U.S. patent application number 10/795860 was filed with the patent office on 2005-02-24 for novel substituted benzimidazole dosage forms and method of using same.
Invention is credited to Phillips, Jeffrey Owen.
Application Number | 20050042304 10/795860 |
Document ID | / |
Family ID | 23911053 |
Filed Date | 2005-02-24 |
United States Patent
Application |
20050042304 |
Kind Code |
A1 |
Phillips, Jeffrey Owen |
February 24, 2005 |
Novel substituted benzimidazole dosage forms and method of using
same
Abstract
A method of treating gastric acid disorders by administering to
a patient a pharmaceutical composition comprising a proton pump
inhibitor (PPI) in a pharmaceutically acceptable carrier. The
present invention provides an oral solution/suspension comprising a
proton pump inhibitor and at least one buffering agent. The PPI can
be any substituted benzimidazole compound having
H.sup.+,K.sup.+-ATPase inhibiting activity and being unstable to
acid. Omeprazole and lansoprazole are the preferred PPIs for use in
oral suspensions in concentrations of at least greater than 1.2
mg/ml and 0.3 mg, respectively. The liquid oral compositions can be
further comprised of parietal cell activators, anti-foaming agents
and/or flavoring agents. The inventive compositions can
alternatively be formulated as a powder, tablet, suspension tablet,
chewable tablet, capsule, effervescent powder, effervescent tablet,
pellets and granules. Such dosage forms are advantageously devoid
of any enteric coating or delayed or sustained-release delivery
mechanisms, and comprise a PPI and at least one buffering agent to
protect the PPI against acid degradation. Similar to the liquid
dosage form, the dry forms can further include anti-foaming agents,
parietal cell activators and flavoring agents. Kits utilizing the
inventive dry dosage forms are also disclosed herein to provide for
the easy preparation of a liquid composition from the dry forms. In
accordance with the present invention, there is further provided a
method of treating gastric acid disorders by administering to a
patient a pharmaceutical composition comprising a proton pump
inhibitor in a pharmaceutically acceptable carrier and at least one
buffering agent wherein the administering step comprises providing
a patient with a single dose of the composition without requiring
further administering of the buffering agent. Additionally, the
present invention relates to a method for enhancing the
pharmacological activity of an intravenously administered proton
pump inhibitor in which at least one parietal cell activator is
orally administered to the patient before, during or after the
intravenous administration of the proton pump inhibitor.
Inventors: |
Phillips, Jeffrey Owen;
(Ashland, MO) |
Correspondence
Address: |
MAYER, BROWN, ROWE & MAW LLP
190 SOUTH LASALLE ST
CHICAGO
IL
60603-3441
US
|
Family ID: |
23911053 |
Appl. No.: |
10/795860 |
Filed: |
July 12, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10795860 |
Jul 12, 2004 |
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10407552 |
Apr 4, 2003 |
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10407552 |
Apr 4, 2003 |
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10260132 |
Sep 30, 2002 |
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6780882 |
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10260132 |
Sep 30, 2002 |
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09481207 |
Jan 11, 2000 |
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6489346 |
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09481207 |
Jan 11, 2000 |
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09183422 |
Oct 30, 1998 |
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09183422 |
Oct 30, 1998 |
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08680376 |
Jul 15, 1996 |
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5840737 |
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60009608 |
Jan 4, 1996 |
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Current U.S.
Class: |
424/717 ;
424/729; 424/747; 424/776; 514/263.32; 514/338 |
Current CPC
Class: |
A61K 9/209 20130101;
A61K 9/2813 20130101; A61K 36/534 20130101; A61K 9/0095 20130101;
A61K 9/2009 20130101; A61K 9/1611 20130101; A61K 9/0056 20130101;
A61K 47/02 20130101; A61P 1/04 20180101; A61K 9/2054 20130101; A61K
9/0007 20130101; A61K 36/74 20130101; A61K 9/2013 20130101; A61K
31/4439 20130101; A61K 33/00 20130101; A61K 31/00 20130101; A61P
43/00 20180101; A61K 9/2086 20130101; A61K 9/4808 20130101; A61P
1/14 20180101; A61K 45/06 20130101; A61P 1/00 20180101; A61K 36/82
20130101; A61K 36/185 20130101; A61K 31/4439 20130101; A61K 2300/00
20130101; A61K 36/185 20130101; A61K 2300/00 20130101; A61K 36/534
20130101; A61K 2300/00 20130101; A61K 36/74 20130101; A61K 2300/00
20130101; A61K 36/82 20130101; A61K 2300/00 20130101; A61K 33/00
20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/717 ;
424/747; 424/776; 424/729; 514/263.32; 514/338 |
International
Class: |
A61K 035/78; A61K
033/00; A61K 031/522; A61K 031/4439 |
Claims
1-22. (Cancelled).
23. A pharmaceutical composition in the form of a suspension,
wherein: (a) the suspension is produced by constituting a storage
stable powder with a liquid medium; (b) the powder comprises a
therapeutically effective amount of at least one acid labile
substituted benzimidazole H.sup.+,K.sup.+-ATPase proton pump
inhibitor and at least one buffering agent; (c) the at least one
buffering agent is present in the powder in a total amount of about
0.1 mEq to about 2.5 mEq per mg of proton pump inhibitor; and (d)
after constitution, the suspension is substantially stable upon
storage in a closed container maintained at 4.degree. C. for a
period of at least about 1 day.
24. The composition of claim 23, wherein after constitution, the
suspension is substantially stable upon storage in a closed
container maintained at 4.degree. C. for a period of at least about
2 days.
25. The composition of claim 23, wherein after constitution, the
suspension is substantially stable upon storage in a closed
container maintained at 4.degree. C. for a period of at least about
7 days.
26. The composition of claim 23, wherein after constitution, the
suspension is substantially stable upon storage in a closed
container maintained at 4.degree. C. for a period of at least about
14 days.
27. The composition of claim 23, wherein after constitution, the
suspension is substantially stable upon storage in a closed
container maintained at 4.degree. C. for a period of at least about
12 months.
28. The composition of claim 23, wherein after constitution and
storage of the suspension in a closed container maintained at
4.degree. C. for a period of at least about 12 months, at least
about 90%, by weight, of said proton pump inhibitor is still
present in the suspension.
29. The composition of claim 23, wherein after constitution, the
suspension is substantially stable upon storage in a closed
container maintained at 25.degree. C. for a period of at least
about 1 day.
30. The composition of claim 23, wherein after constitution, the
suspension is substantially stable upon storage in a closed
container maintained at 25.degree. C. for a period of at least
about 2 days.
31. The composition of claim 23, wherein after constitution, the
suspension is substantially stable upon storage in a closed
container maintained at 25.degree. C. for a period of at least
about 7 days.
32. The composition of claim 23, wherein after constitution, the
suspension is substantially stable upon storage in a closed
container maintained at 25.degree. C. for a period of at least
about 14 days.
33. The composition of claim 23, wherein after constitution, the
suspension is substantially stable upon storage in a closed
container maintained at 25.degree. C. for a period of at least
about 12 months.
34. The composition of claim 23, wherein after constitution and
storage of the suspension in a closed container maintained at
25.degree. C. for a period of at least about 12 months, at least
about 90%, by weight, of said proton pump inhibitor is still
present in the suspension.
35. The composition of claim 23, wherein the at least one proton
pump inhibitor is selected from the group consisting of omeprazole,
lansoprazole, rabeprazole, esomeprazole (s-omeprazole),
pantoprazole, pariprazole, leminoprazole, or an enantiomer, an
alkaline salt of an enantiomer, an isomer, a prodrug, a derivative
or a salt thereof.
36. The composition of claim 23, wherein the at least one proton
pump inhibitor is omeprazole, or an enantiomer, an alkaline salt of
an enantiomer, an isomer, a prodrug, a derivative or a salt
thereof.
37. The composition of claim 23, wherein the at least one proton
pump inhibitor is lansoprazole, or an enantiomer, an alkaline salt
of an enantiomer, an isomer, a prodrug, a derivative or a salt
thereof.
38. The composition of claim 23, wherein the at least one proton
pump inhibitor is esomeprozole, or an enantiomer, an alkaline salt
of an enantiomer, an isomer, a prodrug, a derivative or a salt
thereof.
39. The composition of claim 23, wherein the at least one buffering
agent is selected from the group consisting of a calcium buffering
agent, a magnesium buffering agent, an aluminum buffering agent, a
sodium buffering agent, a bicarbonate salt of a Group IA metal, an
alkaline earth metal buffering agent, an amino acid, an alkali salt
of an amino acid, or mixtures thereof.
40. The composition of claim 23, wherein the at least one buffering
agent is selected from the group consisting of, sodium bicarbonate,
potassium bicarbonate, magnesium hydroxide, magnesium lactate,
magnesium gluconate, magnesium oxide, magnesium aluminate,
magnesium carbonate, magnesium silicate, magnesium citrate,
aluminum hydroxide, aluminum hydroxide/magnesium carbonate,
aluminum hydroxide/sodium bicarbonate coprecipitate, aluminum
glycinate, sodium citrate, calcium citrate, sodium tartrate, sodium
acetate, sodium carbonate, sodium polyphosphate, potassium
polyphosphate, sodium pyrophosphate, potassium pyrophosphate,
disodium hydrogenphosphate, dipotassium hydrogenphosphate,
trisodium phosphate, tripotassium phosphate, potassium carbonate,
potassium metaphosphate, calcium acetate, calcium glycerophosphate,
calcium hydroxide, calcium lactate, calcium carbonate, calcium
gluconate, calcium bicarbonate, potassium phosphate, potassium
citrate, and mixtures thereof.
41. The composition of claim 23, wherein the at least one buffering
agent and the at least one proton pump inhibitor are present in a
mEq:mg ratio of about 1:1 to about 1:3.5.
42. The composition of claim 23, further comprising a
pharmaceutically acceptable excipient selected from the group
consisting of a binder, a flavoring agent, a sweetening agent, a
disintegrant, a flow aid, a lubricant, an adjuvant, an antioxidant,
a chelating agent, an isotonic agent, a thickening agent, a
carrier, a colorant, a diluent, a moistening agent, a preservative,
a parietal cell activator, and an anti-foaming agent, or
combinations thereof.
43. The composition of claim 23, wherein after constitution, the
suspension comprises substantially no solid enteric-coating
material.
44. A method for treating a gastric acid related disorder in a
subject in need thereof, the method comprising administering the
suspension of claim 23 to the subject.
45. The method of claim 44, wherein the proton pump inhibitor is
omeprazole.
46. The method of claim 44, wherein the proton pump inhibitor is
lansoprazole.
47. The method of claim 44, wherein the proton pump inhibitor is
esomeprazole (s-omeprazole).
48. The method of claim 44, wherein the gastric acid related
disorder is selected from the group consisting of a duodenal ulcer
disease, a gastric ulcer disease, a gastroesophageal reflux
disease, a erosive esophagitis, a poorly responsive symptomatic
gastroesophageal reflux disease, a pathological gastrointestinal
hypersecretory disease, and Zollinger Ellison Syndrome.
Description
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 09/183,422 filed on Oct. 30, 1998, which is a
continuation-in-part of U.S. patent application Ser. No.
08/680,376, filed Jul. 15, 1996, which issued on Nov. 24, 1998 as
U.S. Pat. No. 5,840,737.
TECHNICAL FIELD
[0002] The present invention relates to pharmaceutical preparations
comprising substituted benzimidazole proton pump inhibitors.
BACKGROUND OF THE INVENTION
[0003] Omeprazole is a substituted benzimidazole,
5-methoxy-2-[(4-methoxy--
3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, that
inhibits gastric acid secretion. Omeprazole belongs to a class of
antisecretory compounds called proton pump inhibitors ("PPIs") that
do not exhibit anti-cholinergic or H.sub.2 histamine antagonist
properties. Drugs of this class suppress gastric acid secretion by
the specific inhibition of the H.sup.+,K.sup.+-ATPase enzyme system
(proton pump) at the secretory surface of the gastric parietal
cell.
[0004] Typically, omeprazole, lansoprazole and other proton pump
inhibitors are formulated in an enteric-coated solid dosage form
(as either a delayed-release capsule or tablet) or as an
intravenous solution (or as a product for reconstitution), and are
prescribed for short-term treatment of active duodenal ulcers,
gastric ulcers, gastroesophageal reflux disease (GERD), severe
erosive esophagitis, poorly responsive systematic GERD, and
pathological hypersecretory conditions such as Zollinger Ellison
syndrome. These conditions are caused by an imbalance between acid
and pepsin production, called aggressive factors, and mucous,
bicarbonate, and prostaglandin production, called defensive
factors. These above-listed conditions commonly arise in healthy or
critically ill patients, and may be accompanied by significant
upper gastrointestinal bleeding.
[0005] H.sub.2-antagonists, antacids, and sucralfate are commonly
administered to minimize the pain and the complications related to
these conditions. These drugs have certain disadvantages associated
with their use. Some of these drugs are not completely effective in
the treatment of the aforementioned conditions and/or produce
adverse side effects, such as mental confusion, constipation,
diarrhea, and thrombocytopenia. H.sub.2-antagonists, such as
ranitidine and cimetidine, are relatively costly modes of therapy,
particularly in NPO patients, which frequently require the use of
automated infusion pumps for continuous intravenous infusion of the
drug.
[0006] Patients with significant physiologic stress are at risk for
stress-related gastric mucosal damage and subsequent upper
gastrointestinal bleeding (Marrone and Silen, Pathogenesis,
Diagnosis and Treatment of Acute Gastric Mucosa Lesions, CLIN
GASTROENTEROL 13: 635-650 (1984)). Risk factors that have been
clearly associated with the development of stress-related mucosal
damage are mechanical ventilation, coagulopathy, extensive burns,
head injury, and organ transplant (Zinner et al., The Prevention of
Gastrointestinal Tract Bleeding in Patients in an Intensive Care
Unit, SURG. GYNECOL. OBSTET., 153: 214-220 (1981); Larson et al.,
Gastric Response to Severe Head Injury, AM. J. SURG. 147: 97-105
(1984); Czaja et al., Acute Gastroduodenal Disease After Thermal
Injury: An Endoscopic Evaluation of Incidence and Natural History,
N ENGL. J. MED, 291: 925-929 (1974); Skillman et al., Respiratory
Failure, Hypotension, Sepsis and Jaundice: A Clinical Syndrome
Associated with Lethal Hemorrhage From Acute Stress Ulceration, AM.
J. SURG., 117: 523-530 (1969); and Cook et al., Risk Factors for
Gastrointestinal Bleeding in Critically Ill Patients, N. ENGL. J.
MED., 330:377-381 (1994)). One or more of these factors are often
found in critically ill, intensive care unit patients. A recent
cohort study challenges other risk factors previously identified
such as acid-base disorders, multiple trauma, significant
hypertension, major surgery, multiple operative procedures, acute
renal failure, sepsis, and coma (Cook et al., Risk Factors for
Gastrointestinal Bleeding in Critically Ill Patients, N. ENGL. J.
