Salt, ester, hydrate, anhydrate, amide, enan
disorderS Suitable for treatment using compositions and tiomer, isomer, tautomer, prodrug, polymorph, derivative, or
methods of the present invention include, but are not limited the like, provided that the free base, Salt, ester, hydrate,
to, duodenal ulcer disease, gastrointestinal ulcer disease, amide, enantiomer, isomer, tautomer, prodrug, or any other
gastroesophageal reflux disease (GERD), erosive esophagi pharmacologically Suitable derivative is therapeutically
tis, poorly responsive Symptomatic gastroesophageal reflux active.
disease, pathological gastrointestinal hyperSecretory dis 0111. In various embodiments, the proton pump inhibitor
ease, Zollinger Ellison Syndrome, heartburn, esophageal can be a Substituted bicyclic aryl-imidazole, wherein the aryl
disorder, and acid dyspepsia. group can be, e.g., a pyridine, a phenyl, or a pyrimidine
group and is attached to the 4 - and 5-positions of the
0106 AS disclosed herein, proton pump inhibitors and/or imidazole ring. Proton pump inhibitors comprising a Sub
prokinetic agents can be formulated to deliver rapid relief as Stituted bicyclic aryl-imidazoles include, but are not limited
well as Sustained relief of a gastric acid related disorder. to, omeprazole, hydroxyomeprazole, esomeprazole, lanSo
According to the methods of the invention, the formulation prazole, pantoprazole, rabeprazole, dontoprazole, habepra
of the proton pump inhibitor is chosen on the basis of the Zole, perprazole, tenatoprazole, ranSoprazole, pariprazole,
type of gastric acid related disorder Suffered by the Subject. leminoprazole, or a free base, free acid, Salt, hydrate, ester,
amide, enantiomer, isomer, tautomer, polymorph, prodrug,
0107. In one embodiment, a subject is administered a or derivative thereof. See, e.g., The Merck Index, Merck &
composition containing a proton pump inhibitor formulated Co. Rahway, N.J. (2001).
to give rapid relief for an episode of a gastric acid related
disorder. In another embodiment, a Subject is administered a 0.112. Other proton pump inhibitors include but are not
composition including uncoated proton pump inhibitor for limited to: Soraprazan (Altana); ilaprazole (U.S. Pat. No.
mulated to provide rapid relief and coated proton pump 5,703,097) (Il-Yang); AZD-0865 (AstraZeneca); YH-1885
inhibitor to prevent or treat recurring episodes of the gastric (PCT Publication WO 96/05177) (SB-641257) (2-pyrimidi
acid related disorder, where the composition also contains a namine, 4-(3,4-dihydro-1-methyl-2(1H)-isoquinolinyl)-N-
prokinetic agent. In another aspect of the invention, a Subject (4-fluorophenyl)-5,6-dimethyl-monohydrochloride)(Yu
is administered a composition containing a proton pump Han); BY-112 (Altana); SPI-447 (Imidazo(1,2-a)thieno(3,2-
inhibitor and a prokinetic agent, wherein at least Some of the c)pyridin-3-amine.5-methyl-2-(2-methyl-3-thienyl)
prokinetic agent is coated. In yet another aspect of the (Shinnippon); 3-hydroxymethyl-2-methyl-9-phenyl-7H-8.9-
invention, a Subject is administered a composition contain dihydro-pyrano (2,3-c)-imidazo(1,2-a)pyridine (PCT Publi
ing a proton pump inhibitor and a prokinetic agent, wherein cation WO95/27714) (AstraZeneca); Pharmaprojects No.
at least Some of the prokinetic agent is coated with an 4950 (3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihy
immediate release coating for improved shelf-life of the dro-pyrano(2,3-c)-imidazo(1,2-a)pyridine) (AstraZeneca,
pharmaceutical composition. According to another aspect of ceased) WO 95/27714; Pharmaprojects No. 4891 (EP
the invention, a Subject is administered a composition con 700899) (Aventis); Pharmaprojects No. 4697 (PCT Publi
taining a proton pump inhibitor and a prokinetic agent, cation WO95/32959) (AstraZeneca); H-335/25 (AstraZen
wherein at least Some of the prokinetic agent is coated with eca); T-330 (Saitama 335) (Pharmacological Research Lab);
an enteric coating which is designed for a delayed release of Pharmaprojects No. 3177 (Roche); BY-574 (Altana); Phar
the prokinetic agent. maprojects No. 2870 (Pfizer); AU-1421 (EP 264883)
(Merck); AU-2064 (Merck); AY-28200 (Wyeth); Phar
0108. The pharmaceutical agents which make up the maprojects No. 2126 (Aventis); WY-26769 (Wyeth);
combination therapy disclosed herein may be a combined pumaprazole (PCT Publication WO 96/05199) (Altana);
dosage form or in Separate dosage forms intended for YH-1238 (YuHan); Pharmaprojects No. 5648 (PCT Publi
Substantially simultaneous administration. The pharmaceu cation WO 97/32854) (Dainippon); BY-686 (Altana);
tical agents that make up the combination therapy may also YM-020 (Yamanouchi); GYKI-34655 (Ivax); FPL-65372
be administered Sequentially, with either therapeutic com (Aventis); Pharmaprojects No. 3264 (EP 509974) (Astra
pound being administered by a regimen calling for two-step Zeneca); nepaprazole (Toa Eiyo); HN-11203 (Nycomed
administration. The two-step administration regimen may Pharma); OPC-22575; pumilacidin A (BMS); saviprazole
call for Sequential administration of the active agents or (EP 234485) (Aventis); SKandF-95601 (GSK, discontin
Spaced-apart administration of the Separate active agents. ued); Pharmaprojects No. 2522 (EP 204215) (Pfizer);
The time period between the multiple administration Steps S-3337 (Aventis); RS-13232A (Roche); AU-1363 (Merck);
may range from, a few minutes to Several hours, depending SKandF-96067 (EP 259174) (Altana); SUN 8176 (Daiichi
upon the properties of each pharmaceutical agent, Such as Phama); Ro-18-5362 (Roche); ufiprazole (EP74341) (Astra
potency, Solubility, bioavailability, plasma half-life and Zeneca); and Bay-p-1455 (Bayer); or a free base, free acid,
US 2005/0239845 A1 Oct. 27, 2005

Salt, hydrate, ester, amide, enantiomer, isomer, tautomer, eSomeprazole, described in U.S. patent application. Ser. No.
polymorph, prodrug, or derivative of these compounds. 02/0198239 and U.S. Pat. No. 6,511,996. Other salts of
0113 Still other proton pump inhibitors contemplated by esomeprazole are described in U.S. Pat. No. 4,738,974 and
U.S. Pat. No. 6,369,085. Salt forms of pantoprazole and
the present invention include those described in the follow lansoprazole are discussed in U.S. Pat. Nos. 4,758,579 and
ing U.S. Pat. Nos: 4,628,098; 4.689,333; 4,786,505; 4.853, 4,628,098, respectively.
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, 0119). In one embodiment, preparation of esters involves
110; 5,705,517; 5,708,017; 5,731,006; 5,824,339; 5,855, functionalization of hydroxyl and/or carboxyl groups which
914; 5,879,708; 5,948,773; 6,017,560; 6,123,962; 6,187, may be present within the molecular Structure of the drug. In
340; 6,296,875; 6,319,904; 6,328,994; 4,255.431; 4,508, one embodiment, the esters are acyl-Substituted derivatives
905; 4,636,499; 4,738,974; 5,690,960; 5,714,504; 5,753, of free alcohol groups, e.g., moieties derived from carboxy
265; 5,817,338; 6,093,734; 6,013,281; 6,136,344; 6,183, lic acids of the formula RCOOR where R is a lower alkyl
776; 6.328,994; 6,479,075; 6,559,167. group. Esters can be reconverted to the free acids, if desired,
by using conventional procedures Such as hydrogenolysis or
0114. Other substituted bicyclic aryl-imidazole com hydrolysis.
pounds as well as their Salts, hydrates, esters, amides,
enantiomers, isomers, tautomers, polymorphs, prodrugs, and 0120 “Amides' may be prepared using techniques
derivatives may be prepared using Standard procedures known to those skilled in the art or described in the pertinent
known to those skilled in the art of Synthetic organic literature. For example, amides may be prepared from esters,
chemistry. See, e.g., March, Advanced Organic Chemistry. using Suitable amine reactants, or they may be prepared from
Reactions, Mechanisms and Structure, 4th Ed. (New York: an anhydride or an acid chloride by reaction with an amine
Wiley-Interscience, 1992); Leonard et al., Advanced Prac group Such as ammonia or a lower alkyl amine.
tical Organic Chemistry (1992); Howarth et al., Core 0121 “Tautomers” of substituted bicyclic aryl-imida
Organic Chemistry (1998); and Weisermel et al., Industrial Zoles include, e.g., tautomers of omeprazole Such as those
Organic Chemistry (2002). described in U.S. Pat. Nos.: 6,262,085; 6,262,086; 6,268,
0115 “Pharmaceutically acceptable salts,” or “salts.” 385; 6,312,723; 6,316,020; 6,326,384; 6,369,087; and
include, e.g., the Salt of a proton pump inhibitor prepared 6,444,689; and U.S. patent Publication No. 02/0156103.
from formic, acetic, propionic, Succinic, glycolic, gluconic, 0122) An exemplary “isomer' of a substituted bicyclic
lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, aryl-imidazole is the isomer of omeprazole including but not
fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, limited to isomers described in: Oishi et al., Acta Cryst.
meSylic, Stearic, Salicylic, p-hydroxybenzoic, phenylacetic, (1989), C45, 1921-1923; U.S. Pat. No. 6,150,380; U.S.
mandelic, embonic, methaneSulfonic, ethaneSulfonic, ben patent Publication No. 02/0156284; and PCT Publication
ZeneSulfonic, pantothenic, toluenesulfonic, 2-hydroxy No. WO 02/085889.
ethaneSulfonic, Sulfanilic, cyclohexylaminoSulfonic,
algenic, 3-hydroxybutyric, galactaric and galacturonic 0123 Exemplary “polymorphs' include, but are not lim
acids. ited to, those described in PCT Publication No. WO
92/08716, and U.S. Pat. Nos. 4,045,563; 4,182,766; 4,508,
0116. In one embodiment, acid addition salts are prepared 905; 4,628,098; 4,636,499; 4,689,333; 4,758,579; 4,783,
from the free base using conventional methodology involv 974; 4,786,505; 4,808,596; 4,853,230; 5,026,560; 5,013,
ing reaction of the free base with a suitable acid. Suitable 743; 5,035,899; 5,045,321; 5,045,552; 5,093,132; 5,093,
acids for preparing acid addition Salts include both organic 342; 5,433,959; 5,464,632; 5,536,735; 5,576,025; 5,599,
acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic 794; 5,629,305; 5,639,478; 5,690,960; 5,703,110; 5,705,
acid, Oxalic acid, malic acid, malonic acid, Succinic acid, 517; 5,714,504; 5,731,006; 5,879,708; 5,900,424; 5,948,
maleic acid, fumaric acid, tartaric acid, citric acid, benzoic 773; 5,997,903; 6,017,560; 6,123,962; 6,147,103; 6,150,
acid, cinnamic acid, mandelic acid, methaneSulfonic acid, 380; 6,166,213; 6,191,148; 5,187,340; 6,268,385; 6,262,
ethaneSulfonic acid, p-toluenesulfonic acid, Salicylic acid, 086; 6,262,085; 6,296,875; 6,316,020; 6,328,994; 6,326,
and the like, as well as inorganic acids, e.g., hydrochloric 384; 6,369,085; 6,369,087; 6,380,234; 6,428,810; 6,444,
acid, hydrobromic acid, Sulfuric acid, nitric acid, phosphoric 689; and 6,462,0577.
acid, and the like.
0124 Micronized Proton Pump Inhibitor
0117. In other embodiments, an acid addition salt is 0.125 Particle size of the proton pump inhibitor can affect
reconverted to the free base by treatment with a suitable the Solid dosage form in numerous ways. Since decreased
base. In a further embodiment, the acid addition salts of the particle size increases in Surface area (S), the particle size
proton pump inhibitors are halide Salts, which are prepared reduction provides an increase in the rate of dissolution
using hydrochloric or hydrobromic acids. In still other (dM/dt) as expressed in the Noyes-Whitney equation below:
embodiments, the basic Salts are alkali metal Salts, e.g.,
Sodium Salt.
0118 Salt forms of proton pump inhibiting agents 0.126 M=mass of drug dissolved; t=time; D=diffusion
include, but are not limite to: a Sodium Salt form Such as coefficient of drug, S=effective Surface area of drug par
eSomeprazole Sodium, omeprazole Sodium, rabeprazole ticles; H =Stationary layer thickness, CS=concentration of
Sodium, pantoprazole Sodium; or a magnesium Salt form Solution at Saturation; and C=concentration of Solution at
time t.
Such as esomeprazole magnesium or omeprazole magne
sium, described in U.S. Pat. No. 5,900,424; a calcium salt 0127. Because omeprazole, as well as other proton pump
form; or a potassium Salt form Such as the potassium Salt of inhibitors, has poor water Solubility, to aid the rapid absorp
US 2005/0239845 A1 Oct. 27, 2005