MED., 330:377-381 (1994)). Regardless of the risk type,
stress-related mucosal damage results in significant morbidity and
mortality. Clinically significant bleeding occurs in at least
twenty percent of patients with one or more risk factors who are
left untreated (Martin et al., Continuous Intravenous cimetidine
Decreases Stress-related Upper Gastro-intestinal Hemorrhage Without
Promoting Pneumonia, CRIT. CARE MED., 21: 19-39 (1993)). Of those
who bleed, approximately ten percent require surgery (usually
gastrectomy) with a reported mortality of thirty percent to fifty
percent (Czaja et al., Acute Gastroduodenal Disease After Thermal
Injury: An Endoscopic Evaluation of Incidence and Natural History,
N ENGL. J. MED, 291: 925-929 (1974); Peura and Johnson, Cimetidine
for Prevention and Treatment of Gastroduodenal Mucosal Lesions in
Patients in an Intensive Care Unit, ANN INTERN MED., 103: 173-177
(1985)). Those who do not need surgery often require multiple
transfusions and prolonged hospitalization. Prevention of
stress-related upper gastrointestinal bleeding is an important
clinical goal.
[0007] In addition to general supportive care, the use of drugs to
prevent stress-related mucosal damage and related complications is
considered by many to be the standard of care (AMA Drug
Evaluations). However, general consensus is lacking about which
drugs to use in this setting (Martin et al., Continuous Intravenous
Cimetidine Decreases Stress-related Upper Gastrointestinal
Hemorrhage Without Promoting Pneumonia, CRIT. CARE MED., 21: 19-39
(1993); Gafter et al., Thrombocytopenia Associated With
Hypersensitivity to Ranitidine: Possible Cross-reactivity with
Cimetidine, AM. J. GASTROENTEROL, 64: 560-562 (1989); Martin et
al., Stress Ulcers and Organ Failure in Intubated Patients in
Surgical Intensive Care Units, ANN SURG., 215: 332-337 (1992)). In
two recent meta-analyses (Cook et al., Stress Ulcer Prophylaxis in
the Critically Ill: A Meta-analysis, AM. J. MED., 91: 519-527
(1991); Tryba, Stress Ulcer Prophylaxis--Quo Vadis? INTENS. CARE
MED. 20: 311-313 (1994)) Antacids, sucralfate, and
H.sub.2-antagonists were all found to be superior to placebo and
similar to one another in preventing upper gastrointestinal
bleeding. Yet, prophylactic agents are withdrawn in fifteen to
twenty percent of patients in which they are employed because of
failure to prevent bleeding or control pH (Ostro et al., Control of
Gastric pH With Cimetidine Boluses Versus Primed Infusions,
GASTROENTEROLOGY, 89: 532-537 (1985); Siepler, A Dosage Alternative
for H-2 Receptor Antagonists, Continuous-Infusion, CLIN. THER., 8
(SUPPL A) : 24-33 (1986); Ballesteros et al., Bolus or Intravenous
Infusion of Ranitidine: Effects on Gastric pH and Acid Secretion: A
Comparison of Relative Cost and Efficacy, ANN. INTERN. MED.,
112:334-339 (1990)), or because of adverse effects (Gafter et al.,
Thrombocytopenia Associated With Hypersensitivity to Ranitidine:
Possible Cross-reactivity With Cimetidine, AM. J. GASTROENTEROL,
64: 560-562 (1989); Sax, Clinically Important Adverse Effects and
Drug Interactions With H2-Receptor Antagonists: An Update,
PHARMACOTHERAPY 7 (6 PT 2): 110S-115S (1987); Vial et al., Side
Effects of Ranitidine, DRUG SAF, 6:94-117(1991); Cantu and Korek,
Central Nervous System Reactions to Histamine-2 Receptor Blockers,
ANN. INTERN MED., 114: 1027 -1034 (1991); and Spychal and Wickham,
Thrombocytopenia Associated With Ranitidine, BR. MED. J., 291: 1687
(1985) ) . In addition, the characteristics of an ideal agent for
the prophylaxis of stress gastritis were analyzed by Smythe and
Zarowitz, Changing Perspectives of Stress Gastritis Prophylaxis,
ANN PHARMACOTHER, 28: 1073-1084 (1994) who concluded that none of
the agents currently in use fulfill their criteria.
[0008] Stress ulcer prophylaxis has become routine therapy in
intensive care units in most hospitals (Fabian et al., Pneumonia
and Stress Ulceration in Severely Injured Patients, ARCH. SURG.,
128: 185-191 (1993); Cook et al., Stress Ulcer Prophylaxis in the
Critically Ill: A Meta-Analysis, AM. J. MED., 91: 519-527 (1991)).
Controversy remains regarding pharmacologic intervention to prevent
stress-related bleeding in critical care patients. It has been
suggested that the incidence and risk of gastrointestinal bleeding
has decreased in the last ten years and drug therapy may no longer
be needed (Cook et al., Risk Factors for Gastrointestinal Bleeding
in Critically Ill Patients, N. ENGL. J. MED., 330:377-381 (1994);
Tryba, Stress Ulcer Prophylaxis--Quo Vadis? INTENS. CARE MED. 20:
311-313 (1994); Schepp, Stress Ulcer Prophylaxis: Still a Valid
Option in the 1990s?, DIGESTION 54: 189-199 (1993)). This reasoning
is not supported by a recent placebo-controlled study. Martin et
al. conducted a prospective, randomized, double-blind,
placebo-controlled comparison of continuous-infusion cimetidine and
placebo for the prophylaxis of stress-related mucosal damage. The
study was terminated early because of excessive bleeding-related
mortality in the placebo group. It appears that the natural course
of stress-related mucosal damage in a patient at risk who receives
no prophylaxis remains significant. In the placebo group,
thirty-three percent (33%) of patients developed clinically
significant bleeding, nine percent (9%) required transfusion, and
six percent (6%) died due to bleeding-related complications. In
comparison, fourteen percent (14%) of cimetidine-treated patients
developed clinically significant bleeding, six percent (6%)
required transfusions, and one and one-half percent (1.5%) died due
to bleeding-related complication. The difference in bleeding rates
between treatment groups was statistically significant. This study
clearly demonstrated that continuous-infusion cimetidine reduced
morbidity in critical care patients. Although these data were used
to support the approval of continuous-infusion cimetidine by the
Food and Drug Administration for stress ulcer prophylaxis,
H.sub.2-antagonists fall short of being the optimal
pharmacotherapeutic agents for preventing of stress-related mucosal
bleeding.
[0009] Another controversy surrounding stress ulcer prophylaxis is
which drug to use. In addition to the various H.sub.2-antagonists,
antacids and sucralfate are other treatment options for the
prophylaxis of stress-related mucosal damage. An ideal drug in this
setting should possess the following characteristics: prevent
stress ulcers and their complications, be devoid of toxicity, lack
drug interactions, be selective, have minimal associated costs
(such as personnel time and materials), and be easy to administer
(Smythe and Zarowitz, Changing Perspectives of Stress Gastritis
Orophylaxis, ANN PHARMACOTHER, 28: 1073-1084 (1994)). Some have
suggested that sucralfate is possibly the ideal agent for stress
ulcer prophylaxis (Smythe and Zarowitz, Changing Perspectives of
Stress Gastritis Prophylaxis, ANN PHARMACOTHER, 28: 1073-1084
(1994)). Randomized, controlled studies support the use of
sucralfate (Borrero et al., Antacids vs. Sucralfate in Preventing
Acute Gastrointestinal Tract Bleeding in Abdominal Aortic Aurgery,
ARCH. SURG., 121: 810-812 (1986); Tryba, Risk of Acute Stress
Bleeding and Nosocomial Pneumonia in Ventilated Intensive Care
Patients. Sucralfate vs. Antacids, AM. J. MED., 87(3B) : 117-124
(1987); Cioffi et al., Comparison of Acid Neutralizing and Non-acid
Neutralizing Stress Ulcer Prophylaxis in Thermally Injured
Patients. J. TRAUMA, 36: 541-547 (1994); and Driks et al.,
Nosocomial Pneumonia in Intubated Patients Given Sucralfate as
Compared With Antacids or Histamine Type 2 Blockers, N. ENGL. J.
MED., 317: 1376-1382 1987)), but data on critical care patients
with head injury, trauma, or burns are limited. In addition, a
recent study comparing sucralfate and cimetidine plus antacids for
stress ulcer prophylaxis reported clinically significant bleeding
in three of forty-eight (6%) sucralfate-treated patients, one of
whom required a gastrectomy (Cioffi et al., Comparison of Acid
Neutralizing and Non-acid Neutralizing Stress Ulcer Prophylaxis in
Thermally Injured Patients, J. TRAUMA, 36: 541-547 (1994)). In the
study performed by Driks and coworkers that compared sucralfate to
conventional therapy (H.sub.2-antagonists, antacids, or
H.sub.2-antagonists plus antacids), the only patient whose death
was attributed to stress-related upper gastrointestinal bleeding
was in the sucralfate arm (Driks et al., Nosocomial Pneumonia in
Intubated Patients Given Sucralfate as Compared With Antacids or
Histamine Type 2 Blockers, N. ENGL. J. MED., 317:
1376-1382(1987)).
[0010] H.sub.2-antagonists fulfill many of the criteria for an
ideal stress ulcer prophylaxis drug. Yet, clinically significant
bleeds can occur during H.sub.2-antagonist prophylaxis (Martin et
al., Continuous Intravenous Cimetidine Decreases Stress-related
Upper Gastrointestinal Hemorrhage Without Promoting Pneumonia,
CRIT. CARE MED., 21: 19-39 (1993); Cook et al., Stress Ulcer
Prophylaxis in the Critically Ill: A Meta-analysis, AM. J. MED.,
91: 519-527 (1991); Schuman et al., Prophylactic Therapy for Acute
Ulcer Bleeding: A Reappraisal, ANN INTERN. MED, 106: 562-567
(1987)). Adverse events are not uncommon in the critical care
population (Gafter et al., Thrombocytopenia Associated With
Hypersensitivity to Ranitidine: Possible Cross-Reactivity With
Cimetidine, AM. J. GASTROENTEROL, 64: 560-562 (1989); Sax,
Clinically Important Adverse Effects and Drug Interactions With
H2-receptor Antagonists: An Update, PHARMACOTHERAPY 7(6 PT 2):
110S-115S (1987); Vial et al., Side Effects of Ranitidine, DRUG
SAF., 6:94-117(1991); Cantu and Korek, Central Nervous System
Reactions to Histamine-2 Receptor Blockers, ANN. INTERN MED., 114:
1027-1034 (1991); Spychal and Wickham, Thrombocytopenia Associated
With Ranitidine, BR. MED. J., 291: 1687 (1985)).
[0011] One reason proposed for the therapeutic H.sub.2-antagonist
failures is lack of pH control throughout the treatment period
(Ostro et al., Control of Gastric pH With Cimetidine Boluses Versus
Primed Infusions, GASTROENTEROLOGY, 89: 532-537 (1985)). Although
the precise pathophysiologic mechanisms involved in stress
ulceration are not clearly established, the high concentration of
hydrogen ions in the mucosa (Fiddian-Green et al., 1987) or gastric
fluid in contact with mucosal cells appears to be an important
factor. A gastric pH>3.5 has been associated with a lower
incidence of stress-related mucosal damage and bleeding (Larson et
al., Gastric Response to Severe Head Injury, AM. J. SURG. 147:
97-105 (1984); Skillman et al., Respiratory Failure, Hypotension,
Sepsis and Jaundice: A Clinical Syndrome Associated With Lethal
Hemorrhage From Acute Stress Ulceration, AM. J. SURG., 117: 523-530
(1969); Skillman et al., The Gastric Mucosal Barrier: Clinical and
Experimental Studies in Critically Ill and Normal Man and in the
Rabbit, ANN SURG., 172: 564-584 (1970); and Priebe and Skillman,
Methods of Prophylaxis in Stress Ulcer Disease, WORLD J. SURG., 5:
223-233 (1981)). Several studies have shown that
H.sub.2-antagonists, even in maximal doses, do not reliably or
continuously increase intragastric pH above commonly targeted
levels (3.5 to 4.5). This is true especially when used in
fixed-dose bolus regimens (Ostro et al., Control of Gastric pH With
Cimetidine Boluses Versus Primed Infusions, GASTROENTEROLOGY, 89:
532-537 (1985); Siepler, A Dosage Alternative for H-2 Receptor
Antagonists, Continuous-infusion, CLIN. THER., 8 (SUPPL A) 24-33
(1986); Ballesteros et al., Bolus or Intravenous Infusion of
Ranitidine: Effects on Gastric pH and Acid Secretion: A Comparison
of Relative Cost and Efficacy, ANN. INTERN. MED., 112:334-339
(1990)). In addition, gastric pH levels tend to trend downward with
time when using a continuous-infusion of H.sub.2-antagonists, which
may be the result of tachyphylaxis (Ostro et al., Control of
Gastric pH With Cimetidine Boluses Versus Primed Infusions,
GASTROENTEROLOGY, 89: 532-537 (1985); Wilder-Smith and Merki,
Tolerance During Dosing With H.sub.2-receptor Antagonists. An
Overview, SCAND. J. GASTROENTEROL 27(SUPPL. 193): 14-19
(1992)).
[0012] Because stress ulcer prophylaxis is frequently employed in
the intensive care unit, it is essential from both a clinical and
economic standpoint to optimize the pharmacotherapeutic approach.
In an attempt to identify optimal therapy, cost of care becomes an
issue. All treatment costs should be considered, including the
costs of treatment failures and drug-related adverse events. While
the actual number of failures resulting in mortality is low,
morbidity (e.g., bleeding that requires blood transfusion) can be
high, even though its association with the failure of a specific
drug is often unrecognized.
[0013] Initial reports of increased frequency of pneumonia in
patients receiving stress ulcer prophylaxis with agents that raise
gastric pH has influenced the pharmacotherapeutic approach to
management of critical care patients. However, several recent
studies (Simms et al., Role of Gastric Colonization in the
Development of Pneumonia in Critically Ill Trauma Patients: Results
of a Prospective Randomized Trial, J. TRAUMA, 31: 531-536 (1991);
Pickworth et al., Occurrence of Nasocomial Pneumonia in
Mechanically Ventilated Trauma Patients: A Comparison of Sucralfate
and Ranitidine, CRIT. CARE MED., 12: 1856-1862 (1993); Ryan et al.,
Nasocomial Pneumonia During Stress Ulcer Prophylaxis With
Cimetidine and Sucralfate, ARCH. SURG., 128: 1353-1357 (1993);
Fabian et al., Pneumonia and Stress Ulceration in Severely Injured
Patients, ARCH. SURG., 128: 185-191 (1993)), a meta-analysis (Cook
et al., Stress Ulcer Prophylaxis in the Critically Ill: A
Meta-analysis, AM. J. MED., 91: 519-527 (1991)), and a closer
examination of the studies that initiated the elevated
pH-associated pneumonia hypotheses (Schepp, Stress Ulcer
Prophylaxis: Still a Valid Option in the 1990s?, DIGESTION 54:
189-199 (1993)) cast doubt on a causal relationship. The
relationship between pneumonia and antacid therapy is much stronger
than for H.sub.2-antagonists. The shared effect of antacids and
H.sub.2-antagonists on gastric pH seems an irresistible common
cause explanation for nosocomial pneumonia observed during stress
ulcer prophylaxis. However, there are important differences between
these agents that are not often emphasized (Laggner et al.,
Prevention of Upper Gastrointestinal Bleeding in Long-term
Ventilated Patients, AM. J. MED., 86 (SUPPL 6A) : 81-84 (1989)).
When antacids are exclusively used to control pH in the prophylaxis
of stress-related upper gastrointestinal bleeding, large volumes
are needed. Volume, with or without subsequent reflux, may be the
underlying mechanism(s) promoting the development of pneumonia in
susceptible patient populations rather than the increased gastric
pH. The rate of pneumonia (12%) was not unexpected in this critical
care population and compares with sucralfate, which does not
significantly raise gastric pH (Pickworth et al., Occurrence of
Nasocomial Pneumonia in Mechanically Ventilated Trauma Patients: A
Comparison of Sucralfate and Ranitidine, CRIT. CARE MED., 12:
1856-1862 (1993); Ryan et al., Nasocomial Pneumonia During Stress
Ulcer Prophylaxis With Cimetidine and Sucralfate, ARCH. SURG., 128:
1353-1357 (1993)).
[0014] Omeprazole (Prilosec.RTM.), lansoprazole (Prevacid.RTM.) and
other PPIs reduce gastric acid production by inhibiting
H.sup.+,K.sup.+-ATPase of the parietal cell--the final common
pathway for gastric acid secretion (Fellenius et al., Substituted
Benzimidazoles Inhibit Gastric Acid Secretion by Blocking
H.sup.+,K.sup.+-ATPase, NATURE, 290: 159-161 (1981); Wallmark et
al, The Relationship Between Gastric Acid Secretion and Gastric
H.sup.+,K.sup.+-ATPase Activity, J. BIOL. CHEM., 260: 13681-13684
(1985); Fryklund et al., Function and Structure of Parietal Cells
After H.sup.+,K.sup.+-ATPase Blockade, AM. J. PHYSIOL., 254 (3 PT
1); G399-407 (1988)).
[0015] PPIs contain a sulfinyl group in a bridge between
substituted benzimidazole and pyridine rings, as illustrated below.
1
[0016] At neutral pH, omeprazole, lansoprazole and other PPIs are
chemically stable, lipid-soluble, weak bases that are devoid of
inhibitory activity. These neutral weak bases reach parietal cells
from the blood and diffuse into the secretory canaliculi, where the
drugs become protonated and thereby trapped. The protonated agent
rearranges to form a sulfenic acid and a sulfenamide. The
sulfenamide interacts covalently with sulfhydryl groups at critical
sites in the extracellular (luminal) domain of the
membrane-spanning H.sup.+,K.sup.+-ATPase (Hardman et al., Goodman
& Gilman's The Pharmacological Basis of Therapeutics, p. 907
(9.sup.th ed. 1996)). Omeprazole and lansoprazole, therefore, are
prodrugs that must be activated to be effective. The specificity of
the effects of PPIs is also dependent upon: (a) the selective
distribution of H.sup.+,K.sup.+-ATPase; (b) the requirement for
acidic conditions to catalyze generation of the reactive inhibitor;
and (c) the trapping of the protonated drug and the cationic
sulfenamide within the acidic canaliculi and adjacent to the target
enzyme. (Hardman et al., 1996)).
[0017] Omeprazole and lansoprazole are available for oral
administration as enteric coated particles in gelatin capsules.
Other proton pump inhibitors such as rabeprazole and pantoprazole
are supplied as enteric coated tablets. The enteric dosage forms of
the prior art have been employed because it is very important that
these drugs not be exposed to gastric acid prior to absorption.
Although these drugs are stable at alkaline pH, they are destroyed
rapidly as pH falls (e.g., by gastric acid). Therefore, if the
microencapsulation or the enteric coating is disrupted (e.g.,
trituration to compound a liquid, or chewing the capsule), the drug
will be exposed to degradation by the gastric acid in the
stomach.
[0018] The absence of an intravenous or oral liquid dosage form in
the United States has limited the testing and use of omeprazole,
lansoprazole and rabeprazole in the critical care patient
population. Barie et al., Therapeutic Use of Omeprazole for
Refractory Stress-induced Gastric Mucosal Hemorrhage, CRIT. CARE
MED., 20: 899-901 (1992) have described the use of omeprazole
enteric-coated pellets administered through a nasogastric tube to
control gastrointestinal hemorrhage in a critical care patient with
multi-organ failure. However, such pellets are not ideal as they
can aggregate and occlude such tubes, and they are not suitable for
patients who cannot swallow the pellets. AM J. HEALTH-SYST PHARM
56:2327-30 (1999).
[0019] Proton pump inhibitors such as omeprazole represent an
advantageous alternative to the use of H.sub.2-antagonists,
antacids, and sucralfate as a treatment for complications related
to stress-related mucosal damage. However, in their current form
(capsules containing enteric-coated granules or enteric-coated
tablets), proton pump inhibitors can be difficult or impossible to
administer to patients who are either unwilling or unable to
swallow tablets or capsules, such as critically ill patients,
children, the elderly, and patients suffering from dysphagia.
Therefore, it would be desirable to formulate a proton pump
inhibitor solution or suspension which can be enterally delivered
to a patient thereby providing the benefits of the proton pump
inhibitor without the drawbacks of the current enteric-coated solid
dosage forms.
[0020] Omeprazole, the first proton pump inhibitor introduced into
use, has been formulated in many different embodiments such as in a
mixture of polyethylene glycols, adeps solidus and sodium lauryl
sulfate in a soluble, basic amino acid to yield a formulation
designed for administration in the rectum as taught by U.S. Pat.
No. 5,219,870 to Kim.
[0021] U.S. Pat. No. 5,395,323 to Berglund ('323) discloses a
device for mixing a pharmaceutical from a solid supply into a
parenterally acceptable liquid form for parenteral administration
to a patient. The '323 patent teaches the use of an omeprazole
tablet which is placed in the device and dissolved by normal
saline, and infused parenterally into the patient. This device and
method of parenteral infusion of omeprazole does not provide the
omeprazole solution as an enteral product, nor is this omeprazole
solution directly administered to the diseased or affected areas,
namely the stomach and upper gastrointestinal tract, nor does this
omeprazole formulation provide the immediate antacid effect of the
present formulation.
[0022] U.S. Pat. No. 4,786,505 to Lovgren et al. discloses a
pharmaceutical preparation containing omeprazole together with an
alkaline reacting compound or an alkaline salt of omeprazole
optionally together with an alkaline compound as a core material in
a tablet formulation. The use of the alkaline material, which can
be chosen from such substances as the sodium salt of carbonic acid,
are used to form a "micro-pH" around each omeprazole particle to
protect the omeprazole which is highly sensitive to acid pH. The
powder mixture is then formulated to small beads, pellets, tablets
and may be loaded into capsules by conventional pharmaceutical
procedures. This formulation of omeprazole does not provide an
omeprazole dosage form which can be enterally administered to a
patient who may be unable and/or unwilling to swallow capsules,
tablets or pellets, nor does it teach a convenient form which can
be used to make an omeprazole or other proton pump inhibitor
solution or suspension.
[0023] Several buffered omeprazole oral solutions/suspensions have
been disclosed. For example, Pilbrant et al., Development of an
Oral Formulation of Omeprazole, SCAND. J. GASTROENT. 20(Suppl.
108): 113-120 (1985) teaches the use of micronized omeprazole
suspended in water, methylcellulose and sodium bicarbonate in a
concentration of approximately 1.2 mg omeprazole/ml suspension.
[0024] Andersson et el., Pharmacokinetics of Various Single
Intravenous and Oral Doses of Omeprazole, EUR J. CLIN. PHARMACOL.
39: 195-197 (1990) discloses 10 mg, 40 mg, and 90 mg of oral
omeprazole dissolved in PEG 400, sodium bicarbonate and water. The
concentration of omeprazole cannot be determined as volumes of
diluent are not disclosed. Nevertheless, it is apparent from this
reference that multiple doses of sodium bicarbonate were
administered with and after the omeprazole suspension.
[0025] Andersson et al., Pharmacokinetics and Bioavailability of
Omeprazole After Single and Repeated Oral Administration in Healthy
Subjects, BR. J. CLIN. PHARMAC. 29: 557-63 (1990) teaches the oral
use of 20 mg of omeprazole, which was dissolved in 20 g of PEG 400
(sp. gravity=1.14) and diluted with 50 ml of sodium bicarbonate,
resulting in a concentration of 0.3 mg/ml.
[0026] Regardh et al., The Pharmacokinetics of Omeprazole in
Humans--A Study of Single Intravenous and Oral Doses, THER. DRUG
MON. 12: 163-72 (1990) discloses an oral dose of omeprazole at a
concentration 0.4 mg/ml after the drug was dissolved in PEG 400,
water and sodium bicarbonate.
[0027] Landahl et al., Pharmacokinetics Study of Omeprazole in
Elderly Healthy Volunteers, CLIN. PHARMACOKINETICS 23 (6): 469-476
(1992) teaches the use of an oral dose of 40 mg of omeprazole
dissolved in PEG 400, sodium bicarbonate and water. This reference
does not disclose the final concentrations utilized. Again, this
reference teaches the multiple administration of sodium bicarbonate
after the omeprazole solution.
[0028] Andersson et al., Pharmacokinetics of [.sup.14C] Omeprazole
in Patients with Liver Cirrhosis, CLIN. PHARMACOKINETICS 24(1):
71-78 (1993) discloses the oral administration of 40 mg of
omeprazole which was dissolved in PEG 400, water and sodium
bicarbonate. This reference does not teach the final concentration
of the omeprazole solution administered, although it emphasizes the
need for concomitant sodium bicarbonate dosing to prevent acid
degradation of the drug.
[0029] Nakagawa, et al., Lansoprazole: Phase I Study of
lansoprazole (AG-1749) Anti-ulcer Agent, J. CLIN. THERAPEUTICS
& MED. (1991) teaches the oral administration of 30 mg of
lansoprazole suspended in 100 ml of sodium bicarbonate (0.3 mg/ml),
which was administered to patients through a nasogastric tube.
[0030] All of the buffered omeprazole solutions described in these
references were administered orally, and were given to healthy
subjects who were able to ingest the oral dose. In all of these
studies, omeprazole was suspended in a solution including sodium
bicarbonate, as a pH buffer, in order to protect the acid sensitive
omeprazole during administration. In all of these studies, repeated
administration of sodium bicarbonate both prior to, during, and
following omeprazole administration were required in order to
prevent acid degradation of the omeprazole given via the oral route
of administration. In the above-cited studies, as much as 48 mmoles
of sodium bicarbonate in 300 ml of water must be ingested for a
single dose of omeprazole to be orally administered.
[0031] The buffered omeprazole solutions of the above cited prior
art require the ingestion of large amounts of sodium bicarbonate
and large volumes of water by repeated administration. This has
been considered necessary to prevent acid degradation of the
omeprazole. In the above-cited studies, basically healthy
volunteers, rather than sick patients, were given dilute buffered
omeprazole utilizing pre-dosing and post-dosing with large volumes
of sodium bicarbonate.
[0032] The administration of large amounts of sodium bicarbonate
can produce at least six significant adverse effects, which can
dramatically reduce the efficacy of the omeprazole in patients and
reduce the overall health of the patients. First, the fluid volumes
of these dosing protocols would not be suitable for sick or
critically ill patients who must receive multiple doses of
omeprazole. The large volumes would result in the distention of the
stomach and increase the likelihood of complications in critically
ill patients such as the aspiration of gastric contents.
[0033] Second, because bicarbonate is usually neutralized in the
stomach or is absorbed, such that belching results, patients with
gastroesophageal reflux may exacerbate or worsen their reflux
disease as the belching can cause upward movement of stomach acid
(Brunton, Agents for the Control of Gastric Acidity and Treatment
of Peptic Ulcers, IN, Goodman A G, et al. The Pharmacologic Basis
of Therapeutics (New York, p. 907 (1990)).
[0034] Third, patients with conditions such as hypertension or
heart failure are standardly advised to avoid the intake of
excessive sodium as it can cause aggravation or exacerbation of
their hypertensive conditions (Brunton, supra). The ingestion of
large amounts of sodium bicarbonate is inconsistent with this
advice.
[0035] Fourth, patients with numerous conditions that typically
accompany critical illness should avoid the intake of excessive
sodium bicarbonate as it can cause metabolic alkalosis that can
result in a serious worsening of the patient's condition.
[0036] Fifth, excessive antacid intake (such as sodium bicarbonate)
can result in drug interactions that produce serious adverse
effects. For example, by altering gastric and urinary pH, antacids
can alter rates of drug dissolution and absorption,
bioavailability, and renal elimination (Brunton, supra).
[0037] Sixth, because the buffered omeprazole solutions of the
prior art require prolonged administration of sodium bicarbonate,
it makes it difficult for patients to comply with the regimens of
the prior art. For example, Pilbrant et al. disclose an oral
omeprazole administration protocol calling for the administration
to a subject who has been fasting for at least ten hours, a
solution of 8 mmoles of sodium bicarbonate in 50 ml of water. Five
minutes later, the subject ingests a suspension of 60 mg of
omeprazole in 50 ml of water that also contains 8 mmoles of sodium
bicarbonate. This is rinsed down with another 50 ml of 8 mmoles
sodium bicarbonate solution. Ten minutes after the ingestion of the
omeprazole dose, the subject ingests 50 ml of bicarbonate solution
(8 mmoles) . This is repeated at twenty minutes and thirty minutes
post omeprazole dosing to yield a total of 48 mmoles of sodium
bicarbonate and 300 ml of water in total which are ingested by the
subject for a single omeprazole dose. Not only does this regimen
require the ingestion of excessive amounts of bicarbonate and
water, which is likely to be dangerous to some patients, it is
unlikely that even healthy patients would comply with this
regimen.
[0038] It is well documented that patients who are required to
follow complex schedules for drug administration are non-compliant
and, thus, the efficacy of the buffered omeprazole solutions of the
prior art would be expected to be reduced due to non-compliance.
Compliance has been found to be markedly reduced when patients are
required to deviate from a schedule of one or two (usually morning
and night) doses of a medication per day. The use of the prior art
buffered omeprazole solutions which require administration
protocols with numerous steps, different drugs (sodium
bicarbonate+omeprazole+PEG 400 versus sodium bicarbonate alone),
and specific time allotments between each stage of the total
omeprazole regimen in order to achieve efficacious results is
clearly in contrast with both current drug compliance theories and
human nature.
[0039] The prior art (Pilbrant et al., 1985) teaches that the
buffered omeprazole suspension can be stored at refrigerator
temperatures for a week and deep frozen for a year while still
maintaining 99% of its initial potency. It would be desirable to
have an omeprazole or other proton pump inhibitor solution or
suspension that could be stored at room temperature or in a
refrigerator for periods of time which exceed those of the prior
art while still maintaining 99% of the initial potency.
Additionally, it would be advantageous to have a form of the
omeprazole and bicarbonate which can be utilized to instantly make
the omeprazole solution/suspension of the present invention which
is supplied in a solid form which imparts the advantages of
improved shelf-life at room temperature, lower cost to produce,
less expensive shipping costs, and which is less expensive to
store.
[0040] It would, therefore, be desirable to have a proton pump
inhibitor formulation, which provides a cost-effective means for
the treatment of the aforementioned conditions without the adverse
effect profile of H.sub.2 receptor antagonists, antacids, and
sucralfate. Further, it would be desirable to have a proton pump
inhibitor formulation which is convenient to prepare and administer
to patients unable to ingest solid dosage forms such as tablets or
capsules, which is rapidly absorbed, and can be orally or enterally
delivered as a liquid form or solid form. It is desirable that the
liquid formulation not clog indwelling tubes, such as nasogastric
tubes or other similar tubes, and which acts as an antacid
immediately upon delivery.