tion of the drug product, Various embodiments of the present phthalates, tartrate, Succinates and the like, Such as Sodium
invention use micronized proton pump inhibitor is used in or potassium phosphate, citrate, borate, acetate, bicarbonate
the drug product formulation. and carbonate.
0128. In some embodiments, the average particle size of 0133. In various embodiments, a buffering agent includes
at least about 90% the micronized proton pump inhibitor is an amino acid, an alkali metal Salt of an amino acid,
less than about 40 um, or less than about 35 um, or less than aluminum hydroxide, aluminum hydroxide/magnesium car
about 30 lum, or less than about 25 lum, or less than about 20 bonate/calcium carbonate co-precipitate, aluminum magne
tim, or less than about 15 lum, or less than about 10 um. In sium hydroxide, aluminum hydroxide/magnesium hydrox
other embodiments, at least 80% of the micronized proton ide co-precipitate, aluminum hydroxide/sodium bicarbonate
pump inhibitor has an average particle size of less than about coprecipitate, aluminum glycinate, calcium acetate, calcium
40 um, or less than about 35 um, or less than about 30 um, bicarbonate, calcium borate, calcium carbonate, calcium
or less than about 25 tim, or less than about 20 um, or leSS citrate, calcium gluconate, calcium glycerophosphate, cal
than about 15 lum, or less than about 10 um. In still other cium hydroxide, calcium lactate, calcium phthalate, calcium
embodiments, at least 70% of the micronized proton pump phosphate, calcium Succinate, calcium tartrate, dibasic
inhibitor has an average particle Size of less than about 40 Sodium phosphate, dipotassium hydrogen phosphate, dipo
tim, or less than about 35 um, or less than about 30 um, or tassium phosphate, disodium hydrogen phosphate, disodium
less than about 25 tim, or less than about 20 um, or less than Succinate, dry aluminum hydroxide gel, L-arginine, magne
about 15 tim, or less than about 10 lim. Sium acetate, magnesium aluminate, magnesium borate,
0129 Compositions are provided wherein the micronized magnesium bicarbonate, magnesium carbonate, magnesium
proton pump inhibitor is of a size which allows greater than citrate, magnesium gluconate, magnesium hydroxide, mag
75% of the proton pump inhibitor to be released within about nesium lactate, magnesium metasilicate aluminate, magne
1 hour, or within about 50 minutes, or within about 40
sium oxide, magnesium phthalate, magnesium phosphate,
minutes, or within about 30 minutes, or within about 20 magnesium Silicate, magnesium Succinate, magnesium tar
minutes, or within about 10 minutes or within about 5 trate, potassium acetate, potassium carbonate, potassium
minutes of dissoluion testing. In another embodiment of the bicarbonate, potassium borate, potassium citrate, potassium
metaphosphate, potassium phthalate, potassium phosphate,
invention, the micronized proton pump inhibitor is of a size potassium polyphosphate, potassium pyrophosphate, potas
which allows greater than 90% of the proton pump inhibitor sium Succinate, potassium tartrate, Sodium acetate, Sodium
to be released within about 1 hour, or within about 50 bicarbonate, Sodium borate, Sodium carbonate, Sodium cit
minutes, or within about 40 minutes, or within about 30 rate, Sodium gluconate, Sodium hydrogen phosphate, Sodium
minutes, or within about 20 minutes, or within about 10 hydroxide, Sodium lactate, Sodium phthalate, Sodium phos
minutes or within about 5 minutes of dissoluion testing. See phate, Sodium polyphosphate, Sodium pyrophosphate,
U.S. Provisional Application No. 60/488,324 filed Jul. 18, Sodium Sesquicarbonate, Sodium Succinate, Sodium tartrate,
2003, and any Subsequent application claiming priority to Sodium tripolyphosphate, Synthetic hydrotalcite, tetrapotas
this application, all of which are incorporated by reference sium pyrophosphate, tetrasodium pyrophosphate, tripotas
in their entirety. sium phosphate, trisodium phosphate, and trometamol. (See,
0130 Buffering Agents e.g., lists provided in The Merck Index, Merck & Co.
0131 The pharmaceutical composition of the invention Rahway, N.J. (2001)). Certain proteins or protein hydroly
comprises one or more buffering agents. A class of buffering Sates that rapidly neutralize acids can Serve as buffering
agents useful in the present invention include, but are not agents in the present invention. Combinations of the above
limited to, buffering agents possessing pharmacological mentioned buffering agents can be used in the pharmaceu
activity as a weak base or a Strong base. In one embodiment, tical compositions described herein.
the buffering agent, when formulated or delivered with an 0134) The buffering agents useful in the present invention
proton pump inhibiting agent, functions to Substantially also include buffering agents or combinations of buffering
prevent or inhibit the acid degradation of the proton pump agents that interact with HCl (or other acids in the environ
inhibitor by gastrointestinal fluid for a period of time, e.g., ment of interest) faster than the proton pump inhibitor
for a period of time sufficient to preserve the bioavailability interacts with the Same acids. When placed in a liquid phase,
of the proton pump inhibitor administered. The buffering Such as water, these buffering agents produce and maintain
agent can be delivered before, during and/or after delivery of a pH greater than the pKa of the proton pump inhibitor.
the proton pump inhibitor. In one aspect of the present 0135) In various embodiments, the buffering agent is
invention, the buffering agent includes a Salt of a Group IA Selected from Sodium bicarbonate, Sodium carbonate, cal
metal (alkali metal), including, e.g., a bicarbonate Salt of a cium carbonate, magnesium oxide, magnesium hydroxide,
Group IA metal, a carbonate Salt of a Group IA metal; an magnesium carbonate, aluminum hydroxide, and mixtures
alkaline earth metal buffering agent (Group IIA metal); an thereof. In another embodiment, the buffering agent is
aluminum buffering agent; a calcium buffering agent, or a Sodium bicarbonate and is present in about 0.1 mEq/mg
magnesium buffering agent.
proton pump inhibitor to about 5 mEq/mg proton pump
0132). Other buffering agents suitable for the present inhibitor. In yet another embodiment, the buffering agent is
invention include, e.g., alkali metal (a Group IA metal a mixture of Sodium bicarbonate and magnesium hydroxide,
including, but not limited to, lithium, Sodium, potassium, wherein the Sodium bicarbonate and magnesium hydroxide
rubidium, cesium, and francium) or alkaline earth metal are each present in about 0.1 mEq/mg proton pump inhibitor
(Group IIA metal including, but not limited to, beryllium, to about 5 mEq/mg proton pump inhibitor. In Still another
magnesium, calcium, strontium, barium, radium) carbon embodiment, the buffering agent is a mixture of at least two
ates, phosphates, bicarbonates, citrates, borates, acetates, bufferS Selected from Sodium bicarbonate, calcium carbon
US 2005/0239845 A1 Oct. 27, 2005

ate, and magnesium hydroxide, wherein each buffer is about 2800 mg, or about 2900 mg, or about 3000 mg, or
present in about 0.1 mEq/mg proton pump inhibitor to about about 3200 mg, or about 3500 mg.
5 mEq/mg of the proton pump inhibitor.
0141 Prokinetic Agents
0.136 Compositions are provided as described herein,
wherein the buffering agent is present in an amount of about 0.142 Prokinetic agents suitable for use in the present
0.1 mEq/mg to about 5 mEq/mg of the proton pump inhibi invention include but are not limited to 5-HT inhibitors such
tor, or about 0.25 mEq/mg to about 3 mEq/mg of the proton as 5-HT inhibitors (e.g., ondasetron, granisetron, and dola
pump inhibitor, or about 0.3 mEq/mg to about 2.5 mEq/mg inserton) and 5-HT, inhibitors (e.g., cisapride); bulk forming
of the proton pump inhibitor, or about 0.4 mEq/mg to about agents Such as phylium, polycarbophil, and fiber; intralumi
2.0 mEq/mg of the proton pump inhibitor, or about 0.5 nal agents Such as bismuth; antimotility agents Such as
mEq/mg to about 1.5 mEq/mg of the proton pump inhibitor. loperamide and clonidine, Saline laxatives, and luminally
Compositions are provided as described herein, wherein the active osmotic agents Such as magnesium Sulfate and
buffering agent is present in an amount of at least 0.25 Sodium phosphate. Other exemplary prokinetic agents
mEq/mg to about 2.5 mEq/mg of the proton pump inhibitor, include mosapride, metoclopramide, domperidone, clebo
or at least about 0.4 mEq/mg of the proton pump inhibitor. pride, erythromycin (e.g., erythromycin ethylsuccinate and
erythromycin lactobionate), bethanechol and bethanechol
0.137 In one aspect of the invention, compositions are chloride, norcisapride, and neostigmine.
provided wherein the buffering agent is present in the
pharmaceutical compositions of the present invention in an 0143 Stability Enhancers
amount of about 1 mEq to about 160 mEq per dose, or about 0144. In accordance with one aspect of the present inven
5 mEq, or about 10 mEq, or about 11 mEq, or about 15 mEq, tion, compositions may include microencapsulation of one
or about 19 mEq, or about 20 mEq, or about 22 mEq, or or more of the proton pump inhibitor; the prokinetic agent;
about 23 mEq, or about 24 mEq, or about 25 mEq, or about or the buffering agent, in order to enhance the shelf-life of
30 mEq, or about 31 mEq, or about 35 mEq, or about 40 the composition. See U.S. Provisional Application No.
mEq, or about 45 mEq, or about 50 mEq, or about 60 mEq, 60/488,321 filed Jul. 18, 2003, and any Subsequent applica
or about 70 mEq, or about 80 mEq, or about 90 mEq, or tion claiming priority to it, all of which are incorporated by
about 100 mEq, or about 110 mEq, or about 120 mEq, or reference in their entirety. Materials useful for enhancing the
about 130 mEq, or about 140 mEq, or about 150 mEq, or Shelf-life of the pharmaceutical compositions of the present
about 160 mEq per dose. invention include materials compatible with the proton
0.138. In one embodiment, the pharmaceutical composi pump inhibitor of the pharmaceutical compositions which
tion comprises between about 5 mEq to about 20 mEq, or sufficiently isolate the proton pump inhibitor from other
between about 5 mEq to about 15 mEq, or between about 5 non-compatible excipients. Materials compatible with the
mEq to about 12 mEq, or between about 7 mEq to about 12 proton pump inhibitors of the present invention are those
mEq of buffering agent, wherein the pharmaceutical com that enhance the shelf-life of the proton pump inhibitor, i.e.,
position is Substantially free from amino acids. In another by slowing or stopping degradation of the proton pump
embodiment, the pharmaceutical composition comprises inhibitor.
about 5 mEq, or about 7 mEq, or about 10 mEq, or about 12 0145 Exemplary microencapsulation materials useful for
mEq, or about 15 mEq, or about 17 mEq, or about 20 mEq enhancing the shelf-life of pharmaceutical compositions
of buffering agent, wherein the pharmaceutical composition comprising a proton pump inhibitor include, but are not
is Substantially free from amino acids. limited to: cellulose hydroxypropyl ethers (HPC) such as
0.139. In another aspect of the invention, compositions Klucel(R) or Nisso HPC; low-substituted hydroxypropyl
are provided wherein the buffering agent is present in the ethers (L-HPC); cellulose hydroxypropyl methyl ethers
composition in an amount, on a weight to weight (w/w) (HPMC) such as Seppifilm-LC, Pharmacoat(R), Metolose
basis, of more than about 5 times, or more than about 10 SR, Opadry YS, PrimaFlo, Benecel MP824, and Benecel
times, or more than about 20 times, or more than about 30 MP843; methylcellulose polymers such as Methocel(R) and
times, or more than about 40 times, or more than about 50 Metolose(R); Ethylcelluloses (EC) and mixtures thereof such
times, or more than about 60 times, or more than about 70 as E461, Ethocel(R), Aqualon(R)-EC, Surelease(R); Polyvinyl
times, or more than about 80 times, or more than about 90 alcohol (PVA) such as Opadry AMB; hydroxyethylcellulo
times, or more than about 100 times the amount of the proton ses such as Natrosol(R); carboxymethylcelluloses and salts of
pump inhibiting agent. carboxymethylcelluloses (CMC) such as Aqualon(R)-CMC;
polyvinyl alcohol and polyethylene glycol co-polymerS Such
0140. In another aspect of the invention, compositions as Kollicoat IRCR); monoglycerides (Myverol), triglycerides
are provided wherein the amount of buffering agent present (KLX), polyethylene glycols, modified food Starch, acrylic
in the pharmaceutical composition is between 200 and 3500 polymers and mixtures of acrylic polymers with cellulose
mg. In Some embodiments, the amount of buffering agent ethers such as Eudragit(R) EPO, Eudragit R RD100, and
present in the pharmaceutical composition is about 200 mg, Eudragit(R) E100; cellulose acetate phthalate; sepifilms such
or about 300 mg, or about 400 mg, or about 500 mg, or about as mixtures of.HPMC and stearic acid, cyclodextrins; and
600 mg, or about 700 mg, or about 800 mg, or about 900 mg, mixtures of these materials.
or about 1060 mg, or about 1100 mg, or about 1200 mg, or
about 1300 mg, or about 1400 mg, or about 1500 mg, or 0146 In various embodiments, a buffering agent such as
about 1600 mg, or about 1700 mg, or about 1800 mg, or Sodium bicarbonate is incorporated into the microencapsu
about 1900 mg, or about 2000 mg, or about 2100 mg, or lation material. In other embodiments, an antioxidant Such
about 2200 mg, or about 2300 mg, or about 2400 mg, or as BHT is incorporated into the microencapsulation mate
about 2500 mg, or about 2600 mg, or about 2700 mg, or rial. In Still other embodiments, plasticizerS Such as poly
US 2005/0239845 A1 Oct. 27, 2005

ethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG capsulated with a compatible material that enhances the
1450, PEG 3350, and PEG 800, stearic acid, propylene Shelf-life of the pharmaceutical composition, or the proki
glycol, oleic acid, and triacetin are incorporated into the netic agent has been coated with a compatible material that
microencapsulation material. In other embodiments, the enhances the shelf-life of the pharmaceutical composition.
microencapsulating material useful for enhancing the shelf
life of the pharmaceutical compositions is from the USP or 0152. In some embodiments, the pharmaceutical compo
the National Formulary (NF). sitions have an increased shelf-life stability of at least about
5 days at room temperature, or at least about 10 days at room
0147 In further embodiments, one or more other com temperature, or at least about 15 days at room temperature,
patible materials are present in the microencapsulation mate or at least about 20 days at room temperature, or at least
rial. Exemplary materials include, but are not limited to, pH about 25 days at room temperature, or at least about 30 days
modifiers, parietal cell activators, erosion facilitators, diffu at room temperature or at least about 2 months at room
Sion facilitators, anti-adherents, anti-foaming agents, anti temperature, or at least about 3 months at room temperature,
oxidants, flavoring agents, and carrier materials. Such as or at least about 4 months at room temperature, or at least
binders, Suspending agents, disintegration agents, filling about 5 months at room temperature, or at least about 6
agents, Surfactants, Solubilizers, Stabilizers, lubricants, wet months at room temperature, or at least about 7 months at
ting agents, and diluents. room temperature, or at least about 8 months at room
0.148. According to one aspect of the invention, the temperature or at least about 9 months at room temperature,
prokinetic agent is coated. The coating may be, for example, or at least about 10 months at room temperature, or at least
a gastric resistant coating Such as an enteric coating (See, about 11 months at room temperature, or at least about one
e.g., WO91/16895 and WO91/16886), a controlled-release year at room temperature, or at least about 1.5 years at room
coating, an enzymatic-controlled coating, a film coating, a temperature, or at least about 2 years at room temperature,
Sustained-release coating, an immediate-release coating, or a or at least about 2.5 years at room temperature, or about 3
delayed-release coating. According to another aspect of the years at room temperature.
invention, the coating may be useful for enhancing the 0153. In some embodiments of the present invention, the
Stability of the pharmaceutical compositions of the present final formulation of the pharmaceutical composition will be
invention. in the form of a tablet or caplet and at least about 50%, or
0149. A pharmaceutical composition of the present at least about 55%, or at least about 60%, or at least about
invention may have an enhanced shelf-life Stability if, e.g., 65%, or at least about 70%, or at least about 75%, or at least
the proton pump inhibitor has less than about 0.5% degra about 80%, or at least about 85% or at least about 90%, or
dation after one month of Storage at room temperature, or at least about 92%, or at least about 95%, or at least about
less than about 1% degradation after one month at room 98%, or at least about 99% of the microspheres survive the
temperature, or less than about 1.5% degradation after one tabletting process, wherein microSpheres that have Survived
month of Storage at room temperature, or less than about 2% the manufacturing process are those which provide the
degradation after one month Storage at room temperature, or desired properties described herein.
less than about 2.5% degradation after one month of Storage 0154) In other embodiments, the final formulation of the
at room temperature, or less than about 3% degradation after pharmaceutical composition is in the form of a powder for
one month of Storage at room temperature. oral Suspension and the microencapsulation material Sur
0150. In other embodiments, a pharmaceutical composi rounding the proton pump inhibitor or prokinetic agent or
tion of the present invention may have an enhanced shelf the coating Surrounding the prokinetic agent will Sufficiently
life Stability if the pharmaceutical composition contains leSS dissolve in water, with or without Stirring, in less than 1
than about 5% total impurities after about 3 years of storage, hour, or less than 50 minutes, or less than 40 minutes, or leSS
or after about 2.5 years of Storage, or about 2 years of than 30 minutes, or less than 25 minutes, or less than 20
Storage, or about 1.5 years of Storage, or about 1 year of minutes, or less than 15 minutes, or less than 10 minutes or
Storage, or after 11 months of Storage, or after 10 months of less than 5 minutes, or less than 1 minute. “Sufficiently
Storage, or after 9 months of Storage, or after 8 months of dissolves” means that at least about 50% of the encapsula
Storage, or after 7 months of Storage, or after 6 months of tion or coating material has dissolved.
Storage, or after 5 months of Storage, or after 4 months of O155 In various embodiments the material useful for
Storage, or after 3 months of Storage, or after 2 months of enhancing the shelf-life of the pharmaceutical composition
Storage, or after 1 month of Storage. Sufficiently disintegrates to release the proton pump inhibitor
0151. In farther embodiments, a pharmaceutical compo into the gastrointestinal fluid of the Stomach within less than
Sitions of the present invention may have an enhanced about 1.5 hours, or within about 10 minutes, or within about
Shelf-life Stability if the pharmaceutical composition con 20 minutes, or within about 30 minutes, or within about 40
tains leSS degradation of the proton pump inhibitor than minutes, or within about 50 minutes, or within about 1 hour,
proton pump inhibitor in the same formulation where the or within about 1.25 hours, or within about 1.5 hours after
proton pump inhibitor or prokinetic agent are not microen exposure to the gastrointestinal fluid. Sufficiently disinte
capsulated, or the prokinetic agent is not coated, Sometimes grates means that at least about 50% of the microencapsu
referred to as “bare.” For example, if proton pump inhibitor lation material has dissolved.
in the pharmaceutical composition degrades at room tem 0156 Taste-Masking Materials
perature by more than about 2% after one month of Storage
and the microencapsulated or coated material degrades at O157. In accordance with another aspect, compositions
room temperature by less than about 2% after one month of and methods of the present invention may include taste
Storage, then the proton pump inhibitor has been microen masking materials to enhance the taste of the composition.
US 2005/0239845 A1 Oct. 27, 2005

Proton pump inhibitors and Some prokinetic agents are the proton pump inhibitor by Separating the drug from the
inherently bitter tasting. In one embodiment of the present taste receptors. Microencapsulation of the prokinetic agent
invention, these bitter tasting pharmaceuticals are microen can (1) lower the amount of flavoring agents necessary to
capsulated with a taste-masking material. Materials useful create a palatable product and/or (2) mask the bitter taste of
for masking the taste of a pharmaceutical compositions the prokinetic agent by Separating the drug from the taste
include those materials capable of microencapsulating the receptors.
proton pump inhibitor and/or prokinetic agent, thereby pro 0163 Taste-masking materials include, but are not lim
tecting the Senses from its bitter taste. Taste-masking mate ited to: cellulose hydroxypropyl ethers (HPC) such as
rials of the present invention provide Superior pharmaceu Klucel(R) or Nisswo HPC; low-substituted hydroxypropyl
tical compositions by e.g., creating a more palatable ethers (L-HPC); cellulose hydroxypropyl methyl ethers
pharmaceutical composition as compared to pharmaceutical (HPMC) such as Seppifilm-LC, Pharmacoat(R), Metolose
compositions without taste-masking and/or by creating a SR, Opadry YS, PrimaFlo, Benecel MP824, and Benecel
dosage form requiring less of the traditional flavoring MP843; methylcellulose polymers such as Methocel(R) and
agents.
Metolose(R); ethylcelluloses (EC) and mixtures thereof such
0158. The “flavor leadership' criteria used to develop a as E461, Ethocel(R), Aqualon(R)-EC, Surelease(R); polyvinyl
palatable product include (1) immediate impact of identify alcohol (PVA) such as Opadry AMB; hydroxyethylcellulo
ing flavor, (2) rapid development of balanced, full flavor, (3) ses such as Natrosol(R); carboxymethylcelluloses and salts of
compatible mouth feel factors, (4) no “off” flavors, and (5) carboxymethylcelluloses (CMC) such as Aqualon(R)-CMC;
short aftertaste. See, e.g., Worthington, A Matter of Taste, polyvinyl alcohol and polyethylene glycol co-polymerS Such
Pharmaceutical Executive (April 2001). The pharmaceutical as Kollicoat IRCR); monoglycerides (Myverol), triglycerides
compositions of the present invention improve upon one or (KLX), polyethylene glycols, modified food Starch, acrylic
more of these criteria. polymers and mixtures of acrylic polymers with cellulose
ethers such as Eudragit(R) EPO, Eudragit R RD100, and
0159. There are a number of known methods to deter Eudragit(R) E100; cellulose acetate phthalate; sepifilms such
mine the effect of a taste-masking material Such as discrimi as mixtures of HPMC and stearic acid, cyclodextrins, and
nation tests for testing differences between Samples and for mixtures of these materials.
ranking a Series of Samples in order of a specific character
istic, Scaling tests used for Scoring the Specific product 0164. In other embodiments of the present invention,
attributes Such as flavor and appearance; expert tasters used additional taste-masking materials contemplated are those
to both quantitatively and qualitatively evaluate a specific described in U.S. Pat. Nos. 4,851,226, 5,075,114, and 5,876,
Sample, affective tests for either measuring the response 759. For further examples of taste-masking materials. See,
between two products, measuring the degree of like or e.g., Remington. The Science and Practice of Pharmacy,
dislike of a product or Specific attribute, or determine the Nineteenth Ed. (Easton, Pa.; Mack Publishing Company,
appropriateness of a specific attribute; and descriptive meth 1995); Hoover, John E., Remington's Pharmaceutical Sci
ods used in flavor profiling to provide objective description ences (Mack Publishing Co., Easton, Pa. 1975); Liberman,
of a product are all methods used in the field. H. A. and Lachman, L., Eds., Pharmaceutical DOSage
0160 Different sensory qualities of a pharmaceutical Forms (Marcel Decker, New York, N.Y., 1980); and Phar
maceutical Dosage Forms and Drug Delivery Systems,
composition Such as aroma, flavor, character notes, and Seventh Ed. (Lippincott Williams & Wilkins, 1999).
aftertaste can be measured using tests know in the art. See,
e.g., Roy et al., Modifying Bitterness. Mechanism, Ingredi 0.165. In various embodiments, a buffering agent such as
ents, and Applications (1997). For example, aftertaste of a Sodium bicarbonate is incorporated into the microencapsu
product can be measured by using a time VS. intensity lation material. In other embodiments, an antioxidant Such
Sensory measurement. ASSays have been developed to alert as BHT is incorporated into the microencapsulation mate
a processor of formulations to the bitter taste of certain rial. In yet another embodiment, Sodium chloride is incor
Substances. Using information known to one of ordinary porated into the taste masking material. In Still other
skill in the art, one would readily be able to determine embodiments, plasticizerS Such as polyethylene glycol and/
whether one or more Sensory quality of a pharmaceutical or Stearic acid are incorporated into the microencapsulation
composition of the present invention has been improved by material.
the use of the taste-masking material. 0166 In further embodiments, one or more other com
0.161 Taste of a pharmaceutical composition is important patible materials are present in the microencapsulation mate
for both increasing patient compliance as well as for com rial. Exemplary materials include, e.g., pH modifiers, pari
peting with other marketed products used for Similar dis etal cell activators, erosion facilitators, diffusion facilitators,
eases, conditions and disorders. Taste, especially bitterness, anti-adherents, anti-foaming agents, antioxidants, flavoring
is particularly important in pharmaceutical compositions for agents, and carrier materials. Such as binders, Suspending
children Since, because they cannot weigh the positive agents, disintegration agents, filling agents, Surfactants,
outcome (getting better) against the immediate negative Solubilizers, Stabilizers, lubricants, wetting agents, diluents.
experience (the bitter taste in their mouth), they are more 0167. In addition to microencapsulating the proton pump
likely to refuse a drug that tastes bad. Thus, for pharmaceu inhibitors and/or the prokinetic agent with a taste-masking
tical compositions for children, it becomes even more material as described herein, the pharmaceutical composi
important to mask the bitter taste. tions of the present invention may also comprise one or more
0162 Microencapsulation of the proton pump inhibitor flavoring agents.
can (1) lower the amount of flavoring agents necessary to 0168 “Flavoring agents” or “sweeteners' useful in the
create a palatable product and/or (2) mask the bitter taste of pharmaceutical compositions of the present invention
US 2005/0239845 A1 Oct. 27, 2005

include, e.g., acacia Syrup, aceSulfame K, alitame, anise, to 95%, or by greater than 95%. In still other embodiments,
apple, aspartame, banana, Bavarian cream, berry, black no flavoring agent is necessary to create a more palatable
currant, butterScotch, calcium citrate, camphor, caramel, pharmaceutical composition as compared to a similar phar
cherry, cherry cream, chocolate, cinnamon, bubble gum, maceutical composition comprising non-microencapulated
citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, proton pump inhibitor and/or prokinetic agent.
cool cherry, cool citrus, cyclamate, cylamate, dextrose, 0.173) In various embodiments of the invention, the total
eucalyptus, eugenol, fructose, fruit punch, ginger, glycyr amount of flavoring agent present in the pharmaceutical
rhetinate, glycyrrhiza (licorice) Syrup, grape, grapefruit, composition is less than 20 grams, or less than 15 grams, or
honey, isomalt, lemon, lime, lemon cream, monoammonium less than 10 grams, or less than 8 grams, or less than 5
glyrrhizinate (MagnaSweetB), maltol, mannitol, maple, grams, or less than 4 grams, or less than 3.5 grams, or leSS
marshmallow, menthol, mint cream, mixed berry, neohes than 3 grams, or less than 2.5 grams or less than 2 grams, or
peridine DC, neotame, orange, pear, peach, peppermint, less than 1.5 grams, or less than 1 gram, or less than 500 mg,
peppermint cream, ProSweet(E Powder, raspberry, root beer, or less than 250 mg, or less than 150 mg, or less than 100
rum, Saccharin, Safrole, Sorbitol, Spearmint, Spearmint mg, or less than 50 mg.
cream, Strawberry, Strawberry cream, Stevia, Sucralose,
Sucrose, Sodium Saccharin, Saccharin, aspartame, 0.174 Methods of Microencapsulation
aceSulfame potassium, mannitol, talin, Sucralose, Sorbitol, 0.175. The proton pump inhibitor, buffering agent, and/or
Swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, prokinetic agent may be microencapsulated by methods
Vanilla, walnut, watermelon, wild cherry, wintergreen, Xyli known by one of ordinary skill in the art. Such known
tol, or any combination of these flavoring ingredients, e.g., methods include, e.g., Spray drying processes, Spinning
anise-menthol, cherry-anise, cinnamon-orange, cherry-cin disk-Solvent processes, hot melt processes, spray chilling
namon, chocolate-mint, honey-lemon, lemon-lime, lemon methods, fluidized bed, electroStatic deposition, centrifugal
mint, menthol-eucalyptus, orange-cream, Vanilla-mint, and extrusion, rotational Suspension Separation, polymerization
mixtures thereof. In other embodiments, Sodium chloride is at liquid-gas or Solid-gas interface, pressure extrusion, or
incorporated into the pharmaceutical composition. Based on Spraying Solvent extraction bath. In addition to these, Several
the proton pump inhibitor, buffering agent, and excipients, chemical techniques, e.g., complex coacervation, Solvent
as well as the amounts of each one, one of skill in the art evaporation, polymer-polymer incompatibility, interfacial
would be able to determine the best combination of flavors
to provide the optimally flavored product for consumer polymerization in liquid media, in Situ polymerization, in
demand and compliance. See, e.g., Roy et al., Modifying liquid drying, and desolvation in liquid media could also be
used.
Bitterness. Mechanism, Ingredients, and Applications
(1997). 0176) The spinning disk method allows for: 1) an
increased production rate due to higher feed rates and use of
0169. In one embodiment, one or more flavoring agents higher Solids loading in feed Solution, 2) the production of
are mixed with the taste-masking material prior to microen more spherical particles, 3) the production of a more even
capsulating the proton pump inhibitor and/or prokinetic coating, and 4) limited clogging of the spray nozzle during
agent, and are therefore part of the taste-masking material. the process.
In other embodiments, the flavoring agent is mixed with
non-compatible excipients during the formulation proceSS 0177 Spray drying is often more readily available for
and is therefore not in contact with the proton pump inhibitor Scale-up. In various embodiments, the material used in the
and/or prokinetic agent, and not part of the microencapsu Spray-dry encapsulation process is emulsified or dispersed
lation material. into the core material in a concentrated form, e.g., 10-60%
Solids. The microencapsulation material is, in one embodi
0170 In another embodiment, a buffering agent, such as ment, emulsified until about 1 to 3 um droplets are obtained.
Sodium bicarbonate, is also microencapsulated with one or Once a dispersion of proton pump inhibitor and encapsula
more taste-masking materials. tion material are obtained, the emulsion is fed as droplets
0171 In another embodiment, the weight fraction of the into the heated chamber of the spray drier. In some embodi
taste masking material is, e.g., about 98% or less, about 95% ments, the droplets are sprayed into the chamber or Spun off
or less, about 90% or less, about 85% or less, about 80% or a rotating disk. The microSpheres are then dried in the heated
less, about 75% or less, about 70% or less, about 65% or chamber and fall to the bottom of the spray drying chamber
less, about 60% or less, about 55% or less, about 50% or where they are harvested.
less, about 45% or less, about 40% or less, about 35% or 0.178 In some embodiments of the present invention, the
less, about 30% or less, about 25% or less, about 20% or micropheres have irregular geometries. In other embodi
less, about 15% or less, about 10% or less, about 5% or less, ments, the microSpheres are aggregates of Smaller particles.
about 2%, or about 1% or less of the total weight of the
pharmaceutical composition. 0179. In various embodiments, the proton pump inhibitor
and/or the prokinetic agents are present in the microSpheres
0172 In other embodiments of the present invention, the in an amount greater than 1%, greater than 2.5%, greater
amount of flavoring agent necessary to create a palatable than 5%, greater than 10%, greater than 15%, greater than
product, as compared to a pharmaceutical composition com 20%, greater than 25%, greater than 30%, greater than 35%,
prising non-microencapulated proton pump inhibitor and/or greater than 40%, greater than 45%, greater than 50%,
the prokinetic agent, is decreased by 5% or less, or by 5% greater than 55%, greater than 60%, greater than 65%,
to 10%, or by 10% to 20%, or by 20% to 30%, or by 30% greater than 70%, greater than 75%, greater than 80%,
to 40%, or by 40% to 50%, or by 50% to 60%, or by 60% greater than 85%, greater than 90% greater than 95% or
to 70%, or by 70% to 80%, or by 80% to 90%, or by 90% greater than 98% weight percent of the proton pump inhibi
US 2005/0239845 A1 Oct. 27, 2005