[0041] It would further be advantageous to have a potentiator or
enhancer of the pharmacological activity of the PPIs. It has been
theorized by applicant that the PPIs can only exert their effects
on H.sup.+,K.sup.+-ATPase when the parietal cells are active.
Accordingly, applicant has identified, as discussed below, parietal
cell activators that are administered to synergistically enhance
the activity of the PPIs.
[0042] Additionally, the intravenous dosage forms of PPIs of the
prior art are often administered in larger doses than the oral
forms. For example, the typical adult IV dose of omeprazole is
greater than 100 mg/day whereas the adult oral dose is 20 to 40
mg/day. Large IV doses are necessary to achieve the desired
pharmacologic effect because, it is believed, many of the parietal
cells are in a resting phase (mostly inactive) during an IV dose
given to patients who are not taking oral substances by mouth (npo)
and, therefore, there is little active (that which is inserted into
the secretory canalicular membrane) H.sup.+,K.sup.+-ATPase to
inhibit. Because of the clear disparity in the amount of drug
necessary for IV versus oral doses, it would be very advantageous
to have compositions and methods for IV administration where
significantly less drug is required.
SUMMARY OF THE INVENTION AND ADVANTAGES
[0043] The foregoing advantages and objects are accomplished by the
present invention. The present invention provides an oral
solution/suspension comprising a proton pump inhibitor and at least
one buffering agent. The PPI can be any substituted benzimidazole
compound having H.sup.+,K.sup.+-ATPase inhibiting activity and
being unstable to acid. Omeprazole and lansoprazole are the
preferred PPIs for use in oral suspensions in concentrations of at
least 1.2 mg/ml and 0.3 mg/ml, respectively. The liquid oral
compositions can be further comprised of parietal cell activators,
anti-foaming agents and/or flavoring agents.
[0044] The inventive composition can alternatively be formulated as
a powder, tablet, suspension tablet, chewable tablet, capsule,
effervescent powder, effervescent tablet, pellets and granules.
Such dosage forms are advantageously devoid of any enteric coating
or delayed or sustained-release delivery mechanisms, and comprise a
PPI and at least one buffering agent to protect the PPI against
acid degradation. Similar to the liquid dosage form, the dry forms
can further include anti-foaming agents, parietal cell activators
and flavoring agents.
[0045] Kits utilizing the inventive dry dosage forms are also
disclosed herein to provide for the easy preparation of a liquid
composition from the dry forms.
[0046] In accordance with the present invention, there is further
provided a method of treating gastric acid disorders by
administering to a patient a pharmaceutical composition comprising
a proton pump inhibitor in a pharmaceutically acceptable carrier
and at least one buffering agent wherein the administering step
comprises providing a patient with a single dose of the composition
without requiring further administering of the buffering agent.
[0047] Additionally, the present invention relates to a method for
enhancing the pharmacological activity of an intravenously
administered proton pump inhibitor in which at least one parietal
cell activator is orally administered to the patient before, during
and/or after the intravenous administration of the proton pump
inhibitor.
BRIEF DESCRIPTION OF THE DRAWINGS
[0048] Other advantages of the present invention will be readily
appreciated as the same becomes better understood by reference to
the following detailed description when considered in connection
with the accompanying drawing wherein:
[0049] FIG. 1 is a graph showing the effect of the omeprazole
solution of the present invention on gastric pH in patients at risk
for upper gastrointestinal bleeding from stress-related mucosal
damage;
[0050] FIG. 2 is a flow chart illustrating a patient enrollment
scheme;
[0051] FIG. 3 is a bar graph illustrating gastric pH both pre- and
post-administration of omeprazole solution according to the present
invention; and
[0052] FIG. 4 is a graph illustrating the stomach pH values after
the oral administration of both chocolate plus lansoprazole and
lansoprazole alone.
DETAILED DESCRIPTION OF THE INVENTION
[0053] In general, the present invention relates to a
pharmaceutical composition comprising a proton pump inhibitor and a
buffering agent with or without one or more parietal cell
activators. While the present invention may be embodied in many
different forms, several specific embodiments are discussed herein
with the understanding that the present disclosure is to be
considered only as an exemplification of the principles of the
invention, and it is not intended to limit the invention to the
embodiments illustrated.
[0054] For the purposes of this application, the term "proton pump
inhibitor" (PPI) shall mean any substituted benzimidazole
possessing pharmacological activity as an inhibitor of
H.sup.+,K.sup.+-ATPase, including, but not limited to, omeprazole,
lansoprazole, pantoprazole, rabeprazole, dontoprazole, perprazole
(s-omeprazole magnesium), habeprazole, ransoprazole, pariprazole,
and leminoprazole in neutral form or a salt form, a single
enantiomer or isomer or other derivative or an alkaline salt of an
enantiomer of the same.
[0055] The inventive composition comprises dry formulations,
solutions and/or suspensions of the proton pump inhibitors. As used
herein, the terms "suspension" and "solution" are interchangeable
with each other and mean solutions and/or suspensions of the
substituted benzimidazoles.
[0056] After absorption of the PPI (or administration
intravenously) the drug is delivered via the bloodstream to various
tissues and cells of the body including the parietal cells.
Research suggests that the PPI is in the form of a weak base and is
non-ionized and thereby freely passes through physiologic
membranes, including the cellular membranes of the parietal cell.
It is believed that the non-ionized PPI moves into the
acid-secreting portion of the parietal cell, the secretory
canaliculus. Once in the acidic millieu of the secretory
canaliculus, the PPI is apparently protonated (ionized) and
converted to the active form of the drug. Generally, ionized proton
pump inhibitors are membrane impermeable and form disulfide
covalent bonds with cysteine residues in the alpha subunit of the
proton pump.
[0057] The inventive pharmaceutical composition comprising a proton
pump inhibitor such as omeprazole, lansoprazole or other proton
pump inhibitor and derivatives thereof can be used for the
treatment or prevention of gastrointestinal conditions including,
but not limited to, active duodenal ulcers, gastric ulcers,
gastroesophageal reflux disease (GERD), severe erosive esophagitis,
poorly responsive systematic GERD, and pathological hypersecretory
conditions such as Zollinger Ellison Syndrome. Treatment of these
conditions is accomplished by administering to a patient an
effective amount of the pharmaceutical composition according to the
present invention.
[0058] The proton pump inhibitor is administered and dosed in
accordance with good medical practice, taking into account the
clinical condition of the individual patient, the site and method
of administration, scheduling of administration, and other factors
known to medical practitioners. The term "effective amount" means,
consistent with considerations known in the art, the amount of PPI
or other agent effective to achieve a pharmacologic effect or
therapeutic improvement without undue adverse side effects,
including but not limited to, raising of gastric pH, reduced
gastrointestinal bleeding, reduction in the need for blood
transfusion, improved survival rate, more rapid recovery, parietal
cell activation and H.sup.+,K.sup.+-ATPase inhibition or
improvement or elimination of symptoms, and other indicators as are
selected as appropriate measures by those skilled in the art.
[0059] The dosage range of omeprazole or other proton pump
inhibitors such as substituted benzimidazoles and derivatives
thereof can range from approximately <2 mg/day to approximately
300 mg/day. The standard approximate daily oral dosage is typically
20 mg of omeprazole, 30 mg lansoprazole, 40 mg pantoprazole, 20 mg
rabeprazole, and the pharmacologically equivalent doses of the
following PPIs: habeprazole, pariprazole, dontoprazole,
ransoprazole, perprazole (s-omeprazole magnesium), and
leminoprazole.
[0060] A pharmaceutical formulation of the proton pump inhibitors
utilized in the present invention can be administered orally or
enterally to the patient. This can be accomplished, for example, by
administering the solution via a nasogastric (ng) tube or other
indwelling tubes placed in the GI tract. In order to avoid the
critical disadvantages associated with administering large amounts
of sodium bicarbonate, the PPI solution of the present invention is
administered in a single dose which does not require any further
administration of bicarbonate, or large amounts of bicarbonate, or
other buffer following the administration of the PPI solution, nor
does it require a large amount of bicarbonate or buffer in total.
That is, unlike the prior art PPI solutions and administration
protocols outlined above, the formulation of the present invention
is given in a single dose which does not require administration of
bicarbonate either before or after administration of the PPI. The
present invention eliminates the need to pre-or post-dose with
additional volumes of water and sodium bicarbonate. The amount of
bicarbonate administered via the single dose administration of the
present invention is less than the amount of bicarbonate
administered as taught in the prior art references cited above.
[0061] Preparation of Oral Liquids
[0062] The liquid oral pharmaceutical composition of the present
invention is prepared by mixing omeprazole (Prilosec.RTM.
AstraZeneca) or other proton pump inhibitor or derivatives thereof
with a solution including at least one buffering agent (with or
without a parietal cell activator, as discussed below). Preferably,
omeprazole or other proton pump inhibitor, which can be obtained
from a capsule or tablet or obtained from the solution for
parenteral administration, is mixed with a sodium bicarbonate
solution to achieve a desired final omeprazole (or other PPI)
concentration. As an example, the concentration of omeprazole in
the solution can range from approximately 0.4 mg/ml to
approximately 10.0 mg/ml. The preferred concentration for the
omeprazole in the solution ranges from approximately 1.0 mg/ml to
approximately 4.0 mg/ml, with 2.0 mg/ml being the standard
concentration. For lansoprazole (Prevacid.RTM. TAP Pharmaceuticals,
Inc.) the concentration can range from about 0.3 mg/ml to 10 mg/ml
with the preferred concentration being about 3 mg/ml.
[0063] Although sodium bicarbonate is the preferred buffering agent
employed in the present invention to protect the PPI against acid
degradation, many other weak and strong bases (and mixtures
thereof) can be utilized. For the purposes of this application,
"buffering agent" shall mean any pharmaceutically appropriate weak
base or strong base (and mixtures thereof) that, when formulated or
delivered with (e.g., before, during and/or after) the PPI,
functions to substantially prevent or inhibit the acid degradation
of the PPI by gastric acid sufficient to preserve the
bioavailability of the PPI administered. The buffering agent is
administered in an amount sufficient to substantially achieve the
above functionality. Therefore, the buffering agent of the present
invention, when in the presence of gastric acid, must only elevate
the pH of the stomach sufficiently to achieve adequate
bioavailability of the drug to effect therapeutic action.
[0064] Accordingly, examples of buffering agents include, but are
not limited to, sodium bicarbonate, potassium bicarbonate,
magnesium hydroxide, magnesium lactate, magnesium glucomate,
aluminum hydroxide, aluminum hydroxide/ sodium bicarbonate
coprecipitate, a mixture of an amino acid and a buffer, a mixture
of aluminum glycinate and a buffer, a mixture of an acid salt of an
amino acid and a buffer, and a mixture of an alkali salt of an
amino acid and a buffer. Additional buffering agents include sodium
citrate, sodium tartarate, sodium acetate, sodium carbonate, sodium
polyphosphate, potassium polyphosphate, sodium pyrophosphate,
potassium pyrophosphate, disodium hydrogenphosphate, dipotassium
hydrogenphosphate, trisodium phosphate, tripotassium phosphate,
sodium acetate, potassium metaphosphate, magnesium oxide, magnesium
hydroxide, magnesium carbonate, magnesium silicate, calcium
acetate, calcium glycerophosphate, calcium cholride, calcium
hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate,
and other calcium salts.
[0065] The pharmaceutically acceptable carrier of the oral liquid
preferably comprises a bicarbonate salt of Group IA metal as
buffering agent, and can be prepared by mixing the bicarbonate salt
of the Group IA metal, preferably sodium bicarbonate, with water.
The concentration of the bicarbonate salt of the Group IA metal in
the composition generally ranges from approximately 5.0 percent to
approximately 60.0 percent. Preferably, the concentration of the
bicarbonate salt of the Group IA metal ranges from approximately
7.5 percent to approximately 10.0 percent. In a preferred
embodiment of the present invention, sodium bicarbonate is the
preferred salt and is present in a concentration of approximately
8.4 percent.
[0066] More specifically, the amount of sodium bicarbonate 8.4%
used in the solution of the present invention is approximately 1
mEq (or mmole) sodium bicarbonate per 2 mg omeprazole, with a range
of approximately 0.2 mEq (mmole) to 5 mEq (mmole) per 2 mg of
omeprazole.
[0067] In a preferred embodiment of the present invention,
enterically-coated omeprazole particles are obtained from delayed
release capsules (Prilosec.RTM. AstraZeneca). Alternatively,
omeprazole powder can be used. The enterically coated omeprazole
particles are mixed with a sodium bicarbonate (NaHCO.sub.3)
solution (8.4%), which dissolves the enteric coating and forms an
omeprazole solution. The omeprazole solution has pharmacokinetic
advantages over standard time-released omeprazole capsules,
including: (a) more rapid drug absorbance time (about 10 to 60
minutes) following administration for the omeprazole solution
versus about 1 to 3 hours following administration for the
enteric-coated pellets; (b) the NaHCO.sub.3 solution protects the
omeprazole from acid degradation prior to absorption; (c) the
NaHCO.sub.3 acts as an antacid while the omeprazole is being
absorbed; and (d) the solution can be administered through an
existing indwelling tube without clogging, for example, nasogastric
or other feeding tubes (jejunal or duodenal), including small bore
needle catheter feeding tubes.
[0068] Additionally, various additives can be incorporated into the
inventive solution to enhance its stability, sterility and
isotonicity. Further, antimicrobial preservatives, antioxidants,
chelating agents, and additional buffers can be added, such as
ambicin. However, microbiological evidence shows that this
formulation inherently possesses antimicrobial and antifungal
activity. Various antibacterial and antifungal agents such as, for
example, parabens, chlorobutanol, phenol, sorbic acid, and the like
can enhance prevention of the action of microorganisms.
[0069] In many cases, it would be desirable to include isotonic
agents, for example, sugars, sodium chloride, and the like.
Additionally, thickening agents such as methylcellulose are
desirable to use in order to reduce the settling of the omeprazole
or other PPI or derivatives thereof from the suspension.
[0070] The liquid oral solution may further comprise flavoring
agents (e.g., chocolate, root beer or watermelon) or other
flavorings stable at pH 7 to 9, anti-foaming agents (e.g.,
simethicone 80 mg, Mylicon.RTM.) and parietal cell activators
(discussed below).
[0071] The present invention further includes a pharmaceutical
composition comprising omeprazole or other proton pump inhibitor
and derivatives thereof and at least one buffering agent in a form
convenient for storage, whereby when the composition is placed into
an aqueous solution, the composition dissolves yielding a
suspension suitable for enteral administration to a subject. The
pharmaceutical composition is in a solid form prior to dissolution
or suspension in an aqueous solution. The omeprazole or other PPIs
and buffering agent can be formed into a tablet, capsule, pellets
or granules, by methods well known to those skilled in the art.
[0072] The resultant omeprazole solution is stable at room
temperature for several weeks and inhibits the growth of bacteria
or fungi as shown in Example X below. Indeed, as established in
Example XIII, the solution maintains greater than 90% of its
potency for 12 months. By providing a pharmaceutical composition
including omeprazole or other PPI with buffer in a solid form,
which can be later dissolved or suspended in a prescribed amount of
aqueous solution to yield the desired concentration of omeprazole
and buffer, the cost of production, shipping, and storage are
greatly reduced as no liquids are shipped (reducing weight and
cost), and there is no need to refrigerate the solid form of the
composition or the solution. Once mixed the resultant solution can
then be used to provide dosages for a single patient over a course
of time, or for several patients.