tor to the microencapsulation material used to enhance the herein. In accordance with one aspect of the invention, Some
Stability of the pharmaceutical composition or the taste of the proton pump inhibitor is formulated for immediate
masking material. release and Some of the part of the proton pump inhibitor is
0180 Coatings formulated for delayed release. In accordance with one
aspect of the invention, the delayed release coating is an
0181. In accordance with another aspect of the present enteric coating. In accordance with another aspect of the
invention, all or part of the prokinetic agent may be coated. invention, the proton pump inhibitor is coated with a thin
In various embodiments contemplated by the present inven enteric coating.
tion, the prokinetic agent is coated with, for example, a 0186 Dosage
gastric resistant coating Such as an enteric coating, a con
trolled-release coating, an enzymatic-controlled coating, a 0187. The pharmaceutical compositions of the present
film coating, a Sustained-release coating, an immediate invention comprising a proton pump inhibiting agent and a
release coating, a delayed-release coating, or a moisture prokinetic agent are administered and dosed in accordance
barrier coating. See, e.g., Remington's Pharmaceutical Sci with good medical practice, taking into account the clinical
ences, 20th Edition (2000). condition of the individual patient, the site and method of
administration, Scheduling of administration, and other fac
0182. In accordance with another aspect of the invention, tors known to medical practitioners. In human therapy, it is
the prokinetic agent is enterically coated. Suitable enteric important to provide a dosage form that delivers the required
coating materials include, but are not limited to, polymer therapeutic amount of the each therapeutic agent in Vivo, and
ized gelatin, shellac, methacrylic acid copolymer type CNF, renders therapeutic agent bioavailable in a rapid manner.
cellulose butyrate, phthalate, cellulose hydrogen phthalate,
cellulose proprionate phthalate, polyvinyl acetate phthalate 0188 Proton Pump Inhibiting Agents
(PVAP), cellulose acetate phthalate (CAP), cellulose acetate 0189 The proton pump inhibiting agent is administered
trimellitate (CAT), hydroxypropyl methylcellulose phtha and dosed in accordance with good medical practice, taking
late, hydroxypropyl methylcellulose acetate, dioxypropyl into account the clinical condition of the individual patient,
methylcellulose Succinate, carboxymethyl ethylcellulose the site and method of administration, Scheduling of admin
(CMEC), hydroxypropyl methylcellulose succinate, and istration, and other factors known to medical practitioners.
acrylic acid polymers and copolymerS Such as those formed In human therapy, it is important to provide a dosage form
from methyl acrylate, theyl acrylate, methyl methacrylate that delivers the required therapeutic amount of the each
and/or ehtyl methacrylate with copolymers of acrylic and therapeutic agent in Vivo, and renders therapeutic agent
methacrylic acid esters (e.g., Eudragit NE, Eudragit RL, bioavailable in a rapid manner. In addition to the dosage
Eudragit RS). In accordance with one aspect of the present forms described herein, the dosage forms described by
invention, all or part of the proton pump inhibitor may be Phillips et al. in U.S. Pat. Nos. 5,840,737, 6,489,346, 6,699,
coated. In various embodiments contemplated by the present 885 and 6,645,988 are incorporated herein by reference.
invention, the proton pump inhibitor is coated with, for
example, a gastric resistant coating Such as an enteric 0190. The percent of intact drug that is absorbed into the
coating, a controlled-release coating, an enzymatic-con bloodstream is not narrowly critical, as long as a therapeu
trolled coating, a film coating, a Sustained-release coating, tically effective amount, e.g., a gastrointestinal-disorder
an immediate-release coating, a delayed-release coating, or effective amount of a proton pump inhibiting agent, is
a moisture barrier coating. See, e.g., Remington's Pharma absorbed following administration of the pharmaceutical
ceutical Sciences, 20th Edition (2000). composition to a Subject. Gastrointestinal-disorder-effective
amounts in tablets may be found in U.S. Pat. No. 5,622,719.
0183 In accordance with another aspect of the invention, It is understood that the amount of proton pump inhibiting
either the proton pump inhibiting agent or the prokinetic agent and/or buffering agent that is administered to a Subject
agent is coated. In other aspectes of the invention, Some or is dependent on a number of factors, e.g., the Sex, general
all of the proton pump inhibitor and some or all of the health, diet, and/or body weight of the Subject.
prokinetic agent are coated. In accordance with another
aspect of the invention, the dosage form (such as a tablet, 0191 Illustratively, administration of a substituted bicy
caplet, or capsule) is coated to aid Swallowing. The proton clic aryl-imidazole to a young child or a Small animal, Such
pump inhibiting agent may be coated with the same material as a dog, a relatively low amount of the proton pump
as used to coat the prokinetic agent or a different material. inhibitor, e.g., about 1 mg to about 30 mg, will often provide
Additionally, the coating used to coat the whole dosage form blood Serum concentrations consistent with therapeutic
(Such as a film coating) may be the same as or different from effectiveness. Where the Subject is an adult human or a large
the coating used to coat the proton pump inhibiting agent animal, Such as a horse, achievement of a therapeutically
and/or the prokinetic agent. effective blood Serum concentration will require larger dos
age units, e.g., about 10 mg, about 15 mg, about 20 mg,
0184 Pharmaceutical compositions having multisite about 30 mg, about 40 mg, about 80 mg, or about 120 mg
absorption profiles of the prokinetic agent are provided dose for an adult human, or about 150 mg, or about 200 mg,
herein. In accordance with one aspect of the invention, Some or about 400 mg, or about 800 mg, or about 1000 mg dose,
of the prokinetic agent is formulated for immediate release or about 1500 mg dose, or about 2000 mg dose, or about
and Some of the prokinetic agent is formulated for delayed 2500 mg dose, or about 3000 mg dose or about 3200 mg
release. In accordance with one aspect of the invention, the dose or about 3500 mg dose for an adult horse.
delayed release coating is an enteric coating.
0.192 In various other embodiments of the present inven
0185. Pharmaceutical compositions having multisite tion, the amount of proton pump inhibitor administered to a
absorption profiles of the proton pump inhibitor are provided Subject is, e.g., about 0.5-2 mg/Kg of body weight, or about
US 2005/0239845 A1 Oct. 27, 2005

0.5 mg/Kg of body weight, or about 1 mg/Kg of body composition. In another embodiment of the present inven
weight, or about 1.5 mg/Kg of body weight, or about 2 tion, the composition is administered to the Subject in an
mg/Kg of body weight. amount to achieve a measurable Serum concentration of the
proton pump inhibiting agent greater than about 450 ng/ml
0193 Treatment dosages generally may be titrated to within about 15 minutes and to maintain a Serum concen
optimize Safety and efficacy. Typically, dosage-effect rela tration of the proton pump inhibiting agent of greater than
tionships from in vitro and/or in Vivo tests initially can about 450 ng/ml from about 15 minutes to about 1 hour after
provide useful guidance on the proper doses for Subject administration of the composition.
administration. Studies in animal models generally may be
used for guidance regarding effective dosages for treatment 0197). In another embodiment of the present invention,
of gastrointestinal disorders or diseases in accordance with the composition is administered to the Subject in an amount
the present invention. In terms of treatment protocols, it to achieve a measurable Serum concentration of the proton
should be appreciated that the dosage to be administered will pump inhibiting agent greater than about 150 ng/ml within
depend on Several factors, including the particular agent that about 30 minutes and to maintain a Serum concentration of
is administered, the route chosen for administration, the the proton pump inhibiting agent of greater than about 150
condition of the particular Subject. ng/ml from about 30 minutes to about 1 hour after admin
istration of the composition. In yet another embodiment of
0194 In various embodiments, unit dosage forms for the present invention, the composition is administered to the
humans contain about 1 mg to about 120 mg, or about 1 mg, Subject in an amount to achieve a measurable Serum con
or about 5 mg, or about 10 mg, or about 15 mg, or about 20 centration of the proton pump inhibiting agent greater than
mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 250 ng/ml within about 30 minutes and to maintain a
about 60 mg, or about 70 mg, or about 80 mg, or about 90 Serum concentration of the proton pump inhibiting agent of
mg, or about 100 mg, or about 110 mg, or about 120 mg of greater than about 250 ng/ml from about 30 minutes to about
a proton pump inhibitor. 1 hour after administration of the composition. In another
0.195. In a further embodiment of the present invention, embodiment of the present invention, the composition is
the pharmaceutical composition is administered in an administered to the Subject in an amount to achieve a
amount to achieve a measurable Serum concentration of a measurable Serum concentration of the proton pump inhib
non-acid degraded proton pump inhibiting agent greater than iting agent greater than about 350 ng/ml within about 30
about 0.1 ug/ml within about 30 minutes after administration minutes and to maintain a Serum concentration of the proton
of the pharmaceutical composition. In another embodiment pump inhibiting agent of greater than about 350 ng/ml from
about 30 minutes to about 1 hour after administration of the
of the present invention, the pharmaceutical composition is composition. In another embodiment of the present inven
administered to the Subject in an amount to achieve a tion, the composition is administered to the Subject in an
measurable Serum concentration of a non-acid degraded or amount to achieve a measurable Serum concentration of the
non-acid reacted proton pump inhibiting agent greater than proton pump inhibiting agent greater than about 450 ng/ml
about 100 ng/ml within about 15 minutes after administra within about 30 minutes and to maintain a Serum concen
tion of the pharmaceutical composition. In yet another tration of the proton pump inhibiting agent of greater than
embodiment, the pharmaceutical composition is adminis about 450 ng/ml from about 30 minutes to about 1 hour after
tered to the Subject in an amount to achieve a measurable administration of the composition.
Serum concentration of a non-acid degraded or non-acid
reacted proton pump inhibiting agent greater than about 100 0198 In still another embodiment of the present inven
ng/ml within about 10 minutes after administration of the tion, the composition is administered to the Subject in an
pharmaceutical composition. amount to achieve a measurable Serum concentration of a
non-acid degraded or non-acid reacted proton pump inhib
0196. In another embodiment of the present invention, iting agent greater than about 500 ng/ml within about 1 hour
the composition is administered to the Subject in an amount after administration of the composition. In yet another
to achieve a measurable Serum concentration of the proton embodiment of the present invention, the composition is
pump inhibiting agent greater than about 150 ng/ml within administered to the Subject in an amount to achieve a
about 15 minutes and to maintain a Serum concentration of measurable Serum concentration of a non-acid degraded or
the proton pump inhibiting agent of greater than about 150 non-acid reacted proton pump inhibiting agent greater than
ng/ml from about 15 minutes to about 1 hour after admin about 300 ng/ml within about 45 minutes after administra
istration of the composition. In yet another embodiment of tion of the composition.
the present invention, the composition is administered to the 0199 Contemplated compositions of the present inven
Subject in an amount to achieve a measurable Serum con tion provide a therapeutic effect as proton pump inhibiting
centration of the proton pump inhibiting agent greater than
about 250 ng/ml within about 15 minutes and to maintain a agent medications over an interval of about 5 minutes to
Serum concentration of the proton pump inhibiting agent of about 24 hours after administration, enabling, for example,
greater than about 250 ng/ml from about 15 minutes to about once-a-day, twice-a-day, three times a day, etc. administra
tion if desired.
1 hour after administration of the composition. In another
embodiment of the present invention, the composition is 0200 Generally speaking, one will desire to administer
administered to the Subject in an amount to achieve a an amount of the compound that is effective to achieve a
measurable Serum concentration of the proton pump inhib Serum level commensurate with the concentrations found to
iting agent greater than about 350 ng/ml within about 15 be effective in vivo for a period of time effective to elicit a
minutes and to maintain a Serum concentration of the proton therapeutic effect. Determination of these parameters is well
pump inhibiting agent of greater than about 350 ng/ml from within the skill of the art. These considerations are well
about 15 minutes to about 1 hour after administration of the known in the art and are described in Standard textbooks.
US 2005/0239845 A1 Oct. 27, 2005

0201 In one embodiment of the present invention, the 0206. In human therapy, it is important to provide a
composition is administered to a Subject in a gastrointesti dosage form that delivers the required therapeutic amount of
nal-disorder-effective amount, that is, the composition is the drug in Vivo, and renders the drug bioavailable at the
administered in an amount that achieves a therapeutically appropriate time. According to one aspect of the invention,
effective dose of a proton pump inhibiting agent in the blood part of the prokinetic agent is in an immediate release form
Serum of a Subject for a period of time to elicit a desired and part of the prokinetic agent is in a delayed release form.
therapeutic effect. Illustratively, in a fasting adult human According to another aspect of the invention, two therapeu
(fasting for generally at least 10 hours) the composition is tically effective doses are present in the pharmaceutical
administered to achieve a therapeutically-effective dose of a composition, one in an immediate release form and another
proton pump inhibiting agent in the blood Serum of a Subject in a delayed release form. The dosing of prokinetic agents
within about 45 minutes after administration of the compo will vary but can be readily determined by one of skill in the
Sition. In another embodiment of the present invention, a art.
therapeutically-effective dose of the proton pump inhibiting 0207 Combination Therapies
agent is achieved in the blood Serum of a Subject within
about 30 minutes from the time of administration of the 0208. The compositions and methods described herein
composition to the Subject. In yet another embodiment, a may also be used in conjunction with other well known
therapeutically-effective dose of the proton pump inhibiting therapeutic reagents that are Selected for their particular
agent is achieved in the blood Serum of a Subject within usefulneSS against the condition that is being treated. In
about 20 minutes from the time of administration to the general, the compositions described herein and, in embodi
Subject. In Still another embodiment of the present invention, ments where combinational therapy is employed, other
a therapeutically-effective dose of the proton pump inhibit agents do not have to be administered in the same pharma
ing agent is achieved in the blood Serum of a Subject at about ceutical composition, and may, because of different physical
15 minutes from the time of administration of the compo and chemical characteristics, have to be administered by
Sition to the Subject. different routes. The determination of the mode of admin
0202) In further embodiments, greater than about 98%; or istration and the advisability of administration, where pos
greater than about 95%; or greater than about 90%; or Sible, in the same pharmaceutical composition, is well
greater than about 75%; or greater than about 50% of the within the knowledge of the skilled clinician. The initial
drug absorbed into the bloodstream is in a non-acid administration can be made according to established proto
degraded or a non-acid reacted form. cols known in the art, and then, based upon the observed
effects, the dosage, modes of administration and times of
0203. In other embodiments, the pharmaceutical compo administration can be modified by the skilled clinician. The
Sitions provide a release profile of the proton pump inhibitor, particular choice of compounds used will depend upon the
using USP dissolution methods, whereby greater than about diagnosis of the attending physicians and their judgment of
50% of the proton pump inhibitor is released from the the condition of the patient and the appropriate treatment
composition within about 2 hours; or greater than 50% of the protocol. The compounds may be administered concurrently
proton pump inhibitor is released from the composition (e.g., simultaneously, essentially simultaneously or within
within about 1.5 hours; or greater than 50% of the proton the same treatment protocol) or sequentially, depending
pump inhibitor is released from the composition within upon the nature of the proliferative disease, the condition of
about 1 hour after exposure to gastrointestinal fluid. In the patient, and the actual choice of compounds used. The
another embodiment, greater than about 60% of the proton determination of the order of administration, and the number
pump inhibitor is released from the composition within of repetitions of administration of each therapeutic agent
about 2 hours; or greater than 60% of the proton pump during a treatment protocol, is well within the knowledge of
inhibitor is released from the composition within about 1.5 the Skilled physician after evaluation of the disease being
hours; or greater than 60% of the proton pump inhibitor is treated and the condition of the patient.
released from the composition within about 1 hour after
exposure to gastrointestinal fluid. In yet another embodi 0209 Dosage Form
ment, greater than about 70% of the proton pump inhibitor 0210. The pharmaceutical compositions of the present
is released from the composition within about 2 hours, or invention contain desired amounts of proton pump inhibitor,
greater than 70% of the proton pump inhibitor is released a buffering agent and a prokinetic agent and can be in the
from the composition within about 1.5 hours, or greater than form of: a tablet, (including a Suspension tablet, a chewable
70% of the proton pump inhibitor is released from the tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid
composition within about 1 hour after exposure to gas disintegration tablet, an effervescent tablet, or a caplet), a
trointestinal fluid. pill, a powder (including a sterile packaged powder, a
0204 Prokinetic Agents dispensable powder, or an effervescent powder) a capsule
0205 The prokientic agent is administered and dosed in (including both Soft or hard capsules, e.g., capsules made
accordance with good medical practice, taking into account from animal-derived gelatin or plant-derived HPMC) a
the clinical condition of the individual patient, the Site and lozenge, a Sachet, a troche, pellets, granules, or an aerosol.
These pharmaceutical compositions of the present invention
method of administration, Scheduling of administration, and can be manufactured by conventional pharmacological tech
other factors known to medical practitioners. According to niques.
one aspect of the invention, the pharmaceutical composition
comprises two different prokinetic agents. According to 0211 Conventional pharmacological techniques include,
another aspect of the invention, the pharmaceutical com e.g., one or a combination of methods: (1) dry mixing, (2)
position comprises two different prokinetic agents wherein at direct compression, (3) milling, (4) dry or non-aqueous
least one of the prokinetic agents is a 5HT inhibitor. granulation, (5) wet granulation, or (6) fusion. See, e.g.,
US 2005/0239845 A1 Oct. 27, 2005