[0073] Tablets and Other Solid Dosage Forms
[0074] As mentioned above, the formulations of the present
invention can also be manufactured in concentrated forms, such as
tablets, suspension tablets and effervescent tablets or powders,
such that upon reaction with water or other diluent, the aqueous
form of the present invention is produced for oral, enteral or
parenteral administration.
[0075] The present pharmaceutical tablets or other solid dosage
forms disintegrate rapidly in aqueous media and form an aqueous
solution of the PPI and buffering agent with minimal shaking or
agitation. Such tablets utilize commonly available materials and
achieve these and other desirable objectives. The tablets or other
solid dosage forms of this invention provide for precise dosing of
a PPI that may be of low solubility in water. They are particularly
useful for medicating children and the elderly and others in a way
that is much more acceptable than swallowing or chewing a tablet.
The tablets that are produced have low friability, making them
easily transportable.
[0076] The term "suspension tablets" as used herein refers to
compressed tablets which rapidly disintegrate after they are placed
in water, and are readily dispersible to form a suspension
containing a precise dosage of the PPI. The suspension tablets of
this invention comprise, in combination, a therapeutic amount of a
PPI, a buffering agent, and a disintegrant. More particularly, the
suspension tablets comprise about 20 mg omeprazole and about 1-20
mEq of sodium bicarbonate.
[0077] Croscarmellose sodium is a known disintegrant for tablet
formulations, and is available from FMC Corporation, Philadelphia,
Pa. under the trademark Ac-Di-Sol.RTM.. It is frequently blended in
compressed tableting formulations either alone or in combination
with microcrystalline cellulose to achieve rapid disintegration of
the tablet.
[0078] Microcrystalline cellulose, alone or coprocessed with other
ingredients, is also a common additive for compressed tablets and
is well known for its ability to improve compressibility of
difficult to compress tablet materials. It is commercially
available under the Avicel.RTM. trademark. Two different
Avicel.RTM. products are utilized, Avicel.RTM. PH which is
microcrystalline cellulose, and Avicel.RTM. AC-815, a coprocessed
spray dried residue of microcrystalline cellulose and a calcium,
sodium alginate complex in which the calcium to sodium ratio is in
the range of about 0.40:1 to about 2.5:1. While AC-815 is comprised
of 85% microcrystalline cellulose (MCC) and 15% of a calcium,
sodium alginate complex, for purposes of the present invention this
ratio may be varied from about 75% MCC to 25% alginate up to about
95% MCC to 5% alginate. Depending on the particular formulation and
active ingredient, these two components may be present in
approximately equal amounts or in unequal amounts, and either may
comprise from about 10% to about 50% by weight of the tablet.
[0079] The suspension tablet composition may, in addition to the
ingredients described above, contain other ingredients often used
in pharmaceutical tablets, including flavoring agents, sweetening
agents, flow aids, lubricants or other common tablet adjuvants, as
will be apparent to those skilled in the art. Other disintegrants,
such as crospovidone and sodium starch glycolate may be employed,
although croscarmellose sodium is preferred.
[0080] In addition to the suspension tablet, the solid formulation
of the present invention can be in the form of a powder, a tablet,
a capsule, or other suitable solid dosage form (e.g., a pelleted
form or an effervescing tablet, troche or powder), which creates
the inventive solution in the presence of diluent or upon
ingestion. For example, the water in the stomach secretions or
water which is used to swallow the solid dosage form can serve as
the aqueous-diluent.
[0081] Compressed tablets are solid dosage forms prepared by
compacting a formulation containing an active ingredient and
excipients selected to aid the processing and improve the
properties of the product. The term "compressed tablet" generally
refers to a plain, uncoated tablet for oral ingestion, prepared by
a single compression or by pre-compaction tapping followed by a
final compression.
[0082] Such solid forms can be manufactured as is well known in the
art. Tablet forms can include, for example, one or more of lactose,
mannitol, corn starch, potato starch, microcrystalline cellulose,
acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium,
talc, magnesium stearate, stearic acid, and other excipients,
colorants, diluents, buffering agents, moistening agents,
preservatives, flavoring agents, and pharmaceutically compatible
carriers. The manufacturing processes may employ one, or a
combination of, four established methods: (1) dry mixing; (2)
direct compression; (3) milling; and (4) non-aqueous granulation.
Lachman et al., The Theory and Practice of Industrial Pharmacy
(1986). Such tablets may also comprise film coatings, which
preferably dissolve upon oral ingestion or upon contact with
diluent.
[0083] Non-limiting examples of buffering agents which could be
utilized in such tablets include sodium bicarbonate, alkali earth
metal salts such as calcium carbonate, calcium hydroxide, calcium
lactate, calcium glycerophosphate, calcium acetate, magnesium
carbonate, magnesium hydroxide, magnesium silicate, magnesium
aluminate, aluminum hydroxide or aluminum magnesium hydroxide. A
particular alkali earth metal salt useful for making an antacid
tablet is calcium carbonate.
[0084] An example of a low density alkali earth metal salt useful
for making the granules according to the present invention is extra
light calcium carbonate available from Specialty Minerals Inc.,
Adams, Me. The density of the extra light calcium carbonate, prior
to being processed according to the present invention, is about
0.37 gm/ml.
[0085] The granules used to make the tablets according to one
embodiment of the present invention are made by either spray drying
or pre-compacting the raw materials. Prior to being processed into
granules by either process, the density of the alkali earth metal
salts useful in the present invention ranges from about 0.3 gm/ml
to about 0.55 gm/ml, preferably about 0.35 gm/ml to about 0.45
gm/ml, even more preferably about 0.37 gm/ml to about 0.42
gm/ml.
[0086] Additionally, the present invention can be manufactured by
utilizing micronized compounds in place of the granules or powder.
Micronization is the process by which solid drug particles are
reduced in size. Since the dissolution rate is directly
proportional to the surface area of the solid, and reducing the
particle size increases the surface area, reducing the particle
size increases the dissolution rate. Although micronization results
in increased surface area possibly causing particle aggregation,
which can negate the benefit of micronization and is an expensive
manufacturing step, it does have the significant benefit of
increasing the dissolution rate of relatively water insoluble
drugs, such as omeprazole and other proton pump inhibitors.
[0087] The present invention also relates to administration kits to
ease mixing and administration. A month's supply of powder or
tablets, for example, can be packaged with a separate month's
supply of diluent, and a re-usable plastic dosing cup. More
specifically, the package could contain thirty (30) suspension
tablets containing 20 mg omeprazole each, 1 L sodium bicarbonate
8.4% solution, and a 30 ml dose cup. The user places the tablet in
the empty dose cup, fills it to the 30 ml mark with the sodium
bicarbonate, waits for it to dissolve (gentle stirring or agitation
may be used), and then ingests the suspension. One skilled in the
art will appreciate that such kits may contain many different
variations of the above components. For example, if the tablets or
powder are compounded to contain PPI and buffering agent, the
diluent may be water, sodium bicarbonate, or other compatible
diluent, and the dose cup can be larger than 30 ml in size. Also,
such kits can be packaged in unit dose form, or as weekly, monthly,
or yearly kits, etc.
[0088] Although the tablets of this invention are primarily
intended as a suspension dosage form, the granulations used to form
the tablet may also be used to form rapidly disintegrating chewable
tablets, lozenges, troches, or swallowable tablets. Therefore, the
intermediate formulations as well as the process for preparing them
provide additional novel aspects of the present invention.
[0089] Effervescent tablets and powders are also prepared in
accordance with the present invention. Effervescent salts have been
used to disperse medicines in water for oral administration.
Effervescent salts are granules or coarse powders containing a
medicinal agent in a dry mixture, usually composed of sodium
bicarbonate, citric acid and tartaric acid. When the salts are
added to water, the acids and the base react to liberate carbon
dioxide gas, thereby causing "effervescence."
[0090] The choice of ingredients for effervescent granules depends
both upon the requirements of the manufacturing process and the
necessity of making a preparation which dissolves readily in water.
The two required ingredients are at least one acid and at least one
base. The base releases carbon dioxide upon reaction with the acid.
Examples of such acids include, but are not limited to, tartaric
acid and citric acid. Preferably, the acid is a combination of both
tartaric acid and citric acid. Examples of bases include, but are
not limited to, sodium carbonate, potassium bicarbonate and sodium
bicarbonate. Preferably, the base is sodium bicarbonate, and the
effervescent combination has a pH of about 6.0 or higher.
[0091] Effervescent salts preferably include the following
ingredients, which actually produce the effervescence: sodium
bicarbonate, citric acid and tartaric acid. When added to water the
acids and base react to liberate carbon dioxide, resulting in
effervescence. It should be noted that any acid-base combination
which results in the liberation of carbon dioxide could be used in
place of the combination of sodium bicarbonate and citric and
tartaric acids, as long as the ingredients were suitable for
pharmaceutical use, and result in a pH of about 6.0 or higher.
[0092] It should be noted that it requires 3 molecules of NaHCO3
(sodium bicarbonate) to neutralize 1 molecule of citric acid and 2
molecules of NaHCO3 to neutralize 1 molecule of tartaric acid. It
is desired that the approximate ratio of ingredients is as follows
Citric Acid:Tartaric Acid:Sodium Bicarbonate=1:2:3.44 (by weight).
This ratio can be varied and continue to produce an effective
release of carbon dioxide. For example, ratios of about 1:0:3 or
0:1:2 are also effective.
[0093] The method of preparation of the effervescent granules of
the present invention employs three basic processes: wet and dry
granulation, and fusion. The fusion method is used for the
preparation of most commercial effervescent powders. It should be
noted that although these methods are intended for the preparation
of granules, the formulations of effervescent salts of the present
invention could also be prepared as tablets, according to well
known prior art technology for tablet preparation.
[0094] Wet granulation is the oldest method of granule preparation.
The individual steps in the wet granulation process of tablet
preparation include milling and sieving of the ingredients; dry
powder mixing; wet massing; granulation; and final grinding.
[0095] Dry granulation involves compressing a powder mixture into a
rough tablet or "slug" on a heavy-duty rotary tablet press. The
slugs are then broken up into granular particles by a grinding
operation, usually by passage through an oscillation granulator.
The individual steps include mixing of the powders; compressing
(slugging); and grinding (slug reduction or granulation). No wet
binder or moisture is involved in any of the steps.
[0096] The fusion method is the most preferred method for preparing
the granules of the present invention. In this method, the
compressing (slugging) step of the dry granulation process is
eliminated. Instead, the powders are heated in an oven or other
suitable source of heat.
[0097] PPIs Administered with Parietal Cell Activators
[0098] Applicant has unexpectedly discovered that certain
compounds, such as chocolate, calcium and sodium bicarbonate and
other alkaline substances, stimulate the parietal cells and enhance
the pharmacologic activity of the PPI administered. For the
purposes of this application, "parietal cell activator" shall mean
any compound or mixture of compounds possessing such stimulatory
effect including, but not limited to, chocolate, sodium
bicarbonate, calcium (e.g., calcium carbonate, calcium gluconate,
calcium hydroxide, calcium acetate and calcium glycerophosphate),
peppermint oil, spearmint oil, coffee, tea and colas (even if
decaffeinated), caffeine, theophylline, theobromine, and amino
acids (particularly aromatic amino acids such as phenylalanine and
tryptophan) and combinations thereof and the salts thereof.
[0099] Such parietal cell activators are administered in an amount
sufficient to produce the desired stimulatory effect without
causing untoward side effects to patients. For example, chocolate,
as raw cocoa, is administered in an amount of about 5 mg to 2.5 g
per 20 mg dose of omeprazole (or equivalent pharmacologic dose of
other PPI). The dose of activator administered to a mammal,
particularly a human, in the context of the present invention
should be sufficient to effect a therapeutic response (i.e.,
enhanced effect of PPI) over a reasonable time frame. The dose will
be determined by the strength of the particular compositions
employed and the condition of the person, as well as the body
weight of the person to be treated. The size of the dose also will
be determined by the existence, nature, and extent of any adverse
side effects that might accompany the administration of a
particular composition.
[0100] The approximate effective ranges for various parietal cell
activators per 20 mg dose of omeprazole (or equivalent dose of
other PPI) are:
[0101] Chocolate (raw cocoa)--5 mg to 2.5 g
[0102] Sodium bicarbonate--7 mEq to 25 mEq
[0103] Calcium carbonate--1 mg to 1.5 Gm
[0104] Calcium gluconate--1 mg to 1.5 Gm
[0105] Calcium lactate--1 mg to 1.5 Gm
[0106] Calcium hydroxide--1 mg to 1.5 Gm
[0107] Calcium acetate--0.5 mg to 1.5 Gm
[0108] Calcium glycerophosphate--0.5 mg to 1.5 Gm
[0109] Peppermint oil--(powdered form) 1 mg to 1 Gm
[0110] Spearmint oil--(powdered form) 1 mg to 1 Gm
[0111] Coffee--20 ml to 240 ml
[0112] Tea--20 ml to 240 ml
[0113] Cola--20 ml to 240 ml
[0114] Caffeine--0.5 mg to 1.5 GM
[0115] Theophylline--0.5 mg to 1.5 GM
[0116] Theobromine--0.5 mg to 1.5 GM
[0117] Phenylalanine--0.5 mg to 1.5 GM
[0118] Tryptophan--0.5 mg to 1.5 GM
[0119] Pharmaceutically acceptable carriers are well-known to those
who are skilled in the art. The choice of carrier will be
determined, in part, both by the particular composition and by the
particular method used to administer the composition. Accordingly,
there is a wide variety of suitable formulations of the
pharmaceutical compositions of the present invention.
EXAMPLE I
[0120] A. Fast Disintegrating Suspension Tablets of Omeprazole.
[0121] A fast disintegrating tablet is compounded as follows:
Croscarmellose sodium 300 g is added to the vortex of a rapidly
stirred beaker containing 3.0 kg of deionized water. This slurry is
mixed for 10 minutes. Omeprazole 90 g (powdered) is placed in the
bowl of a Hobart mixer. After mixing, the slurry of croscarmellose
sodium is added slowly to the omeprazole in the mixer bowl, forming
a granulation which is then placed in trays and dried at 70.degree.
C. for three hours. The dry granulation is then placed in a
blender, and to it is added 1,500 g of Avicel.RTM. AC-815 (85%
microcrystalline cellulose coprocessed with 15% of a calcium,
sodium alginate complex) and 1,500 g of Avicel.RTM. PH-302
(microcrystalline cellulose). After this mixture is thoroughly
blended, 35 g of magnesium stearate is added and mixed for 5
minutes. The resulting mixture is compressed into tablets on a
standard tablet press (Hata HS). These tablets have an average
weight of about 1.5 g, and contain about 20 mg omeprazole. These
tablets have low friability and rapid disintegration time. This
formulation may be dissolved in an aqueous solution containing a
buffering agent for immediate oral administration.
[0122] Alternatively, the suspension tablet may be swallowed whole
with a solution of buffering agent. In both cases, the preferred
solution is sodium bicarbonate 8.4%. As a further alternative,
sodium bicarbonate powder (about 975 mg per 20 mg dose of
omeprazole (or an equipotent amount of other PPI) is compounded
directly into the tablet. Such tablets are then dissolved in water
or sodium bicarbonate 8.4%, or swallowed whole with an aqueous
diluent.
[0123] B. 10 mg Tablet Formula.
1 Omeprazole 10 mg (or lansoprazole or pantoprazole or other PPI in
an equipotent amount) Calcium lactate 175 mg Calcium
glycerophosphate 175 mg Sodium bicarbonate 250 mg Aspartame calcium
(phenylalanine) 0.5 mg Colloidal silicon dioxide 12 mg Corn starch
15 mg Croscarmellose sodium 12 mg Dextrose 10 mg Peppermint 3 mg
Maltodextrin 3 mg Mannitol 3 mg Pregelatinized starch 3 mg
[0124] C. 20 mg Tablet Formula.
2 Omeprazole 20 mg (or lansoprazole or pantoprazole or other PPI in
an equipotent amount) Calcium lactate 175 mg Calcium
glycerophosphate 175 mg Sodium bicarbonate 250 mg Aspartame calcium
(phenylalanine) 0.5 mg Colloidal silicon dioxide 12 mg Corn starch
15 mg Croscarmellose sodium 12 mg Dextrose 10 mg Calcium hydroxide
10 mg Peppermint 3 mg Maltodextrin 3 mg Mannitol 3 mg
Pregelatinized starch 3 mg
[0125] D. Tablet for Rapid Dissolution.
3 Omeprazole 20 mg (or lansoprazole or pantoprazole or other PPI in
an equipotent amount) Calcium lactate 175 mg Calcium
glycerophosphate 175 mg Sodium bicarbonate 500 mg Calcium hydroxide
50 mg Croscarmellose sodium 12 mg
[0126] E. Powder for Reconstitution for Oral Use (or per ng
tube).
4 Omeprazole 20 mg (or lansoprazole or pantoprazole or other PPI in
an equipotent amount) Calcium lactate 175 mg Calcium
glycerophosphate 175 mg Sodium bicarbonate 500 mg Calcium hydroxide
50 mg Glycerine 200 mg
[0127] F. 10 mg Tablet Formula.
5 Omeprazole 10 mg (or lansoprazole or pantoprazole or other PPI in
an equipotent amount) Calcium lactate 175 mg Calcium
glycerophosphate 175 mg Sodium bicarbonate 250 mg Polyethylene
glycol 20 mg Croscarmellose sodium 12 mg Peppermint 3 mg Magnesium
silicate 1 mg Magnesium stearate 1 mg
[0128] G. 10 mg Tablet Formula.
6 Omeprazole 10 mg (or lansoprazole or pantoprazole or other PPI in
an equipotent amount) Calcium lactate 200 mg Calcium
glycerophosphate 200 mg Sodium bicarbonate 400 mg Croscarmellose
sodium 12 mg Pregelatinized starch 3 mg
EXAMPLE II
[0129] Standard Tablet of PPI and Buffering Agent.
[0130] Ten (10) tablets were prepared using a standard tablet
press, each tablet comprising about 20 mg omeprazole and about 975
mg sodium bicarbonate uniformly dispersed throughout the tablet. To
test the dissolution rate of the tablets, each was added to 60 ml
of water. Using previously prepared liquid omeprazole/sodium
bicarbonate solution as a visual comparator, it was observed that
each tablet was completely dispersed in under three (3)
minutes.
[0131] Another study using the tablets compounded according to this
Example evaluated the bioactivity of the tablets in five (5) adult
critical care patients. Each subject was administered one tablet
via ng with a small amount of water, and the pH of ng aspirate was
monitored using paper measure. The pH for each patient was
evaluated for 6 hours and remained above 4, thus demonstrating the
therapeutic benefit of the tablets in these patients.
[0132] Tablets were also prepared by boring out the center of
sodium bicarbonate USP 975 mg tablets with a knife. Most of the
removed sodium bicarbonate powder was then triturated with the
contents of a 20 mg Prilosec.RTM. capsule and the resulting mixture
was then packed into the hole in the tablet and sealed with
glycerin.
EXAMPLE III
[0133] PPI Central Core Tablet Tablets are prepared in a two-step
process. First, about 20 mg of omeprazole is formed into a tablet
as is known in the art to be used as a central core. Second, about
975 mg sodium bicarbonate USP is used to uniformly surround the
central core to form an outer protective cover of sodium
bicarbonate. The central core and outer cover are both prepared
using standard binders and other excipients to create a finished,
pharmaceutically acceptable tablet.
EXAMPLE IV
[0134] Effervescent Tablets and Granules
[0135] The granules of one 20mg Prilosec.RTM. capsule were emptied
into a mortar and triturated with a pestle to a fine powder. The
omeprazole powder was then geometrically diluted with about 958 mg
sodium bicarbonate USP, about 832 mg citric acid USP and about 312
mg potassium carbonate USP to form a homogeneous mixture of
effervescent omeprazole powder. This powder was then added to about
60 ml of water whereupon the powder reacted with the water to
create effervescence. A bubbling solution resulted of omeprazole
and principally the antacids sodium citrate and potassium citrate.
The solution was then administered orally to one adult male subject
and gastric pH was measured using pHydrion paper. The results were
as follows:
7 Time Interval pH Measured Immediately prior to dose 2 1 hour post
dose 7 2 hours post dose 6 4 hours post dose 6 6 hours post dose 5
8 hours post dose 4
[0136] One skilled in the art of pharmaceutical compounding will
appreciate that bulk powders can be manufactured using the above
ratios of ingredients, and that the powder can be pressed into
tablets using standard binders and excipients. Such tablets are
then mixed with water to activate the effervescent agents and
create the desired solution. In addition, lansoprazole 30 mg (or an
equipotent dose of other PPI) can be substituted for
omeprazole.
[0137] The effervescent powder and tablets can alternatively be
formulated by employing the above mixture but adding an additional
200 mg of sodium bicarbonate USP to create a resulting solution
with a higher pH. Further, instead of the excess 200 mg of sodium
bicarbonate, 100 mg of calcium glycerophosphate or 100 mg of
calcium lactate can be employed. Combinations of the same can also
added.
EXAMPLE V
[0138] Parietal Cell Activator "Choco-Base.TM." Formulations and
Efficacy.
[0139] Children are affected by gastroesophageal reflux disease
(GERD) with atypical manifestations. Many of these atypical
symptoms are difficult to control with traditional drugs such as
H.sub.2-antagonists, cisapride, or sucralfate. PPIs are more
effective in controlling gastric pH and the symptoms of GERD than
other agents. However, PPIs are not available in dosage forms that
are easy to administer to young children. To address this problem,
applicant employed omeprazole or lansoprazole in a buffered
chocolate suspension (Choco-Base, in children with manifestations
of GERD.
[0140] Applicant performed a retrospective evaluation of children
with GERD referred to the University of Missouri-Columbia from 1995
to 1998 who received treatment with the experimental omeprazole or
lansoprazole Choco-Base suspension formulated in accordance with
Formulation 1 stated below. Data were included on all patients with
follow up information sufficient to draw conclusions about pre/post
treatment (usually >6 months). There were 25 patients who met
the criteria for this evaluation. Age range was several weeks to
greater than 5 years. Most patients had a history of numerous
unsuccessful attempts at ameliorating the effects of GERD.
Medication histories indicated many trials of various drugs.
[0141] The primary investigator reviewed all charts for uniformity
of data collection. When insufficient data was available in the
University charts, attempts were made to review charts in the local
primary care physicians' offices for follow-up data. If information
was still unavailable to review, attempts were made to contact
family for follow-up. If data were still unavailable the patients
were considered inevaluable.
[0142] Patient charts were reviewed in detail. Data noted were date
of commencement of therapy, date of termination of therapy and any
reason for termination other than response to treatment. Patient
demographics were also recorded, as were any other medical
illnesses. Medical illnesses were divided grossly into those that
are associated with or exacerbate GERD and those that do not.
[0143] Patient charts were examined for evidence of response to
therapy. As this was largely a referral population, and a
retrospective review, quantification of symptomatology based on
scores, office visits and ED visits was difficult. Therefore,
applicant examined charts for evidence of an overall change in
patient symptoms. In specific, any data to point towards
improvement, decline or lack of change were examined and
recorded.
[0144] Results.
[0145] A total of 33 pediatric patients to date have been treated
with the above-described suspension at the University of
Missouri--Columbia. Of the 33 patients, 9 were excluded from the
study, all based upon insufficient data about commencement,
duration or outcome in treatment with PPI therapy. This left 24
patients with enough data to draw conclusions.
[0146] Of the 24 remaining patients, 18 were males and 6 females.
Ages at implementation of PPI therapy ranged from 2 weeks of age to
9 years old. Median age at start of therapy was 26.5 months [mean
of 37 mo.] Early on, reflux was usually documented by endoscopy and
confirmed by pH probe. Eventually, pH probe was dropped and
endoscopy was the sole method for documenting reflux, usually at
the time of another surgery (most often T-tubes or adenoidectomy).
Seven patients had pH probe confirmation of GERD, whereas 18 had
endoscopic confirmation of reflux including all eight who had pH
probing done (See Graphs 1 and 2 below). Reflux was diagnosed on
endoscopy most commonly by cobblestoning of the tracheal wall, with
laryngeal and pharyngeal cobblestoning as findings in a few
patients. Six patients had neither pH nor endoscopic documentation
of GERD, but were tried on PPI therapy based on symptomatology
alone.
[0147] Past medical history was identified in each chart. Ten
patients had reflux-associated diagnoses. These were most commonly
cerebral palsy, prematurity and Pierre Robin sequence. Other
diagnoses were Charcot-Marie-Tooth disease, Velocardiofacial
syndrome, Down syndrome and De George's syndrome. Non-reflux
medical history was also identified and recorded separately (See
Table 2 below).
[0148] Patients were, in general, referral patients from local
family practice clinics, pediatricians, or other pediatric health
care professionals. Most patients were referred to ENT for upper
airway problems, sinusitis, or recurrent/chronic otitis media that
had been refractory to medical therapy as reported by the primary
care physician. Symptoms and signs most commonly found in these
patients were recorded and tallied. All signs and symptoms were
broken down into six major categories: (1) nasal; (2) otologic; (3)
respiratory; (4) gastrointestinal; (5) sleep-related; and (6)
other. The most common problems fell into one or all of the first 3
categories (See Table 1 below).
[0149] Most patients had been treated in the past with medical
therapy in the form of antibiotics, steroids, asthma medications
and other diagnosis-appropriate therapies. In addition, nine of the
patients had been on reflux therapy in the past, most commonly in
the form of conservative therapy such as head of bed elevation
30.degree., avoidance of evening snacks, avoidance of caffeinated
beverages as well as cisapride and ranitidine (See Graph 3
below).
[0150] The proton pump inhibitor suspension used in this group of
patients was Choco-Base suspension of either lansoprazole or
omeprazole. The dosing was very uniform, with patients receiving
doses of either 10 or 20 mg of omeprazole and 23 mg of
lansoprazole. Initially, in April of 1996 when therapy was first
instituted 10 mg of omeprazole was used. There were 3 patients in
this early phase who were treated initially with 10 mg po qd of
omeprazole. All three subsequently were increased to either 20 mg
po qd of omeprazole or 23 mg po qd of lansoprazole. All remaining
patients were given either the 20 mg omeprazole or the 23 mg
lansoprazole treatment qd, except in one case, where 30 mg of
lansoprazole was used. Patients were instructed to take their doses
once per day, preferably at night in most cases. Suspensions were
all filled through the University of Missouri Pharmacy at Green
Meadows. This allowed for tracking of usage through refill
data.
[0151] Most patients responded favorably to and tolerated the once
daily dosing of Choco-Base proton pump inhibitor suspension. Two
patients had documented adverse effects associated with the use of
the PPI suspension. In one patient, the mother reported increased
burping up and dyspepsia, which was thought to be related to
treatment failure. The other patient had small amounts of bloody
stools per mother. This patient never had his stool tested, as his
bloody stool promptly resolved upon cessation of therapy, with no
further sequellae. The other 23 patients had no documented adverse
effects.
[0152] Patients were categorized based on review of clinic notes
and chart review into general categories: (1) improved; (2)
unchanged; (3) failed; and (4) inconclusive. Of 24 patients with
sufficient data for follow up, 18 showed improvement in
symptomatology upon commencement of PPI therapy [72%]. The seven
who did not respond were analyzed and grouped. Three showed no
change in symptomatology and clinical findings while on therapy,
one complained of worsening symptoms while on therapy, one patient
had therapy as prophylaxis for surgery, and two stopped therapy
just after its commencement (see graph 4). Setting aside the cases
in which therapy was stopped before conclusions could be drawn and
the case in which PPI therapy was for purely prophylactic reasons,
leaves (17/21) 81% of patients that responded to Choco-Base
suspension. This means that 19% (4/21) of patients received no
apparent benefit from PPI therapy. Of all these patients, only 4%
complained of worsening symptoms and the side effects were 4%
(1/21) and were mild bloody stool that completely resolved upon
cessation of therapy.
[0153] Discussion.
[0154] GERD in the pediatric population is relatively common,
affecting almost 50% of newborns. Even though most infants outgrow
physiologic reflux, pathologic reflux still affects approximately
5% of all children throughout childhood. Recently considerable data
has pointed to reflux as an etiologic factor in extra-esophageal
areas. GERD has been attributed to sinusitis, dental caries, otitis
media, asthma, apnea, arousal, pneumonia, bronchitis, and cough,
among others. Despite the common nature of reflux, there seems to
have been little improvement in therapy for reflux, especially in
the non-surgical arena.
[0155] The standard of therapy for the treatment of GERD in the
pediatric population has become a progression from conservative
therapy to a combination of a pro-kinetic agent and H-2 blocker
therapy. Nonetheless, many patients fail this treatment protocol
and become surgical candidates. In adults, PPI therapy is effective
in 90% of those treated for gastroesophageal reflux disease. As a
medical alternative to the H-2 blockers, the proton pump inhibitors
have not been studied extensively in the pediatric population. Part
of the reason for this lack of data may be related to the absence
of a suitable dosage formulation for this very young population,
primarily under 2 years of age, that does not swallow capsules or
tablets. It would be desirable to have a true liquid formulation
(solution or suspension) with good palatability such as is used for
oral antibiotics, decongestants, antihistamines, H-2 blockers,
cisapride, metoclopramide, etc. The use of lansoprazole granules
(removed from the gelatin capule) and sprinkled on applesauce has
been approved by the Food and Drug Administration as an alternative
method of drug administration in adults but not in children.
Published data are lacking on the efficacy of the lansoprazole
sprinkle method in children. Omeprazole has been studied for
bioequivalence as a sprinkle in adults and appears to produce
comparable serum concentrations when compared to the standard
capsule. Again no data are available on the omeprazole sprinkle in
children. An additional disadvantage of omeprazole is its taste
which is quinine-like. Even when suspended in juice, applesauce or
the like, the bitter nature of the medicine is easily tasted even
if one granule is chewed. For this reason applicant eventually
progressed to use lansoprazole in Choco-Base. Pantoprazole and
rabeprazole are available as enteric-coated tablets only.