Lachman et al., The Theory and Practice of Industrial 0218 Compressed tablets are solid dosage forms pre
Pharmacy (1986). Other methods include, e.g., prilling, pared by compacting the bulk blend compositions described
Spray drying, pan coating, melt granulation, granulation, above. In various embodiments, compressed tablets of the
Wurster coating, tangential coating, top Spraying, tableting, present invention will comprise one or more functional
extruding, coacervation and the like. excipients Such as binding agents and/or disintegrants. In
0212. In one embodiment, the proton pump inhibitor and other embodiments, the compressed tablets will comprise a
prokinetic agent are microencapsulated prior to being for film Surrounding the final compressed tablet. In other
mulated into one of the above forms. In another embodi embodiments, the compressed tablets comprise one or more
ment, all or Some of the proton pump inhibitor is microen excipients and/or flavoring agents.
capsualted prior to being formulated into one of the above 0219. A chewable tablet may be prepared by compacting
forms. In another embodiment, some or all of the buffering bulk blend compositions, described above. In one embodi
agent is microencapsulated prior to being formulated into ment, the chewable tablet comprises a material useful for
one of the above forms. In other embodiments, all or some enhancing the shelf-life of the pharmaceutical composition.
of the prokinetic agent is microencapsulated prior to being In another embodiment, microencapsulated material has
further formulated into one of the above forms. In still taste-masking properties. In various other embodiments, the
another embodiment, Some or all of the prokinetic agent is chewable tablet comprises one or more flavoring agents and
coated prior to being further formulated into one of the one or more taste-masking materials. In yet other embodi
above forms by using Standard coating procedures, Such as ments the chewable tablet comprised both a material useful
those described in Remington's Pharmaceutical Sciences, for enhancing the shelf-life of the pharmaceutical formula
20th Edition (2000). In yet other embodiments contemplated tion and one or more flavoring agents.
by the present invention, a film coating is provided around 0220. In various embodiments, the microencapsulated
the pharmaceutical composition. proton pump inhibitor, buffering agent, prokinetic agent, and
0213. In other embodiments, the pharmaceutical compo optionally one or more excipients, are dry blended and
Sitions further comprise one or more additional materials compressed into a mass, Such as a tablet, having a hardneSS
Such as a pharmaceutically compatible carrier, binder, filling Sufficient to provide a pharmaceutical composition that
agent, Suspending agent, flavoring agent, Sweetening agent, Substantially disintegrates within less than about 30 minutes,
disintegrating agent, Surfactant, preservative, lubricant, less than about 35 minutes, less than about 40 minutes, less
colorant, diluent, Solubilizer, moistening agent, Stabilizer, than about 45 minutes, less than about 50 minutes, less than
wetting agent, anti-adherent, parietal cell activator, anti about 55 minutes, or less than about 60 minutes, after oral
foaming agent, antioxidant, chelating agent, antifungal administration, thereby releasing the buffering agent and the
agent, antibacterial agent, or one or more combination proton pump inhibitor into the gastrointestinal fluid. When
thereof. at least 50% of the pharmaceutical composition has disin
0214) Parietal cell activators are administered in an tegrated, the compressed mass has Substantially disinte
amount Sufficient to produce the desired Stimulatory effect grated.
without causing untoward Side effects to patients. In one 0221) A capsule may be prepared by placing the bulk
embodiment, the parietal cell activator is administered in an blend composition, described above, inside a capsule.
amount of about 5 mg to about 2.5 grams per 20 mg dose of 0222 Exemplary Powder Compositions
the proton pump inhibitor.
0215. In other embodiments, one or more layers of the 0223) A powder for suspension may be prepared by
pharmaceutical formulation are plasticized. Illustratively, a combining proton pump inhibitor, one or more buffering
plasticizer is generally a high boiling point Solid or liquid. agent and one or more prokinetic agents. In various embodi
Suitable plasticizers can be added from about 0.01% to ments, the powder may comprise one or more pharmaceu
about 50% by weight (w/w) of the coating composition. tical excipients and flavors. Powder for Suspension is pre
Plasticizers include, e.g., diethyl phthalate, citrate esters, pared by mixing the proton pump inhibitor, one or emore
polyethylene glycol, glycerol, acetylated glycerides, triace buffering agetns, one or more prokinetic agents, and optional
tin, polypropylene glycol, polyethylene glycol, triethyl cit pharmaceutical excipients to form a bulk blend composition.
rate, dibutyl Sebacate, Stearic acid, Stearol, Stearate, and This bulk blend is uniformly subdivided into unit dosage
castor oil. packaging or multi-dosage packaging units. The term "uni
0216 Exemplary Solid Oral Dosage Compositions form” means the homogeneity of the bulk blend is substan
tially maintained during the packaging process.
0217 Solid oral dosage compositions, e.g., tablets, chew 0224. In some embodiments, some or all of the proton
able tablets, effervescent tablets, caplets, and capsules, are pump inhibitor is micronized. In other embodiments, Some
prepared by mixing the proton pump inhibitor, one or more or all of the prokinetic agent is micronized. Additional
buffering agent, at least one prokinetic agent, and pharma embodiments of the present invention also comprise a
ceutical excipients to form a bulk blend composition. When Suspending agent and/or a Wetting agent.
referring to these bulk blend compositions as homogeneous,
it is meant that the proton pump inhibitor, buffering agent, 0225. Effervescent powders are also prepared in accor
and prokinetic agent are dispersed evenly throughout the dance with the present invention. Effervescent Salts have
composition So that the composition may be readily Subdi been used to disperse medicines in water for oral adminis
Vided into equally effective unit dosage forms, Such as tration. Effervescent Salts are granules or coarse powders
tablets, pills, and capsules. The individual unit dosages may containing a medicinal agent in a dry mixture, usually
also comprise film coatings, which disintegrate upon oral composed of Sodium bicarbonate, citric acid and/or tartaric
ingestion or upon contact with diluent. acid. When salts of the present invention are added to water,
US 2005/0239845 A1 Oct. 27, 2005

the acids and the base react to liberate carbon dioxide gas, concentration at various points involves dividing the Sus
thereby causing “effervescence.” Examples of effervescent pension into three Substantially equal Sections: top, middle
Salts include the following ingredients: Sodium bicarbonate and bottom. The layers are divided starting at the top of the
or a mixture of Sodium bicarbonate and Sodium carbonate, Suspension and ending at the bottom of the Suspension. Any
citric acid and/or tartaric acid. Any acid-base combination number of Sections Suitable for determining the uniformity
that results in the liberation of carbon dioxide can be used in of the Suspension can be used, Such as for example, two
place of the combination of Sodium bicarbonate and citric Sections, three Sections, four Sections, five Sections, or Six or
and tartaric acids, as long as the ingredients were Suitable for more Sections. The Sections can be named in any appropriate
pharmaceutical use and result in a pH of about 6.0 or higher. manner, Such as relating to their location (e.g., top, middle,
0226. The method of preparation of the effervescent bottom), numbered (e.g., one, two, three, four, five, Six, etc.),
granules of the present invention employs three basic pro or lettered (e.g., A, B, C, D, E, F, G, etc.). The Sections can
cesses: wet granulation, dry granulation and fusion. The be divided in any Suitable configuration. In one embodiment,
fusion method is used for the preparation of most commer the sections are divided from top to bottom, which allows a
cial effervescent powders. It should be noted that, although comparison of Sections from the top and Sections from the
these methods are intended for the preparation of granules, bottom in order to determine whether and at what rate the
the formulations of effervescent salts of the present inven proton pump inhibitor is Settling into the bottom Sections.
tion could also be prepared as tablets, according to known Any number of the assigned Sections Suitable for determin
technology for tablet preparation. ing uniformity of the Suspension can be evaluated, Such as,
e.g., all sections, 90% of the sections, 75% of the sections,
0227 Wet granulation is one the oldest methods of gran 50% of the sections, or any other suitable number of
ule preparation. The individual Steps in the wet granulation Sections.
process of tablet preparation include milling and Sieving of
the ingredients, dry powder mixing, wet massing, granula 0233 Concentration is easily determined by methods
tion, and final grinding. In various embodiments, the known in the art, Such as, e.g., methods described herein. In
microencapsulated PPI is added to the other excipients of the one embodiment, concentration is determined using percent
pharmaceutical composition after they have been wet granu label claim. “Percent label claim” (% label claim) is calcu
lated. lated using the actual amount of proton pump inhibitor or
0228) Dry granulation involves compressing a powder prokinetic agent per Sample compared with the intended
mixture into a rough tablet or "slug on a heavy-duty rotary amount of proton pump inhibitor or prokinetic agent per
tablet press. The Slugs are then broken up into granular Sample. The intended amount of proton pump inhibitor or
particles by a grinding operation, usually by passage through prokinetic agent per Sample can be determined based on the
an oscillation granulator. The individual Steps include mix formulation protocol or from any other Suitable method,
ing of the powders, compressing (slugging) and grinding Such as, for example, by referencing the "label claim,” that
is, the intended amount of proton pump inhibitor or proki
(slug reduction or granulation). No wet binder or moisture is netic agent depicted on labeling complying with the regu
involved in any of the Steps. In Some embodiments, the lations promulgated by the United States Food and Drug
microencapsulated PPI is dry granulated with other excipi Administration.
ents in the pharmaceutical composition. In other embodi
ments, the microencapsulated omeprazole is added to other 0234. In one aspect of the present invention, the suspen
excipients of the pharmaceutical composition after they have Sion is divided into Sections and the percent label claim is
been dry granulated. determined for each Section. The Suspension is determined
0229 Powder for Suspension to be Substantially uniform if the Suspension comprises at
least one of (a) at least about a set threshold percent label
0230 Compositions are provided comprising a pharma claim throughout the evaluated Sections or (b) has less than
ceutical composition comprising at least one proton pump a Set percentage variation in percent label claim throughout
inhibitor, at least one buffering agent, at least one prokinetic the evaluated Sections. The Suspension can comprise either
agent, and at least one Suspending agent for oral adminis (a) or (b) or can comprise both (a) and (b). The evaluated
tration to a Subject. The composition may be a powder for Sections of the Suspension can have any Set threshold percent
Suspension, and upon admixture with water, a Substantially label claim Suitable for determining that the Suspension is
uniform Suspension is obtained. Substantially uniform. For example, the Sections can com
0231. A suspension is “substantially uniform” when it is prise, e.g., at least about 70, at least about 75, at least about
mostly homogenous, that is, when the Suspension is com 80, at least about 85, at least about 87, at least about 88, at
posed of approximately the same concentration of proton least about 89, at least about 90, at least about 93, at least
pump inhibitor at any point throughout the Suspension. A about 95, at least about 98, at least about 100, at least about
Suspension is determined to be composed of approximately 105, at least about 110, at least about 115 percent label claim
the same concentration of proton pump inhibitor throughout of proton pump inhibitor or any range that falls therein, Such
the suspension when there is less than about 20%, less than as, e.g., from about 80 to about 115, from about 85 to about
about 15%, less than about 13%, less than about 11%, less 110, from about 87 to about 108, from about 89 to about 106,
than about 10%, less than about 8%, less than about 5%, or from about 90 to about 105, and so on, percent label claim
less than about 3% variation in concentration among of proton pump inhibitor. The evaluated sections of the
Samples taken from various points in the Suspension. Suspension can have less than any Set percentage variation in
percent label claim Suitable for determining that the Suspen
0232 The concentration at various points throughout the Sion is Substantially uniform, Such as, e.g., about 25%, about
Suspension can be determined by any Suitable means known 20%, about 17%, about 15%, about 13%, about 11%, about
in the art. For example, one Suitable method of determining 10%, about 7%, about 5%, about 3% or about 0% variation.
US 2005/0239845 A1 Oct. 27, 2005
22

0235. In another aspect of the present invention, the ally administered to the patient. The Suspension can be
Suspension is Substantially uniform if it comprises at least administered to the patient at any time after admixture as
one of (a) at least about 87% label claim of proton pump long as the Suspension remains Substantially uniform. In one
inhibitor in top, middle and bottom sections determined by embodiment, the Suspension is administered to the patient
Separating the Suspension into three Substantially equal from any time after admixture until the Suspension is no
Sections from top to bottom for at least about five minutes longer uniform. For example, the Suspension can be admin
after admixture with water, or (b) less than about 11% istered to the patient from about 5 minutes, about 10
variation in % label claim among each of the top, middle and
bottom Sections for at least about five minutes after admix minutes, about 15 minutes, about 20 minutes, about 30
ture with water. minutes, about 45 minutes, about 60 minutes (1 hour), about
75 minutes, about 90 minutes, about 105 minutes, about 120
0236. In an alternate aspect of the present invention, the minutes (2 hours), about 150 minutes, about 180 minutes (3
Suspension is Substantially uniform if it comprises at least hours), about 210 minutes, about 4 hours, about 5 hours or
one of (a) at least about 80% label claim of proton pump more after admixture with water. In one embodiment, the
inhibitor in top, middle and bottom sections determined by Suspension is administered to the patient from about 5
Separating the Suspension into three Substantially equal minutes to about 4 hours after admixture. In another embodi
sections from top to bottom for at least about 60 minutes
after admixture with water, or (b) less than about 15% ment, the Suspension is administered to the patient from
variation in % label claim among each of the top, middle and about 15 minutes to about 3 hours after admixture. In yet
bottom Sections for at least about Sixty minutes after admix another embodiment, the Suspension is administered to the
ture with water. patient from at least about 1 to at least about 3 hours after
admixture.
0237. In some embodiments, the composition will remain
Substantially uniform for a Suitable amount of time corre 0240. In one embodiment, the composition comprises at
sponding to the intended use of the composition, Such as, least one proton pump inhibitor, at least one buffering agent,
e.g., for at least about 5 minutes, about 10 minutes, about 15 at least one prokinetic agent, and Xanthan gum. The com
minutes, about 20 minutes, about 30 minutes, about 45 position is a powder for Suspension, and upon admixture
minutes, about 60 minutes (I hour), about 75 minutes, about with water, a first Suspension is obtained that is Substantially
90 minutes, about 105 minutes, about 120 minutes (2 hours), more uniform when compared to a Second Suspension com
about 150 minutes, about 180 minutes (3 hours), about 210 prising the proton pump inhibitor, the buffering agent, the
minutes, about 4 hours, about 5 hours or more after admix prokinetic agent, and Suspending agent, wherein the Sus
ture with water. In one embodiment, the Suspension remains pending agent is not Xanthan gum. In one embodiment, the
substantially uniform from about 5 minutes to about 4 hours first Suspension comprises at least one of (a) at least about
after admixture with water. In another embodiment, the 87% label claim of proton pump inhibitor in top, middle and
Suspension remains Substantially uniform from about 15 bottom Sections determined by Separating the Suspension
minutes to about 3 hours after admixture with water. In yet into three Substantially equal Sections from top to bottom for
another embodiment, the Suspension is remains Substantially
uniform from at least about 1 to at least about 3 hours after at least about five minutes after admixture with water, or (b)
admixture with water. less than about 11% variation in % label claim among each
of the top, middle and bottom sections for at least about five
0238. In one embodiment of the present invention, the minutes after admixture with water.
composition will remain Substantially uniform at least until
the Suspension is prepared for administration to the patient. 0241. In another embodiment, the first suspension com
The Suspension can be prepared for administration to the prises at least one of (a) at least about 80% label claim of
patient at any time after admixture as long as the Suspension proton pump inhibitor in top, middle and bottom Sections
remains Substantially uniform. In another embodiment, the determined by Separating the Suspension into three Substan
Suspension is prepared for administration to the patient from tially equal Sections from top to bottom for at least about
any time after admixture until the Suspension is no longer Sixty minutes after admixture with water, or (b) less than
uniform. For example, the Suspension can be prepared for about 15% variation in % label claim among each of the top,
administration to the patient from about 5 minutes, about 10 middle and bottom Sections for at least about Sixty minutes
minutes, about 15 minutes, about 20 minutes, about 30 after admixture with water.
minutes, about 45 minutes, about 60 minutes (1 hour), about
75 minutes, about 90 minutes, about 105 minutes, about 120 0242. In one embodiment, the composition comprises
minutes (2 hours), about 150 minutes, about 180 minutes (3 omeprazole, Sodium bicarbonate and Xanthan gum. The
hours), about 210 minutes, about 4 hours, about 5 hours or composition is a powder for Suspension, and upon admixture
more after admixture with water. In one embodiment, the with water, a Substantially uniform Suspension is obtained.
Suspension is prepared for administration to the patient from In one embodiment, the Suspension comprises at least one of
about 5 minutes to about 4 hours after admixture. In another (a) at least about 87% label claim of proton pump inhibitor
embodiment, the Suspension is prepared for administration in top, middle and bottom Sections determined by Separating
to the patient from about 15 minutes to about 3 hours after the Suspension into three Substantially equal Sections from
admixture. In yet another embodiment, the Suspension is top to bottom for at least about five minutes after admixture
prepared for administration to the patient from at least about with water, or (b) less than about 11% variation in % label
1 to at least about 3 hours after admixture.
claim among each of the top, middle and bottom Sections for
0239). In an alternate embodiment, the composition at least about five minutes after admixture with water. In
remains Substantially uniform until the composition is actu another embodiment, the Suspension comprises at least one
US 2005/0239845 A1 Oct. 27, 2005
23