Currently, none of the proton pump inhibitors available in the
United States are approved for pediatric use. There is some
controversy as to what the appropriate dosage should be in this
group of patients. A recent review by Israel D., et al. suggests
that effective PPI dosages should be higher than that originally
reported, i.e., from 0.7 mg/kg to 2 or 3 mg/kg omeprazole. Since
toxicity with the PPI's is not seen even at >50mg/kg, there
appears little risk associated with the higher dosages. Based on
observations at the University of Missouri consistent with the
findings of this review, applicant established a simple fixed
dosage regimen of 10 ml Choco-Base suspension daily. This 10 ml
dose provided 20 mg omeprazole and 23 mg lansoprazole.
[0156] In the ICU setting, the University of Missouri--Columbia has
been using an unflavored PPI suspension given once daily per
various tubes (nasogastric, g-tube, jejunal feeding tube, duo tube,
etc.) for stress ulcer prophylaxis. It seemed only logical that if
this therapy could be made into a palatable form, it would have
many ideal drug characteristics for the pediatric population.
First, it would be liquid, and therefore could be administered at
earlier ages. Second, if made flavorful it could help to reduce
noncompliance. Third, it could afford once daily dosing, also
helping in reducing noncompliance. In the process, applicant
discovered that the dosing could be standardized, which nearly
eliminated dosing complexity.
[0157] Choco-Base is a product which protects drugs which are acid
labile, such as proton pump inhibitors, from acid degradation. The
first few pediatric patients with reflux prescribed Choco-Base were
sicker patients. They had been on prior therapy and had been
diagnosed both by pH probe and endoscopy. In the first few months,
applicant treated patients with 10 mg of omeprazole qd (1 mg/kg)
and found this to be somewhat ineffective, and quickly increased
the dosing to 20 mg (2 mg/kg) of omeprazole. About halfway through
the study, applicant began using lansoprazole 23 mg po qd.
Applicant's standard therapy was then either 20 mg of omeprazole or
23 mg of lansoprazole once daily. The extra 3 mg of lansoprazole is
related only to the fact that the final concentration was 2.25
mg/ml, and applicant desired to keep dosing simple, so he used a 10
ml suspension.
[0158] The patients that were treated represented a tertiary care
center population, and they were inherently sicker and refractory
to medical therapy in the past. The overall 72% success rate is
slightly lower than the 90% success rates of PPIs in the adult
population, but this can be attributed to the refractory nature of
their illness, most having failed prior non-PPI treatment. The
population in this study is not indicative of general practice
populations.
[0159] Conclusion.
[0160] PPI therapy is a beneficial therapeutic option in the
treatment of reflux related symptoms in the pediatric population.
Its once daily dosing and standard dosing scheme combined with a
palatable formulation makes it an ideal pharmacologic agent.
8 TABLE 1 Symptoms Patient Numbers Nasal: 35 Sinusitis 7 Congestion
8 Nasal discharge 16 Other 4 Otologic: 26 Otitis Media 17 Otorrhea
9 Respiratory: 34 Cough 10 Wheeze 11 Respiratory Distress: 5
Pneumonia 2 Other 6 Gastrointestinal: 10 Abdominal Pain 1
Reflux/Vomiting 4 Other 4 Sleep Disturbances: 11 Other 2
[0161]
9 TABLE 2 Past Medical History Number of Patients Reflux
Associated: 12 Premature 5 Pierre-Robin 2 Cerebral Palsy 2 Down
Syndrome 1 Charcot-Marie-Tooth 1 Velocardiofacial Syndrome 1 Other
Medical History 12 Cleft Palate 3 Asthma 3 Autism 2 Seizure
Disorder 1 Diabetes Mellitus 1 Subglottic Stenosis 1 Tracheostomy
Dependent 1
[0162]
[0163] The Choco-Base product is formulated as follows:
10 FORMULATION 1 PART A INGREDIENTS AMOUNT (mg) Omeprazole 200
Sucrose 26000 Sodium Bicarbonate 9400 Cocoa 1800 Corn Syrup Solids
6000 Sodium Caseinate 1000 Soy Lecithin 150 Sodium Chloride 35
Tricalcium Phosphate 20 Dipotassium Phosphate 12 Silicon Dioxide 5
Sodium Stearoyl Lactylate 5 PART B INGREDIENTS AMOUNT (ml)
Distilled Water 100 COMPOUNDING INSTRUCTIONS Add Part B to Part A
to create a total volume of approximately 130 ml with an omeprazole
concentration of about 1.5 mg/ml. FORMULATION 2 PART A INGREDIENTS
(mg) AMOUNT (mg) Sucrose 26000 Cocoa 1800 Corn Syrup Solids 6000
Sodium Caseinate 1000 Soy Lecithin 150 Sodium Chloride 35
Tricalcium Phosphate 20 Dipotassium Phosphate 12 Silicon Dioxide 5
Sodium Stearoyl Lactylate 5 PART B INGREDIENTS AMOUNT Distilled
Water 100 ml Sodium Bicarbonate 8400 mg Omeprazole 200 mg
COMPOUNDING INSTRUCTIONS Mix the constituents of Part B together
thoroughly and then add to Part A. This results in a total volume
of approximately 130 ml with an omeprazole concentration of about
1.5 mg/ml. FORMULATION 3 PART A INGREDIENTS (mg) AMOUNT (mg)
Sucrose 26000 Sodium Bicarbonate 9400 Cocoa 1800 Corn Syrup Solids
6000 Sodium Caseinate 1000 Soy Lecithin 150 Sodium Chloride 35
Tricalcium Phosphate 20 Dipotassium Phosphate 12 Silicon Dioxide 5
Sodium Stearoyl Lactylate 5 PART B INGREDIENTS AMOUNT Distilled
Water 100 ml Omeprazole 200 mg COMPOUNDING INSTRUCTIONS This
formulation is reconstituted at the time of use by a pharmacist.
Part B is mixed first and is then uniformly mixed with the
components of Part A. A final volume of about 130 ml is created
having an omeprazole concentration of about 1.5 mg/ml. FORMULATION
4 PART A INGREDIENTS (mg) AMOUNT (mg) Sucrose 26000 Cocoa 1800 Corn
Syrup Solids 6000 Sodium Caseinate 1000 Soy Lecithin 150 Sodium
Chloride 35 Tricalcium Phosphate 20 Dipotassium Phosphate 12
Silicon Dioxide 5 Sodium Stearoyl Lactylate 5 PART B INGREDIENTS
AMOUNT Distilled Water 100 ml Sodium Bicarbonate 8400 mg Omeprazole
200 mg COMPOUNDING INSTRUCTIONS This formulation is reconstituted
at the time of use by a pharmacist. Part B is mixed first and is
then uniformly mixed with the components of Part A. A final volume
of about 130 ml is created having an omeprazole concentration of
about 1.5 mg/ml.
[0164] In all four of the above formulations, lansoprazole or other
PPI can be substituted for omeprazole in equipotent amounts. For
example, 300 mg of lansoprazole may be substituted for the 200 mg
of omeprazole. Additionally, aspartame can be substituted for
sucrose, and the following other ingredients can be employed as
carriers, adjuvants and excipients: maltodextrin, vanilla,
carragreenan, mono and diglycerides, and lactated monoglycerides.
One skilled in the art will appreciate that not all of the
ingredients are necessary to create a Choco-Base formulation that
is safe and effective.
[0165] Omeprazole powder or enteric coated granules can be used in
each formulation. If the enteric coated granules are used, the
coating is either dissolved by the aqueous diluent or inactivated
by trituration in the compounding process.
[0166] Applicant additionally analyzed the effects of a
lansoprazole Choco-Base formulation on gastric pH using a pH meter
(Fisher Scientific) in one adult patient versus lansoprazole alone.
The patient was first given a 30 mg oral capsule of Prevacid.RTM.,
and the patient's gastric pH was measured at 0, 4, 8, 12, and 16
hours post dose. The results are illustrated in FIG. 4.
[0167] The Choco-Base product was compounded according to
Formulation 1 above, except 300 mg of lansoprazole was used instead
of omeprazole. A dose of 30 mg lansoprazole Choco-Base was orally
administered at hour 18 post lansoprazole alone. Gastric pH was
measured using a pH meter at hours 18, 19, 24, 28, 32, 36, 40, 48,
52, and 56 post lansoprazole alone dose.
[0168] FIG. 4 illustrates the lansoprazole/cocoa combination
resulted in higher pH, at hours 19-56 than lansoprazole alone at
hours 4-18. Therefore, the combination of the lansoprazole with
chocolate enhanced the pharmacologic activity of the lansoprazole.
The results establish that the sodium bicarbonate as well as
chocolate flavoring and calcium were all able to stimulate the
activation of the proton pumps, perhaps due to the release of
gastrin. Proton pump inhibitors work by functionally inhibiting the
proton pump and effectively block activated proton pumps (primarily
those inserted into the secretory canalicular membrane). By further
administering the proton pump inhibitor with one of these
activators or enhancers, there is a synchronization of activation
of the proton pump with the absorption and subsequent parietal cell
concentrations of the proton pump inhibitor. As illustrated in FIG.
4, this combination produced a much longer pharmacologic effect
than when the proton pump inhibitor was administered alone.
EXAMPLE VI
[0169] Combination Tablet Delivering Bolus and Time-Released Doses
of PPI
[0170] Tablets were compounded using known methods by forming an
inner core of 10 mg omeprazole powder mixed with 750 mg sodium
bicarbonate, and an outer core of 10 mg omeprazole enteric-coated
granules mixed with known binders and excipients. Upon ingestion of
the whole tablet, the tablet dissolves and the inner core is
dispersed in the stomach where it is absorbed for immediate
therapeutic effect. The enteric-coated granules are later absorbed
in the duodenum to provide symptomatic relief later in the dosing
cycle. This tablet is particularly useful in patients who
experience breakthrough gastritis between conventional doses, such
as while sleeping or in the early morning hours.
EXAMPLE VII
[0171] Therapeutic Application
[0172] Patients were evaluable if they met the following criteria:
had two or more risk factors for SRMD (mechanical ventilation, head
injury, severe burn, sepsis, multiple trauma, adult respiratory
distress syndrome, major surgery, acute renal failure, multiple
operative procedures, coagulotherapy, significant hyportension,
acid-base disorder, and hepatic failure), gastric pH of .ltoreq.4
prior to study entry, and no concomitant prophylaxis for SRMD.
[0173] The omeprazole solution was prepared by mixing 10 ml of 8.4%
sodium bicarbonate with the contents of a 20 mg capsule of
omeprazole (Merck & Co. Inc., West Point, Pa.) to yield a
solution having a final omeprazole concentration of 2 mg/ml.
[0174] Nasogastric (ng) tubes were placed in the patients and an
omeprazole dosage protocol of buffered 40 mg omeprazole solution (2
mg omeprazole/l ml NaHCO.sub.3--8.4%) followed by 40 mg of the same
buffered omeprazole solution in eight hours, then 20 mg of the same
buffered omeprazole solution per day, for five days. After each
buffered omeprazole solution administration, nasogastric suction
was turned off for thirty minutes.
[0175] Eleven patients were evaluable. All patients were
mechanically ventilated. Two hours after the initial 40 mg dose of
buffered omeprazole solution, all patients had an increase in
gastric pH to greater than eight as shown in FIG. 1. Ten of the
eleven patients maintained a gastric pH of greater than or equal to
four when administered 20 mg omeprazole solution. One patient
required 40 mg omeprazole solution per day (closed head injury,
five total risk factors for SRMD). Two patients were changed to
omeprazole solution after having developed clinically significant
upper gastrointestinal bleeding while receiving conventional
intravenous H.sub.2-antagonists. Bleeding subsided in both cases
after twenty-four hours. Clinically significant upper
gastrointestinal bleeding did not occur in the other nine patients.
Overall mortality was 27%, mortality attributable to upper
gastrointestinal bleeding was 0%. Pneumonia developed in one
patient after initiating omeprazole therapy and was present upon
the initiation of omeprazole therapy in another patient. The mean
length of prophylaxis was five days.
[0176] A pharmacoeconomic analysis revealed a difference in the
total cost of care for the prophylaxis of SRMD:
[0177] ranitidine (Zantac.RTM.) continuous infusion intravenously
(150 mg/24 hours).times.five days $125.50;
[0178] cimetidine (Tagamet.RTM.) continuous infusion intravenously
(900 mg/24 hours).times.five days $109.61;
[0179] sucralfate one gm slurry four times a day per (ng)
tube.times.five days $73.00; and
[0180] buffered omeprazole solution regimen per (ng)
tube.times.five days $65.70.
[0181] This example illustrates the efficacy of the buffered
omeprazole solution of the present invention based on the increase
in gastric pH, safety and cost of the buffered omeprazole solution
as a method for SRMD prophylaxis.
EXAMPLE VIII
[0182] Effect on pH
[0183] Experiments were carried out in order to determine the
effect of the omeprazole solution (2 mg omeprazole/1 ml
NaHCO.sub.3--8.4%) administration on the accuracy of subsequent pH
measurements through a nasogastric tube.
[0184] After preparing a total of 40 mg of buffered omeprazole
solution, in the manner of Example VII, doses were administered
into the stomach, usually, through a nasogastric (ng) tube.
Nasogastric tubes from nine different institutions were gathered
for an evaluation. Artificial gastric fluid (gf) was prepared
according to the USP. pH recordings were made in triplicate using a
Microcomputer Portable pH meter model 6007 (Jenco Electronics Ltd.,
Taipei, Taiwan).
[0185] First, the terminal portion (tp) of the nasogastric tubes
was placed into a glass beaker containing the gastric fluid. A 5 ml
aliquot of gastric fluid was aspirated through each tube and the pH
recorded; this was called the "pre-omeprazole solution/suspension
measurement." Second, the terminal portion (tp) of each of the
nasogastric tubes was removed from the beaker of gastric fluid and
placed into an empty beaker. Twenty (20) mg of omeprazole solution
was delivered through each of the nasogastric tubes and flushed
with 10 ml of tap water. The terminal portion (tp) of each of the
nasogastric tubes was placed back into the gastric fluid. After a
one hour incubation, a 5 ml aliquot of gastric fluid was aspirated
through each nasogastric tube and the pH recorded; this was called
the "after first dose SOS [Simplified Omeprazole Solution]
measurement." Third, after an additional hour had passed, the
second step was repeated; this was called the "after second dose
SOS [Simplified Omeprazole Solution] measurement." In addition to
the pre-omeprazole measurement, the pH of the gastric fluid was
checked in triplicate after the second and third steps. A change in
the pH measurements of +/-0.3 units was considered significant. The
Friedman test was used to compare the results. The Friedman test is
a two way analysis of variance which is used when more than two
related samples are of interest, as in repeated measurements.
[0186] The results of these experiments are outlined in Table
1.
11 TABLE 1 ng1 ng2 ng3 ng4 ng5 ng6 ng7 ng8 ng9 [1] gf 1.3 1.3 1.3
1.3 1.3 1.3 1.3 1.3 1.3 Pre SOS [2] gf p 1.3 1.3 1.3 1.3 1.3 1.3
1.3 1.3 1.3 1.sup.st dose 1.3.left brkt-top.check of fg pH [3] gf p
1.3 1.3 1.4 1.4 1.4 1.3 1.4 1.3 1.3 2.sup.nd Dose 1.3.left
brkt-top.check of gf pH SOS pH = 9.0
[0187] Table 1 illustrates the results of the pH measurements that
were taken during the course of the experiment. These results
illustrate that there were no statistically significant latent
effects of omeprazole solution administration (per nasogastric
tube) on the accuracy of subsequent pH measurements obtained
through the same nasogastric tube.