of (a) at least about 80% label claim of proton pump 0248. The invention has been described in an illustrative
inhibitor in top, middle and bottom sections determined by manner, and it is to be understood that the terminology used
Separating the Suspension into three Substantially equal is intended to be in the nature of description rather than of
Sections from top to bottom for at least about Sixty minutes limitation.
after admixture with water, or (b) less than about 15%
variation in % label claim among each of the top, middle and Example 1
bottom Sections for at least about Sixty minutes after admix
ture with water. Spinning Disk Microencapsulation ProceSS
0243 In yet another embodiment, the composition com 0249. The basic operation for the spinning disk-solvent
prises omeprazole, Sodium bicarbonate, at least one proki process used is as follows: An encapsulation Solution is
netic agent, Xanthan gum, and at least one Sweetener or prepared by dissolving the encapsulation material in the
flavoring agent. The composition is a powder for Suspen appropriate solvent. Proton pump inhibitor (PPI) in combi
Sion. Upon admixture with water, a Substantially uniform nation with buffering agent and prokinetic agent, or proton
Suspension is obtained. In one embodiment, the Suspension pump inhibitor alone if intended to be microencapsulated
comprises at least one of (a) at least about 87% label claim and then combined with a buffering agent and prokinetic
of proton pump inhibitor in top, middle and bottom Sections agent, is dispersed in the coating Solution and fed onto the
determined by Separating the Suspension into three Substan center of the Spinning disk. A thin film is produced acroSS the
tially equal Sections from top to bottom for at least about five Surface of the disk and atomization occurs as the coating
minutes after admixture with water, or (b) less than about material left the periphery of the disk. The microSpheres are
11% variation in % label claim among each of the top, formed by removal of the solvent using heated airflow inside
middle and bottom sections for at least about five minutes the atomization chamber and collected as a free-flowing
after admixture with water. In another embodiment, the powder using a cyclone separator.
Suspension comprises at least one of (a) at least about 80%
label claim of proton pump inhibitor in top, middle and Example 2
bottom Sections determined by Separating the Suspension
into three Substantially equal Sections from top to bottom for Spray Drying Microencapsulation ProceSS
at least about sixty minutes after admixture with water, or (b)
less than about 15% variation in % label claim among each 0250) A spray dryer consists of the same components as
of the top, middle and bottom Sections for at least about Sixty a spinning disk except atomization is achieved through an
minutes after admixture with water. air nozzle instead of a spinning disk.
0244. Other Exemplary Compositions Example 3
0245 Pharmaceutical compositions suitable for buccal or Preparation of Powder for Suspension for Oral
Sublingual administration include intra-oral batch or Solid Dosing
dosage forms, e.g., lozenges. Other types of release delivery
Systems are available and known to those of skill in the art. 0251 Powder for suspension (liquid oral pharmaceutical
Examples of Such delivery Systems include, but are not composition) according to the present invention, is prepared
limitd to: polymer-based Systems. Such as polylactic acid, by mixing PPI (40 mg omeprazole in the form of microen
polyglycolic acid, polyanhydrides and polycaprolactone; capsulated omeprazole, omeprazole powder or omeprazole
nonpolymer-based Systems that are lipids, including Sterols base) with at least one buffering agent and a prokinetic
Such as cholesterol, cholesterol esters and fatty acids, or agent. In one embodiment, omeprazole or other proton pump
neutral fats, Such as mono-, di- and triglycerides, hydrogel inhibitor, which can be obtained from powder, capsules,
release Systems, Silastic Systems, peptide-based Systems, tablets, or from the Solution for parenteral administration, is
wax coatings, compressed tablets using conventional bind mixed with Sodium bicarbonate (1680 mg), prokinetic agent,
erS and excipients partially fused implants and the like. See, and SweetenerS and flavors.
e.g., Liberman et al., Pharmaceutical DOSage Forms, 2 Ed.,
Vol. 1, pp. 209-214 (1990). Example 4
0246 For the sake of brevity, all patents and other Microencapsulated Proton Pump Inhibitor
references cited herein are incorporated by reference in their
entirety. 0252) The amount of microencapsulated omeprazole
used in each tablet batch varies based on the actual payload
EXAMPLES of each Set of microcapsules to achieve the theoretical dose
of 40 mg. The omeprazole is microencapsulated in a similar
0247 The present invention is further illustrated by the manner as that described in Example 1 and Example 2. All
following examples, which should not be construed as ingredients are mixed well to achieve a homogenious blend.
limiting in any way. The experimental procedures to gener
ate the data shown are discussed in more detail below. For 0253 Omeprazole microspheres were prepared using a
all formulations herein, multiple doses may be proportion high-speed rotary tablet press (TBCB Pharmaceutical
ally compounded as is known in the art. The coatings, layers, Equipment Group, Model ZPY15). Round, convex tablets
and encapsulations are applied in conventional ways using with diameters of about 10 mm and an average weight of
equipment customary for these purposes. approximately 600 mg per tablet were prepared.
US 2005/0239845 A1 Oct. 27, 2005
24

TABLE 4A

No Microencapsulation Material Method Size

Myverol Disk-hot melt 120-2OO micron

Myverol Disk-hot melt 120-2OO micron
KLX & BHT (0.1% of KLX) Disk-hot melt 25-125 micron
KLX & BHT (0.1% of KLX) Disk-hot melt 25-125 micron
Methocel A15LV & PEG 3350 (5%) Spray dry 5-30 micron
Methocel A15LV, PEG 300 (5%) & BHT (0.1%) Spray dry 5-30 micron
Methocel A15LV, Span 20 (5%) & BHT (0.1%) Spray dry 5-30 micron
Methocel A15LV BHT (0.1%) Spray dry 5-30 micron
Modified food starch, PEG 3350 (2.5%) & BHT (0.1%) Spray dry 5-30 micron
1. O Methocel A15LV, PEG 3350 (5%), BHT (0.1%) & Sodium Spray dry 5-30 micron
bicarbonate
11 Opadry YS-1-7003 PEG 3350 (5%) BHT (0.1%) Spray dry 5-30 micron
12 Methocel K4M PEG 3350 (10%) BHT Spray dry 5-30 micron
13 Kollicoat IR, PEG 3350 (5%) & BHT Spray dry 5-30 micron
14 Eudragit RD 100, PEG 3350 (5%) & BHT (0.1%) Spray dry 5-30 micron
15 Klucel (HPC), PEG 3350 (5%) & BHT (0.1%) Spray dry 5-30 micron
16 Ethocel Disk-solven 25-125 micron
17 Ethocel (50%) Methocel E5 (50%) Disk-solven 25-125 micron
18 Ethocel (75%) Methocel (25%) Disk-solven 25-125 micron
19 Methocel Disk-solven 25-125 micron
2O Ethocel Sodium Bicarbonate Disk-solven 25-125 micron
21 Ethocel & PEG 3350 (5%) Disk-solven 25-125 micron
22 Ethocel (50%) & Klucel EXAF (50%) Disk-solven 25-125 micron
23 Klucel Disk-solven 25-100 micron
24 Sepifilm LP Disk-solven 25-100 micron
25 Eudragit E100 Disk-solven 25-8O micron
26 Eudragit E100 Disk-solven 25-80 micron
27 Eudragit E100 & Span 20 (5%) Disk-solven 25-80 micron
28 Eudragit E100 & PEG 300 (5%) Disk-solven 25-80 micron
29 Eudragit EPO Disk-solven 25-80 micron
3O Eudragit EPO Disk-solven 25-90 micron
31 Opadry AMB Spray dry &30 micron
32 Sucralose Spray dry
33 Sepifilm LP Spray dry
34 Kollicoat IR Spray dry
35 Kollicoat IR & Sodium bicarbonate Spray dry &30 micron
36 Klucel & Sucralose (20%) Spray dry
37 Klucel & Sucrose (20%) Spray dry
38 Klucel & Sodium bicarbonate Spray dry &30 micron
39 Klucel (60%) Sucraolse (10%) Sodium bicarbonate (30%) Spray dry SO micron
40 Eudragit EPO Disk-solvent 20-75 micron
41 Eudragit EPO Disk-solvent 2O-90 micron
42 Eudragit EPO(67%) Sodium bicarb(33%) Disk-solvent 20-85 micron
43 EudragitEPO(61.5%) PEG 300(11.5%) PEG 3350 (3.8%) Disk-solvent 2O-110 micron
Sod Bicarb (23.2%)
44 Eudragit EPO Disk-solvent 20-100 micron
45 Opadry AMB (No TiO) Spray dry
46 Opadry AMB (No TiO.) Spray dry
47 Opadry AMB (No TiO) BHT (0.1%) Spray dry
48 Cavamax W8 (gamma-CD) Spray dry (pH = 10) 5-30 microns
49 Cavamax W8 & L-lysine Spray dry (pH = 10) 5-30 micron
50 Cavamax W8 & Methocel A15 LV Spray dry (pH = 10) 5-40 micron
52 Opadry AMB & BHT Spray Dry (aqueous) 5-30 micron

0254 Stability studies were performed on the microen microcrystalline cellulose (128 mg), Sucralose (162 mg),
capsulated omeprazole. The various tablets used in the peppermint duraromer (34 mg), peach duraromer (100 mg),
Stability Studies were manufactured using the following masking powder (60 mg), FD&C Lake No. 40 Red (3 mg),
materials: Encapsulated omeprazole, Sodium bicarbonate and magnesium Stearate (32 mg). An exemplary formulation
(1260 mg), calcium carbonate (790 mg), croScarmellose used to make each of the tablets, as well as the blending
sodium (64 mg), Klucel (160 mg), Xylitab 100 (380 mg), methods used, are shown in Table 4.B., below.
US 2005/0239845 A1 Oct. 27, 2005
25

TABLE 4B
Feed
Method and Rate Inlet? Outlet
Sample Solvent Microencapsulation Material Wt % of material (g/min) Temp( C.)
53 Spray dry Methocel A15 LV 5% 4.2 125/70
Water PEG 3350
54 Spray dry Methocel A15 LV 5% 4.0 125/70
Water BHT
55 Spray dry Opadry YS-1-7003 5% 4.2 126/60
Water PEG 3350
BHT
56 Spray dry Kollicoat IR 10% 3.0 128/85
Water PEG 3350
BHT
57 Spray dry Eudragit RD100 5% 4.0 127/87
Water PEG 3350
BHT
58 Spray dry Klucel 5% 4.2 126/83
Water PEG 3350
BHT
59 Spinning disk** Klucel 10% 90 f52
75% Methanol
25% Acetone
60 Spray dry Kollicoat 5% 4.5 129/86
Water Sodium Bicarb
61 Spray dry Klucel 5% 4.5 122/84
Water Sodium Bicarb
62 Spinning disk Eudragit EPO 10% 90 f50
75% Methanol
25% Acetone
63 Spray dry Opadry AMB 10% 4.4 124/79
Water BHT

*Used a concentric nozzle with 0.055 inch air opening and a 0.028 inch fluid opening.
**Used a 3-inch stainless steel disk rotating at approximately 4,500 rpm.

Example 5 controlled environmental chambers which were maintained

at 25s2 C./60.5% RH and 402 C./755% RH.
Stability of Microencapsulated Omeprazole 0256 Microspheres that exhibited dissolution results
with greater than 80% omeprazole release after 2 hours were
0255 The tablets used in the stability study were pack placed on Stability. The microSpheres were Stored in opened
aged into 60 ml HDPE 33/400 bottles with two 1 gram, 2 in vials at 25 C. All samples showed degradation after 4 weeks
1 desiccant canisters. The HDPE bottles were closed hand
at elevated temperatures. The open vials stored at 25 C.
were analyzed after 6-8 weeks for potency and for impurities
tight and induction sealed using a 33/400 CRC SFGD 75M using the Omeprazole EP method. The stability results are
cap with a polypropylene liner. Samples were placed in Summarized in the Table 5.A.

TABLE 5.A

OME Loading 4-Week Potency Values AUC

Microencapsulation Material (Initial) (Omeprazole Loading) Purity
Methocel A15LV & PEG 3350 (5%) 23.3 25.0 (107% of initial) (a 25° C. 95.65
Methocel A15LV, PEG 300 (5%) & BHT (0.1%) 26.0 24.9(95.8% of initial) (a 25° C. 99.90
Methocel A15LV BHT (0.1%) 24.8 26.4 (106.6% of initial) (a 25° C. 99.95
Methocel A15LV, PEG 3350 (5%), BHT (0.1%) & 2.2 2.3 (106% of initial) (a 25° C. 76.16
Sodium bicarbonate
Opadry YS-1-7003 PEG 3350 (5%) BHT (0.1%) 20.5 22.6 (110% of initial) (a 25° C. 1OO.O
Kollicoat IR, PEG 3350 (5%) & BHT 26.2 23.8 (90.8% of initial) (a 25° C. 99.54
Eudragit RD 100, PEG 3350 (5%) & BHT (0.1%) 21.3 19.1 (89.5% of initial) (a 25° C. 98.88
Klucel (HPC), PEG 3350 (5%) & BHT (0.1%) 26.0 22.8 (87.8% of initial) (a 25° C. 99.70
Ethocel (50%) Methocel E5 (50%) 25.8 21.9 (84.9% of initial) (a 25° C. 98.22
(99.3(aT)
Klucel 22.2 20.7 (93.2% of initial) (a 25° C. 97.69
Kollicoat IR & Sodium bicarbonate 26.0 21.7 (83.6% of initial) (a 25° C. 97.88

*AUC Purity = Area Under the Curve after 6-8 weeks at 25 C. in open container.
US 2005/0239845 A1 Oct. 27, 2005
26

Example 6 0260
Capsule Formulations TABLE 6.D

0257 The following specific formulations are provided Lansoprazole (30 mg)-Mosapride (2.5 mg) Capsule
by way of reference only and are not intended to limit the
Scope of the invention. Each formulation contains therapeu PPI Buffering Agent Prokinetic Agent Excipient
tically effective doses of PPI and prokinetic agent as well as
Sufficient buffering agent to prevent acid degradation of at
least some of the PPI by raising the pH of gastric fluid. 30 mg 17.1 mEq or 500 mg 2.5 mg Mosapride 20 mg Ac-Di-Sol
Amounts of buffer are expressed in weight as well as in lansoprazole Mg(OH)2 per capsule 30 mg Klucel
molar equivalents (mEq). Amounts of prokinetic agents are per capsule 4.2 mEq or 350 mg 10 mg
typically expressed in a per unit dose amount. The capsules NaHCO magnesium
are prepared by blending the PPI and prokinetic agent with
buffering agents, and homogeneously blending with excipi 21.3 mEq or 850 Stearate
ents as shown in Tables 6.A. to 6.H. below. The appropriate mg total buffer
weight of bulk blend composition is filled into a hard
gelatine capsule (e.g., Size 00) using an automatic encapsu
altor (H & K 1500 or MG2 G60). 0261)
TABLE 6A
TABLE 6.E
Omeprazole (20 mg)-Metoclopramide (10 mg) Capsule
Omeprazole (60 mg)-Domperidone (10 mgs) Capsule
PPI Buffering Agent Prokinetic Agent Excipient
PPI Buffering Agent Prokinetic Agent Excipient
20 mg 17.1 mEq or 500 mg 10 mg 50 mg Ac-Di-Sol
omeprazole Mg(OH), Metoclopramide 30 mg Klucel 60 mg 17.1 mEq or 500 mg 10 mg 20 mg Ac-Di-Sol
per capsule 3.0 mEq or 250 per capsule 10 mg ompeprazole Mg(OH), Domperidone 25 mg Klucel
mg NaHCOs magnesium per capsule 3.0 mEq or 250 mg per capsule 10 mg
NaHCO magnesium
20.1 mEq or 750 mg Stearate
total buffer 20.1 mEq or 750 mg Stearate
total buffer

0258
0262)
TABLE 6.B
TABLE 6.F
Ompeprazole (40 mg)-Cisapride (10 mg) Capsule
Omeprazole (60 mg)-Clebopride (10 mg) Capsule
PPI Buffering Agent Prokinetic Agent Excipient
PPI Buffering Agent Prokinetic Agent Excipient
40 mg 20.6 mEq or 600 mg 10 mg Cisapride 40 mg Ac-Di-Sol
omeprazole Mg(OH), per capsule 35 mg Klucel 60 mg 17.1 mEq or 500 mg 10 mg Clebopride 30 mg Ac-Di-Sol
per capsule 4.2 mEq or 350 mg 10 mg ompeprazole Mg(OH), per capsule 15 mg Klucel
NaHCO magnesium per capsule 3.0 mEq or 250 mg 7 mg
NaHCO magnesium
24.8 mEq or 950 Stearate
mg total buffer 20.1 mEq or 750 mg Stearate
total buffer

0259
0263)
TABLE 6.C
TABLE 6.G
Lansoprazole (15 mg)-Mosapride (5 mg) Capsule
Omeprazole (10 mg)-Clebopride (20 mg) Capsule
Prokinetic
PPI Buffering Agent Agent Excipient PPI Buffering Agent Prokinetic Agent Excipient
15 mg 17.1 mEq or 500 mg 5 mg 30 mg Ac-Di-Sol 10 mg 17.1 mEq or 500 mg 20 mg Clebopride 30 mg Ac-Di-Sol
microencapsulated Mg(OH)2 Mosapride 15 mg Klucel ompeprazole Mg(OH), per capsule 15 mg Klucel
lansoprazole per 3.0 mEq or 250 mg per 7 mg per capsule 3.0 mEq or 250 mg 7 mg
capsule NaHCO capsule magnesium NaHCO magnesium
20.7 mEq or 750 mg Stearate 20.1 mEq or 750 mg Stearate
total buffer total buffer
 Oct. 27, 2005
27

0264) 0267
TABLE 6.H TABLE 7C
Omeprazole (40 mg)-Enterie Coated Norcisapride (10 mg) Capsule
Lansoprazole (15 mg)-Clebopride (10 mg) Tablet
Prokinetic
PPI Buffering Agent Agent Excipient
Prokinetic
40 mg 15.4 mEq or 450 10 mg 30 mg Ac-Di-Sol PPI Buffering Agent Agent Excipient
microencapsulated mg Mg(OH)2 Norcisapride 7 mg
ompeprazole per 2.4 mEq or 200 per capsule magnesium
capsule mg NaHCO Stearate 15 mg 17.1 mEq or 500 10 mg 20 mg Ac-Di-Sol
17.8 mEq or 650 microencapsulated mg Mg(OH)2 Clebopride 80 mg Klucel
mg total buffer lansoprazole per 3.0 mEq or 250 per tablet 10 mg
tablet mg NaHCOs magnesium

Example 7 20.1 mEq or 750 Stearate

mg total buffer
Tablet Formulations
0265. The following specific formulations are provided
by way of reference only and are not intended to limit the 0268)
Scope of the invention. Each formulation contains therapeu TABLE 7D
tically effective doses of PPI and prokinetic agent as well as
Sufficient buffering agent to prevent acid degradation of at Lansoprazole (30 mg)-Domperidone (10 mg) Tablet
least some of the PPI by raising the pH of gastric fluid.
Amounts of buffer are expressed in weight as well as in PPI Buffering Agent Prokinetic Agent Excipient
molar equivalents (mEq). Amounts of prokinetic agents are 30 mg 20.6 mEq or 500 mg 10 mg 20 mg Ac-Di-Sol
typically expressed in a per unit dose amount. The tablets are lansoprazole Mg(OH), Domperidone 80 mg Klucel
prepared by blending the PPI and prokinetic agent with per tablet 4.2 mEq or 350 mg per tablet 10 mg
NaHCO, magnesium
buffering agents, and homogeneously blending with excipi
ents as shown in Tables 7.A. to 7.H. below. The appropriate 24.8 mEq or 850 mg Stearate
total buffer
weight of bulk blended composition is compressed using
12-inch FFBE toolings in a rotary press (Manesty Epxress)
to achieve a hardness of 20-24 kPa.
0269)
TABLE 7. A
TABLE 7...E
Ompeprazole (20 mg)-Norcisapride (10 mg) Tablet
Omeprazole (60 mg)-Mosapride (2.5 mg) Tablet
PPI Buffering Agent Prokinetic Agent Excipient
PPI Buffering Agent Prokinetic Agent Excipient
20 mg 13.7 mEq or 400 mg 10 mg 30 mg Ac-Di-Sol
omeprazole Mg(OH), Norcisapride 80 mg Klucel 60 mg 20.6 mEq or 600 mg 2.5 mg Mosapride 20 mg Ac-Di-Sol
per tablet 3.0 mEq or 250 mg per tablet 10 mg omeprazole Mg(OH), per tablet 80 mg Klucel
NaHCO magnesium per tablet 3.0 mEq or 250 mg 10 mg
16.7 mEq or 650 Stearate NaHCO magnesium
mg total buffer 23.6 mEq or 850 mg Stearate
total buffer

0266
0270)
TABLE 7.B
TABLE 7.F
Omeprazole (40 mg)-Clebopride (20 mg) Tablet
Omeprazole (60 mg)-Naproxen (5 mg) Tablet
Prokinetic
PPI Buffering Agent Agent Excipient PPI Buffering Agent Prokinetic Agent Excipient
40 mg 17.1 mEq or 500 20 mg 20 mg Ac-Di-Sol 60 mg 17.1 mEq or 500 mg 5 mg Mosapride 20 mg Ac-Di-Sol
microencapsulated mg Mg(OH)2 Clebopride 80 mg Klucel omprazole Mg(OH), per tablet 60 mg Klucel
omeprazole per 3.0 mEq or 250 per tablet 10 mg per tablet 3.0 mEq or 250 mg 10 mg magnesium
tablet mg NaHCOs magnesium NaHCO Stearate

20.1 mEq or 850 Stearate 20.1 mEq or 850 mg

mg total buffer total buffer
US 2005/0239845 A1 Oct. 27, 2005

0271)
TABLE 7. H-continued
TABLE 7.G
Ompeprazole (40 mg)-Metoclopramide (10 mg) Tablet
Ompeprazole (10 mg)-Cisapride (10 mg) Tablet PPI Buffering Agent Prokinetic Agent Excipient
omeprazole per 3.0 mEq or 250 per tablet 80 mg
Prokinetic tablet mg NaHCOs Klucel
PPI Buffering Agent Agent Excipient 23.6 mEq or 850 10 mg
mg total buffer magnesium
10 mg 13.7 mEq or 400 mg 10 mg 20 mg Ac-Di-Sol Stearate
microencapsulated Mg(OH)2 Cisapride 80 mg Klucel
omeprazole per 3.0 mEq or 250 mg pre tablet 10 mg Example 8
tablet NaHCO magnesium
o Chewable Tablet Formulations
16.7 mEq or 650 mg Stearate 0273. The following specific formulations are provided
total buffer by way of reference only and are not intended to limit the
Scope of the invention. Each formulation contains therapeu
tically effective doses of PPI and prokinetic agent as well as
Sufficient buffering agent to prevent acid degradation of at
0272 least some of the PPI by raising the pH of gastric fluid.
Amounts of buffer are expressed in weight as well as in
molar equivalents (mEq). Amounts of prokinetic agents are
TABLE 7.H typically expressed in a per unit dose amount. The tablets are
Ompeprazole (40 mg)-Metoclopramide (10 mg) Tablet prepared by blending the PPI and prokinetic agent with
buffering agents, and homogeneously blending with excipi
PPI Buffering Agent Prokinetic Agent Excipient ents as shown in Tables 8. A to 8.H. below. The appropriate
40 mg 20.6 mEq or 600 10 mg 20 mg weight of bulk blended composition is compressed using
microencapsulated mg Mg(OH)2 Metoclopramide Ac-Di-Sol 5/8-inch FFBE toolings in a rotary press (Manesty EpXress)
to achieve a hardness of 17-20 kPa.

TABLE 8A
Ompeprazole (20 mg)-Mosapride (5 mg) Chewable Tablet
PPI Buffering Agent Prokinetic Agent Excipient
20 mg 20.6 mEq or 600 mg 5 mg Mosapride per 170 mg Xylitab
microencapsulated Mg(OH)2 tablet 30 mg Ac-Di-Sol
omeprazole per 5.0 mEq or 420 mg 100 mg Klucel
tablet NaHCO 40 mg Sucralose
25.6 mEq or 1020 mg 25 mg cherry flavor
total buffer 15 mg magnesium
Stearate
3 mg Red #40 Lake

0274)
TABLE 8.B

Omeprazole (40 mg)-Domperidone (10 mg) Chewable Tablet

PPI Buffering Agent Prokinetic Agent Excipient
40 mg 24.0 mEq or 700 mg 10 mg Domperidone 170 mg Dipac Sugar
microencapsulated Mg(OH)2 per tablet 30 mg Ac-Di-Sol
omeprazole per 7.1 mEq or 600 mg 120 mg Klucel
tablet NaHCO 27 mg grape flavor
27.1 mEq or 1300 mg 15 mg magnesium
total buffer Stearate
1 mg Red #40 Lake
1 mg Blue #2 Lake
US 2005/0239845 A1 Oct. 27, 2005

0275 0279)
TABLE 8C TABLE 8.G
Lansoprazole (15 mg)-Cleopride (10 mg) Chewable Tablet Omeprazole (10 mg)-Metoclopramide (10 mg) Chewable Tablet
PPI Buffering Agent Prokinetic Agent Excipient PPI Buffering Agent Prokinetic Agent Excipient
15 mg 17.1 mEq or 500 10 mg cleopride 170 mg Xylitab 10 mg 15 mEq or 750 mg 10 mg 170 mg Xylitab
lansoprazole mg Mg(OH)2 pre tablet 30 mg Ac-Di-Sol omprazole Ca(OH), Metoclopramide 30 mg Ac-Di-Sol
per tablet 8.0 mEq or 672 120 mg Klucel per tablet 10 mEq or 840 mg per tablet 100 mg Klucel
mg NaHCOs 100 mg Asulfame-K NaHCO 15 mg mint flavor
25.1 mEq or 1172 27 mg grape flavor 25 mEq or 1590 mg 15 mg magnesium
mg total buffer 15 mg magnesium total buffer Stearate
Stearate
1 mg red #40 lake
1 mg blue #2 lake 0280
TABLE 8H
0276)
Omeprazole (40 mg)-Cisapride (10 mg) Chewable Tablet
TABLE 8.D Prokinetic
PPI Buffering Agent Agent Excipient
Lansoprazole (30 mg-Clebopride (20 mg) Chewable Tablet
40 mg 15 mEq or 750 mg 10 mg 170 mg Xylitab
Prokinetic micro- Ca(OH), Cisapride 30 mg Ac-Di-Sol
PPI Buffering Agent Agent Excipient encapsulated 10 mEq or 840 mg per tablet 100 mg Klucel
30 mg 24.0 mEq or 700 mg 20 mg 170 mg Xylitab
omprazole NaHCO 15 mg mint flavor
micro- Mg(OH)2 Clebopride 30 mg Ac-Di-Sol per tablet 25 mEq or 1590 mg 15 mg magnesium
encapsulated 5.0 mEq or 420 mg per tablet 100 mg Klucel total buffer Stearate
lansoprazole NaHCO 25 mg cherry flavor
per tablet 29.0 mEq or 1120 15 mg magnesium
mg total buffer Stearate
3 mg Red #40 Lake Example 9
Bite-Disintegration Chewable Tablet Formulations
0277 0281. The following specific formulations are provided
by way of reference only and are not intended to limit the
TABLE 8.E Scope of the invention. Each formulation contains therapeu
Omeprazole (60 mg)-Norcisapride (10 mg) Chewable Tablet
tically effective doses of PPI and prokinetic agent as well as
Sufficient buffering agent to prevent acid degradation of at
Prokinetic least some of the PPI by raising the pH of gastric fluid.
PPI Buffering Agent Agent Excipient Amounts of buffer are expressed in weight as well as in
molar equivalents (med). Amounts of prokinetic agent are
60 mg 15 mEq or 750 mg 10 mg 170 mg Xylitab typically expressed in a per unit dose amount. The tablets are
micro- Ca(OH), Norcisapride 30 mg Ac-Di-Sol prepared by blending the PPI and prokinetic agent with
encapsulated 15 mEq or 1260 mg per tablet 100 mg Klucel buffering agents, and homogeneously blending with excipi
omeprazole NaHCO 25 mg cherry flavor
ents as shown in Tables 9.A to 9.H. below. The appropriate
per tablet 30 mEq or 2010 mg 15 mg magnesium weight of bulk blended composition is compressed using
total buffer Stearate 5/8-inch FFBE toolings in a rotary press (Manesty Epxress)
3 mg Red #40 Lake to achieve a hardness of 8-12 kPa.

TABLE 9A
0278) Ompeprazole (20 mg)-Metoclopramide (10 mg)
Bite-Disintegration Chewable Tablet
TABLE 8.F
PPI Buffering Agent Prokinetic Agent Excipient
Omeprazole (60 mg)-Clebopride (10 mg) Chewable Tablet
20 mg 20.6 mEq or 600 mg 10 mg 60 mg sucralose
PPI Buffering Agent Prokinetic Agent Excipient per Mg(OH)2 Metoclopramide 60 mg Ac-Di-Sol
tablet 5.0 mEq or 420 mg per tablet 60 mg pregelatinized
60 mg 15 mEq or 750 mg 10 mg 170 mg Xylitab NaHCO starch
omprazole Ca(OH), Clebopride 30 mg Ac-Di-Sol
per tablet 10 mEq or 840 mg per tablet 100 mg Klucel 25.6 mEq or 1020 30 mg Klucel
NaHCO 15 mg mint flavor mg total buffer 25 mg cherry flavor
15 mg magnesium
25 mEq or 1590 mg 15 mg magnesium Stearate
total buffer Stearate 3 mg Red #40 Lake
US 2005/0239845 A1 Oct. 27, 2005
30

0282) 0285)
TABLE 9.B TABLE 9.E

Omeprazole (40 mg)-Cisapride (10 mg) Omeprazole (60 mg)-Domperidone (10 mg)
Bite-Disintegration Chewable Tablet Bite-Disintegration Chewable Tablet

Prokinetic Prokinetic
PPI Buffering Agent Agent Excipient PPI Buffering Agent Agent Excipient
40 mg 23.7 mEq or 700 mg 10 mg 60 mg sucralose 60 mg 15 mEq or 750 mg 10 mg 60 mg sucralose
micro- Mg(OH)2 Cisapride 60 mg Ac-Di-Sol micro Ca(OH), Domperidone 60 mg Ac-Di-Sol
encapsulated 7.2 mEq or 600 mg per tablet 60 mg pregelatinized encapsulated 15 mEq or 1260 mg per tablet 60 mg
omeprazole NaHCOs starch
omeprazole NaHCO, pregelatinized
per tablet 30.9 mEq or 1300 mg 30 mg Klucel
per tablet 30 mEq or 2010 mg starch
total buffer 27 mg grape flavor
total buffer 30 mg Klucel
15 mg magnesium
25 mg cherry flavor
Stearate
15 mg magnesium
1 mg Red #40 Lake Stearate
1 mg Blue #2 Lake
3 mg Red #40 Lake

0283) 0286)
TABLE 9.C
TABLE 9.F
Lansoprazole (15 mg)-Mosapride (5 mg)
Bite-Disintegration Chewable Tablet Omeprazole (60 mg)-Clebopride (10 mg)
Bite-Disintegration Chewable Tablet
Prokinetic
PPI Buffering Agent Agent Excipient Prokinetic
15 mg 17.1 mEq or 500 mg 5 mg 60 mg sucralose PPI Buffering Agent Agent Excipient
lansoprazole Mg(OH)2 Mosapride 70 mg Ac-Di-Sol
per tablet 7.2 mEq or 600 mg per tablet 70 mg pregelatinized 60 mg 15 mEq or 750 mg 10 mg 60 mg sucralose
NaHCO, starch omprazole Ca(OH), Clebopride 60 mg Ac-Di-Sol
per tablet 10 mEq or 840 mg per tablet 60 mg pregelatinized
24.2 mEq or 1100 mg 30 mg Klucel NaHCO starch
total buffer 27 mg grape flavor
15 mg magnesium 25 mEq or 1590 mg 30 mg Klucel
Stearate
1 mg Red #40 Lake
total buffer 15 mg mint flavor
1 mg Blue #2 lake 15 mg magnesium
Stearate

0284)
0287)
TABLE 9.D
TABLE 9.G
Lansoprazole (30 mg)-Mosapride (2.5 mg)
Bite-Disintegration Chewable Tablet Omeprazole (10 mg)-Clebopride (20 mg)
Bite-Disintegration Chewable Tablet
Prokinetic
PPI Buffering Agent Agent Excipient Prokinetic
PPI Buffering Agent Agent Excipient
30 mg 17.1 mEq or 500 mg 2.5 mg 60 mg sucralose
micro- Mg(OH)2 Mosapride 60 mg Ac-Di-Sol 10 mg 15 mEq or 750 mg 20 mg 60 mg sucralose
encapsulated 5 mEq or 420 mg per tablet 70 mg pregelatinized omprazole Ca(OH), Clebopride 60 mg Ac-Di-Sol
lansoprazole NaHCO starch per tablet 10 mEq or 840 mg per tablet 60 mg pregelatinized
NaHCO starch
per tablet 22.1 mEq or 1020 mg 30 mg Klucel
total buffer 25 mg cherry flavor 25 mEq or 1590 mg 30 mg Klucel
15 mg magnesium total buffer 15 mg mint flavor
Stearate 15 mg magnesium
3 mg Red #40 Lake Stearate
US 2005/0239845 A1 Oct. 27, 2005

0288
TABLE 9.H-continued
TABLE 9.H
Omeprazole (40 mg)-Norcisapride (10 mg)
Bite-Disintegration Chewable Tablet
Omeprazole (40 mg)-Norcisapride (10 mg)
Prokinetic
Bite-Disintegration Chewable Tablet PPI Buffering Agent Agent Excipient

Prokinetic 15 mg mint flavor

15 mg magnesium
PPI Buffering Agent Agent Excipient Stearate

40 mg 15 mEq or 750 mg 10 mg 60 mg sucralose

Norcisapride 60 mg Ac-Di-Sol
Example 10
micro Ca(OH),
encapsulated 10 mEq or 840 mg 60 mg Powder for Suspension Formulations
omprazole NaHCO pregelatinized 0289. The following specific formulations are provided by
way of reference only and are not intended to limit the Scope
of the invention. Each formulation contains therapeutically
per tablet 25 mEq or 1590 mg starch
effective doses of PPI and prokinetic agent as well as
total buffer 30 mg Klucel Sufficient buffering agent to prevent acid degredation of at
least some of the PPI by raising the pH of gastric fluid.

TABLE 1.O.A
Omeprazole (20 mg) - Cisapride
1. 2 3 4 5 6 7 8 9 1O

Omeprazole 2O 2O 2O 2O 2O 2O 2O 2O 2O 2O
Cisapride 2.5 5 1O 2O 2O 1O 5 2.5 1O 15
Sodium Bicarbonate 1895 168O 1825 1895 1375 1650 1825 1650 162O 1600
Xylitol 300 (sweetener) 2OOO 2OOO 1500 1750 1750 2500 2000 1500 2OOO 2SOO
Sucrose-powder (sweetener) 1750 2OOO 2250 2000 2500 1500 1750 2500 2OOO 15OO
Sucralose (sweetener) 125 1OO 150 75 100 70 8O 130 125 8O
Xanthan Gum 17 55 31 8O 39 48 72 25 64 68
Peach Flavor 47 15 75 32 60 50 77 38 35 62
Peppermint 26 1O 29 28 36 42 56 17 16 50
Total Weight 588O 588O 5880 5880 588O 5880 5880 588O 588O 588O

0290)
TABLE 10.B
Omeprazole (40 mg) - Metoclopramide
1. 2 3 4 5 6 7 8 9 1O

Omeprazole 40 40 40 40 40 40 40 40 40 40
Metoclopramide 2.5 5 1O 15 2O 15 1O 5 2.5 1O
Sodium Bicarbonate 2010 1375 1680 152O 1400 1825 168O 16SO 2030 1375
Xylitol 300 (sweetener) 15OO 2750 2000 2500 2000 1750 2000 2500 1500 1750
Sucrose-powder (sweetener) 2OOO 15OO 20OO 15OO 22SO 20OO 20OO 1500 2000 2500
Sucralose (sweetener) 150 1OO 75 125 100 95 8O 8O 130 125
Xanthan Gum 75 74 22 45 8O 17 58 39 40 64 33
Peach Flavor 64 8O 28 76 55 68 3O 35 82 32
Peppermint 42 13 12 39 18 44 11 35 34 25
Total Weight 588O 588O 5880 5880 588O 5880 5880 5880 588O 588O

0291)
TABLE 1.O.C
Omeprazole (60 mg) - Ondasetron
1. 2 3 4 5 6 7 8 9 1O

Omeprazole 60 60 60 60 60 60 60 60 60 60
Ondasetron 2.5 5 1O 15 2O 15 1O 5 2.5 1O
US 2005/0239845 A1 Oct. 27, 2005

TABLE 10.C-continued
Omeprazole (60 mg) - Ondasetron
1. 2 3 4 5 6 7 8 9 1O

Sodium Bicarbonate 17SO 247S 131O 2130 2005 158O 1110 23OO 1325 1400
Xylitol 300 (sweetener) 2OOO 15OO 2OOO 15OO 20OO 2500 22SO 15OO 17SO 25OO
Sucrose-powder (sweetener) 1750 1500 2250 2000 1500 1500 225O 1750 2500 1750
Sucralose (sweetener) 145 130 75 7O 150 150 6O 100 8O 75
Xanthan Gum 75 15 57 22 19 64 39 33 29 44 50
Peach Flavor 92 105 87 78 57 31 69 95 88 25
Peppermint 68 53 76 23 44 2O 48 46 33 2O
Total Weight 588O 5880 5880 588O 5880 5880 5880 588O 588O 588O

Example 11 free base, free acid, Salt, hydrate, ester, amide, enantiomer,
isomer, tautomer, polymorph, or prodrug thereof.
Combination Tablet Delivering Bolus and 4. The composition of claim 3, wherein the proton pump
Time-Released Doses of PPI
inhibitor is omeprazole or a free base, free acid, Salt, hydrate,
0292 Tablets may be compounded using known methods ester, amide, enantiomer, isomer, tautomer, polymorph, or
by forming an inner core of 10 mg omeprazole powder, prodrug thereof.
mixed with 750 mg Sodium bicarbonate, and an outer core 5. The composition of claim 1 comprising about 5 mg to
of 5-200 mg omeprazole enteric-coated granules and a about 200 mg of the proton pump inhibitor.
therapeutically effective amount of a prokinetic agent mixed 6. The composition of claim 1 comprising about 20 mg of
with known binders and excipients. Upon ingestion of the the proton pump inhibitor.
whole tablet, the tablet dissolves and the inner core is 7. The composition of claim 1 comprising about 40 mg of
dispersed in the stomach where it is absorbed for immediate the proton pump inhibitor.
therapeutic effect. The enteric-coated granules are later
absorbed in the duodenum to provide Symptomatic relief 8. The composition of claim 1, wherein the composition
later in the dosing cycle. This tablet is particularly useful in is administered in an amount to maintain a Serum concen
patients who experience breakthrough gastritis between con tration of the proton pump inhibitor greater than about 150
ventional doses. ng/ml from about 15 minutes to about 1 hour after admin
istration of the composition.
0293 Modifications, equivalents, and variations of the 9. The composition of claim 1, wherein upon oral admin
present invention are possible in light of the teachings istration to a Subject, the composition provides a pharma
above, such that the invention may be embodied in other cokinetic profile such that at least about 50% of total area
forms without departing from the Spirit or essential charac under Serum concentration time curve (AUC) for the proton
terstics of the invention. The present embodiments are pump inhibitor occurs within about 2 hours after adminis
therefore to be considered as illustrative and not restrictive, tration of a Single dose of the composition to the Subject.
the Scope of the invention being indicated by the appended 10. The composition of claim 1, wherein upon oral
claims rather than by the foregoing description. All changes administration to the Subject, the composition provides a
that come within the meaning and range of equivalency of pharmacokinetic profile Such that the proton pump inhibitor
the claims are therefore intended to be embraced therein.
reaches a maximum Serum concentration within about 1
What is claimed is: hour after administration of a Single dose of the composition.
1. A pharmaceutical composition comprising: 11. The composition of claim 1, wherein the proton pump
(a) a therapeutically effective amount of at least one acid inhibitor is microencapsulated with a material that enhances
labile proton pump inhibitor; the shelf-life of the pharmaceutical composition.
12. The composition of claim 1, wherein the prokinetic
(b) at least one buffering agent in an amount Sufficient to agent is microencapsulated with a material that enhances the
increase gastric fluid pH to a pH that prevents acid Shelf-life of the pharmaceutical composition.
degradation of at least Some of the proton pump inhibi
tor in the gastric fluid; and 13. The composition of claim 11 or claim 12, wherein the
material that enhances the shelf-life of the pharmaceutical
(c) a therapeutically effective amount of at least one composition is Selected from the group consisting of cellu
prokinetic agent. lose hydroxypropyl ethers, low-Substituted hydroxypropyl
2. The composition of claim 1, wherein an initial Serum ethers, cellulose hydroxypropyl methyl ethers, ethylcellu
concentration of the proton pump inhibitor is greater than lose polymers, ethylcelluloses and mixtures thereof, poly
about 100 ng/ml at any time within about 30 minutes after Vinyl alcohol, hydroxyethylcelluloses, carboxymethylcellu
administration of the composition. loses and Salts of carboxymethylcelluloses, polyvinyl
3. The composition of claim 1, wherein the proton pump alcohol and polyethylene glycol co-polymers, monoglycer
inhibitor Selected from the group consisting of omeprazole, ides, triglycerides, polyethylene glycols, modified food
hydroxyomeprazole, esomeprazole, tenatoprazole, lanSopra Starch, acrylic polymers, mixtures of acrylic polymers with
Zole, pantoprazole, rabeprazole, dontoprazole, habeprazole, cellulose ethers, cellulose acetate phthalate, Sepifilms, cyclo
perprazole, ranSoprazole, pariprazole, leminoprazole, or a dextrins, and mixtures thereof.
US 2005/0239845 A1 Oct. 27, 2005
33

14. The composition of claim 12, wherein the material 27. The composition of claim 1, wherein the composition
that enhances the shelf-life of the pharmaceutical composi is in a dosage form Selected from a powder, a tablet, a
tion is Klucel(R) or Nisso HPC. bite-disintegration tablet, a chewable tablet, a caplet, a
15. The composition of claim 13, wherein the material capsule, an effervescent powder, a rapid-disintegration tab
that enhances the shelf-life of the pharmaceutical composi let, or an aqueous Suspension produced from powder.
tion further comprises a buffering agent. 28. A method of treating a gastric acid related disorder in
16. The composition of claim 1, wherein at least some of a Subject by administering:
the prokinetic agent is coated.
17. The composition of claim 1, wherein some of the (a) a therapeutically effective amount of at least one acid
proton pump inhibitor is coated. labile proton pump inhibitor;
18. The composition of claim 16 or claim 17, wherein the
coating is Selected from a gastric resistant coating, a con (b) at least one buffering agent in an amount Sufficient to
trolled-release coating, an enzymatic-controlled coating, a increase gastric fluid pH to a pH that prevents acid
film coating, a Sustained-release coating, an immediate degradation of atl east Some of the proton pump inhibi
release coating, and a delayed-release coating. tor in the gastric fluid; and
19. The composition of claim 1, wherein the buffering
agent is an alkaline earth metal Salt or a Group IA metal (c) a therapeutically effective amount of at least one
Selected from a bicarbonate Salt of a Group IA metal, a prokinetic agent.
carbonate Salt of a Group IA metal. 29. The method of claim 28, wherein the pharmaceutical
20. The composition of claim 1, wherein the buffering composition is formulated for Stomach delivery of at least
agent is Selected from Sodium bicarbonate, calcium carbon Some of the proton pump inhibitor.
ate, magnesium hydroxide, and mixtures thereof.
21. The composition of claim 1, wherein the buffering 30. The method of claim 28, wherein the gastric acid
agent is present in an amount of at least about 5 mEq. related disorder is duodenal ulcer disease, gastric ulcer
22. The composition of claim 1, wherein the buffering disease, gastroesophageal reflux disease, erosive esophagi
agent is present in an amout from about 5 mEq to about 50 tis, poorly responsive Symptomatic gastroesophageal reflux
mEq. disease, pathological gastrointestinal hyperSecretory dis
23. The composition of claim 1 comprising from about ease, Zollinger Ellison Syndrome, heartburn, esophageal
500 to about 3000 mg of buffering agent. disorder, or acid dyspepsia.
24. The composition of claim 1, wherein the prokinetic 31. The method of claim 28, wherein the proton pump
agent is Selected from the group consisting of 5-HT inhibi inhibitor treats an episode of gastric acid related disorder.
tors, bulk forming agents, intraluminal agents, antimotility 32. The method of claim 28, wherein the proton pump
agents, Saline laxatives, and luminally active OSmotic inhibitor treats a medicament induced gastric acid related
agents. disorder.
25. The composition of claim 24, wherein the 5-HT 33. The method of claim 28, wherein at least Some of the
inhibitor is a 5-HT inhibitor or a 5-HT inhibitor. proton pump inhibitor is microencapsulated.
26. The composition of claim 24, wherein the prokinetic
agent is Selected from ondasetron, granisetron, dolanserton, 34. The method of claim 28, wherein at least Some of the
cisapride, phylium, polycarbophil, fiber, bismuth, loperam prokinetic agent is microencapsulated or coated.
ide, clonidine, magnesium Sulfate, Sodium phosphate, 35. The method of claim 76, wherein the composition is
moSapride, metoclopramide, domperidone, clebopride, in a dosage form Selected from a powder, a tablet, a
erythromycin ethylsuccinate, erythromycin lactobionate, bite-disintegration tablet, a chewable tablet, a caplet, a
bethanechol, bethanechol chloride, norcisapride, and neo capsule, an effervescent powder, a rapid-disintegration tab
Stigmine; or a free base, free acid, Salt, hydrate, ester, amide, let, or an aqueous Suspension produced from powder.
enantiomer, isomer, tautomer, polymorph, or prodrug
thereof.