EXAMPLE X
[0188] Efficacy of Buffered Omeprazole Solution in Ventilated
Patients
[0189] Experiments were performed in order to determine the
efficacy, safety, and cost of buffered omeprazole solution in
mechanically ventilated critically ill patients who have at least
one additional risk factor for stress-related mucosal damage.
[0190] Patients:
[0191] Seventy-five adult, mechanically ventilated patients with at
least one additional risk factor for stress-related mucosal
damage.
[0192] Interventions:
[0193] Patients received 20 ml omeprazole solution (prepared as per
Example VII and containing 40 mg of omeprazole) initially, followed
by a second 20 ml dose six to eight hours later, then 10 ml (20 mg)
daily. Omeprazole solution according to the present invention was
administered through a nasogastric tube, followed by 5-10 ml of tap
water. The nasogastric tube was clamped for one to two hours after
each administration.
[0194] Measurements and Main Results:
[0195] The primary outcome measure was clinically significant
gastrointestinal bleeding determined by endoscopic evaluation,
nasogastric aspirate examination, or heme-positive coffee ground
material that did not clear with lavage and was associated with a
five percent decrease in hematocrit. Secondary efficacy measures
were gastric pH measured four hours after omeprazole was first
administered, mean gastric pH after omeprazole was started, and the
lowest gastric pH during omeprazole therapy. Safety-related
outcomes included the incidence of adverse events and the incidence
of pneumonia. No patient experienced clinically significant upper
gastrointestinal bleeding after receiving omeprazole suspension.
The four-hour post omeprazole gastric pH was 7.1 (mean), the mean
gastric pH after starting omeprazole was 6.8 (mean) and the lowest
pH after starting omeprazole was 5.6 (mean). The incidence of
pneumonia was twelve percent. No patient in this high-risk
population experienced an adverse event or a drug interaction that
was attributable to omeprazole.
[0196] Conclusions:
[0197] Omeprazole solution prevented clinically significant upper
gastrointestinal bleeding and maintained gastric pH above 5.5 in
mechanically ventilated critical care patients without producing
toxicity.
[0198] Materials and Methods:
[0199] The study protocol was approved by the Institutional Review
Board for the University of Missouri at Columbia.
[0200] Study Population:
[0201] All adult (>18 years old) patients admitted to the
surgical intensive care and burn unit at the University of Missouri
Hospital with an intact stomach, a nasogastric tube in place, and
an anticipated intensive care unit stay of at least forty-eight
hours were considered for inclusion in the study. To be included
patients also had to have a gastric pH of <4, had to be
mechanically ventilated and have one of the following additional
risk factors for a minimum of twenty-four hours after initiation of
omeprazole suspension: head injury with altered level of
consciousness, extensive burns (>20% Body Surface Area), acute
renal failure, acid-base disorder, multiple trauma, coagulopathy,
multiple operative procedures, coma, hypotension for longer than
one hour or sepsis (see Table 2). Sepsis was defined as the
presence of invasive pathogenic organisms or their toxins in blood
or tissues resulting in a systematic response that included two or
more of the following: temperature greater than 38.degree. C. or
less than 36.degree. C., heart rate greater than 90 beats/minute,
respiratory rate greater than 20 breaths/minute (or .sub.pO.sub.2
less than 75 mm Hg), and white blood cell count greater than 12,000
or less than 4,000 cells/mm.sup.3 or more than 10 percent bands
(Bone, Let's Agree on Terminology: Definitions of Sepsis, CRIT.
CARE MED., 19: 27 (1991)). Patients in whom H.sub.2-antagonist
therapy had failed or who experienced an adverse event while
receiving H.sub.2-antagonist therapy were also included.
[0202] Patients were excluded from the study if they were receiving
azole antifungal agents through the nasogastric tube; were likely
to swallow blood (e.g., facial and/or sinus fractures, oral
lacerations); had severe thrombocytopenia (platelet count less than
30,000 cells/mm.sup.3); were receiving enteral feedings through the
nasogastric tube; or had a history of vagotomy, pyloroplasty, or
gastroplasty. In addition, patients with a gastric pH above four
for forty-eight hours after ICU admission (without prophylaxis)
were not eligible for participation. Patients who developed
bleeding within the digestive tract that was not stress-related
mucosal damage (e.g., endoscopically verified variceal bleeding or
Mallory-Weiss tears, oral lesions, nasal tears due to placement of
the nasogastric tube) were excluded from the efficacy evaluation
and categorized as having non-stress-related mucosal bleeding. The
reason for this exclusion is the confounding effect of
non-stress-related mucosal bleeding on efficacy-related outcomes,
such as the use of nasogastric aspirate inspection to define
clinically significant upper gastrointestinal bleeding.
[0203] Study Drug Administration:
[0204] Omeprazole solution was prepared immediately before
administration by the patient's nurse using the following
instructions: empty the contents of one or two 20 mg omeprazole
capsule(s) into an empty 10 ml syringe (with 20 gauge needle in
place) from which the plunger has been removed. (Omeprazole
delayed-release capsules, Merck & Co., Inc., West Point, Pa.);
replace the plunger and uncap the needle; withdraw 10 ml of 8.4%
sodium bicarbonate solution or 20 ml if 40 mg given (Abbott
Laboratories, North Chicago, Ill.), to create a concentration of 2
mg omeprazole per ml of 8.4% sodium bicarbonate; and allow the
enteric coated pellets of omeprazole to completely breakdown,
.apprxeq.30 minutes (agitation is helpful). The omeprazole in the
resultant preparation is partially dissolved and partially
suspended. The preparation should have a milky white appearance
with fine sediment and should be shaken before administration. The
solution was not administered with acidic substances. A high
pressure liquid chromatography study was performed that
demonstrated that this preparation of simplified omeprazole
suspension maintains >90% potency for seven days at room
temperature. This preparation remained free of bacterial and fungal
contamination for thirty days when stored at room temperature (See
Table 5).
[0205] The initial dose of omeprazole solution was 40 mg, followed
by a second 40 mg dose six to eight hours later, then a 20 mg daily
dose administered at 8:00 AM. Each dose was administered through
the nasogastric tube. The nasogastric tube was then flushed with
5-10 ml of tap water and clamped for at least one hour. Omeprazole
therapy was continued until there was no longer a need for stress
ulcer prophylaxis (usually after the nasogastric tube was removed
and the patient was taking water/food by mouth, or after the
patient was removed from mechanical ventilation).
[0206] Primary Outcome Measures:
[0207] The primary outcome measure in this study was the rate of
clinically significant stress-related mucosal bleeding defined as
endoscopic evidence of stress-related mucosal bleeding or bright
red blood per nasogastric tube that did not clear after a 5-minute
lavage or persistent Gastroccult (SmithKline Diagnostics,
Sunnyville, Calif.) positive coffee ground material for four
consecutive hours that did not clear with lavage (at least 100 ml)
and produced a 5% decrease in hematocrit.
[0208] Secondary Outcome Measures:
[0209] The secondary efficacy measures were gastric pH measured
four hours after omeprazole was administered, mean gastric pH after
starting omeprazole and lowest gastric pH during omeprazole
administration. Gastric pH was measured immediately after
aspirating gastric contents through the nasogastric tube. pH paper
(pHydrion improved pH papers, Microessential Laboratory, Brooklyn,
N.Y.) was used to measure gastric aspirate pH. The pH range of the
test strips was 1 to 11, in increments of one pH unit. Gastric pH
was measured before the initiation of omeprazole solution therapy,
immediately before each dose, and every four hours between
doses.
[0210] Other secondary outcome measures were incidence of adverse
events (including drug interactions) and pneumonia. Any adverse
event that developed during the study was recorded. Pneumonia was
defined using indicators adapted from the Centers for Disease
Prevention and Control definition of nosocomial pneumonia (Garner
et al., 1988). According to these criteria, a patient who has
pneumonia is one who has rales or dullness to percussion on
physical examination of the chest or has a chest radiograph that
shows new or progressive infiltrate(s), consolidation, cavitation,
or pleural effusion and has at least two of the following present:
new purulent sputum or changes in character of the sputum, an
organism isolated from blood culture, fever or leukocytosis, or
evidence of infection from a protective specimen brush or
bronchoalveolar lavage. Patients who met the criteria for pneumonia
and were receiving antimicrobial agents for the treatment of
pneumonia were included in the pneumonia incidence figure. These
criteria were also used as an initial screen before the first dose
of study drug was administered to determine if pneumonia was
present prior to the start of omeprazole suspension.
[0211] Cost of Care Analysis:
[0212] A pharmacoeconomic evaluation of stress ulcer prophylaxis
using omeprazole solution was performed. The evaluation included
total drug cost (acquisition and administration), actual costs
associated with adverse events (e.g., psychiatry consultation for
mental confusion), costs associated with clinically significant
upper gastrointestinal bleeding. Total drug cost was calculated by
adding the average institutional costs of omeprazole 20 mg
capsules, 50 ml sodium bicarbonate vials, and 10 ml syringes with
needle; nursing time (drug administration, pH monitoring); pharmacy
time (drug preparation); and disposal costs. Costs associated with
clinically significant upper gastrointestinal bleeding included
endoscopy charges and accompanying consultation fees, procedures
required to stop the bleeding (e.g., surgery, hemostatic agents,
endoscopic procedures), increased hospital length of stay (as
assessed by the attending physician), and cost of drugs used to
treat the gastrointestinal bleeding.
[0213] Statistical Analysis:
[0214] The paired t-test (two-tailed) was used to compare gastric
pH before and after omeprazole solution administration and to
compare gastric pH before omeprazole solution administration with
the mean and lowest gastric pH value measured after beginning
omeprazole.
[0215] Results:
[0216] Seventy-seven patients met the inclusion and exclusion
criteria and received omeprazole solution (See FIG. 2). Two
patients were excluded from the efficacy evaluation because the
protocol for omeprazole administration was not followed. In one
case, the omeprazole enteric-coated pellets had not completely
broken down prior to the administration of the first two doses,
which produced an erratic effect on gastric pH. The gastric pH
increased to above six as soon as the patient was given a dose of
omeprazole solution (in which the enteric coated pellets of
omeprazole had been allowed to completely breakdown).
[0217] The reason for the second exclusion was that nasogastric
suctioning was not turned off after the omeprazole dose was
administered. This resulted in a transient effect on gastric pH.
The suction was turned off with subsequent omeprazole doses, and
control of gastric pH was achieved. Two patients were considered
efficacy failures because omeprazole failed to maintain adequate
gastric pH control on the standard omeprazole 20 mg/day maintenance
dose. When the omeprazole dose was increased to 40 mg/day (40 mg
once/day or 20 mg twice/day), gastric pH was maintained above four
in both patients. These two patients were included in the safety
and efficacy evaluations, including the gastric pH analysis. After
the two patients were declared failures, their pH values were no
longer followed.
[0218] The ages of the remaining seventy-five patients ranged from
eighteen to eighty-seven years; forty-two patients were male and
thirty-three were female. All patients were mechanically ventilated
during the study. Table 2 shows the frequency of risk factors for
stress-related bleeding that were exhibited by the patients in this
study. The most common risk factors in this population were
mechanical ventilation and major surgery. The range of risk factors
for any given patient was two to ten, with a mean of 3 (.+-.1)
(standard deviation). Five patients enrolled in the study had
developed clinically significant bleeding while receiving
continuous infusions of ranitidine (150 mg/24 hr) or cimetidine
(900 mg/24 hr). In all five cases, the bleeding subsided and the
gastric pH rose to above five within thirty-six hours after
initiating omeprazole therapy. Three patients were enrolled after
having developed two consecutive gastric pH values below three
while receiving an H.sub.2-antagonist (in the doses outlined
above). In all three cases, gastric pH rose to above five within
four hours after omeprazole therapy was initiated. Four other
patients were enrolled in this study after experiencing confusion
(n=2) or thrombocytopenia (n=2) during H.sub.2-antigens therapy.
Within thirty-six hours of switching therapy, these adverse events
resolved.
[0219] Stress-related Mucosal Bleeding and Mortality:
[0220] None of the sixty-five patients who received buffered
omeprazole solution as their initial prophylaxis against
stress-related mucosal bleeding developed overt or clinically
significant upper gastrointestinal bleeding. In four of the five
patients who had developed upper gastrointestinal bleeding before
study entry, bleeding diminished to the presence of occult blood
only (Gastroccult-positive) within eighteen hours of starting
omeprazole solution; bleeding stopped in all patients within
thirty-six hours. The overall mortality rate in this group of
critically ill patients was eleven percent. No death was
attributable to upper gastrointestinal bleeding or the use of
omeprazole solution.
[0221] Gastric pH:
[0222] The mean (.+-.standard deviation) pre-omeprazole gastric pH
was 3.5.+-.1.9. Within four hours of omeprazole administration, the
gastric pH rose to 7.1.+-.1.1 (See FIG. 3); this difference was
significant (p<0.001). The differences between pre-omeprazole
gastric pH and the mean and lowest gastric pH measurements during
omeprazole administration (6.8.+-.0.6 and 5.6.+-.1.3, respectively)
were also statistically significant (p<0.001).
[0223] Safety:
[0224] Omeprazole solution was well tolerated in this group of
critically ill patients. Only one patient with sepsis experienced
an adverse event that may have been drug-related thrombocytopenia.
However, the platelet count continued to fall after omeprazole was
stopped. The platelet count then returned to normal despite
reinstitution of omeprazole therapy. Of note, one patient on a jet
ventilator continuously expelled all liquids placed in her stomach
up and out through her mouth, and thus was unable to continue on
omeprazole. No clinically significant drug interactions with
omeprazole were noted during the study period. As stated above,
metabolic alkalosis is a potential concern in patients receiving
sodium bicarbonate. However, the amount of sodium bicarbonate in
omeprazole solution was small (.apprxeq.12 mEq/10 ml) and no
electrolyte abnormalities were found.
[0225] Pneumonia:
[0226] Pneumonia developed in nine (12%) patients receiving
omeprazole solution. Pneumonia was present in an additional five
patients before the start of omeprazole therapy.
[0227] Pharmacoeconomic Evaluation:
[0228] The average length of treatment was nine days. The cost of
care data are listed in Tables 3 and 4. The costs of drug
acquisition, preparation, and delivery for some of the traditional
agents used in the prophylaxis of stress-related upper
gastrointestinal bleeding are listed in Table 3. There were no
costs to add from toxicity associated with omeprazole solution.
Since two of seventy-five patients required 40 mg of omeprazole
solution daily to adequately control gastric pH, the
acquisition/preparation cost should reflect this. The additional 20
mg of omeprazole with vehicle adds seven cents per day to the cost
of care. Therefore, the daily cost of care for omeprazole solution
in the prophylaxis of stress-related mucosal bleeding was $12.60
(See Table 4).
[0229] Omeprazole solution is a safe and effective therapy for the
prevention of clinically significant stress-related mucosal
bleeding in critical care patients. The contribution of many risk
factors to stress-related mucosal damage has been challenged
recently. All of the patients in this study had at least one risk
factor that has clearly been associated with stress-related mucosal
damage--mechanical ventilation. Previous trials and data from a
recently published study show that stress ulcer prophylaxis is of
proven benefit in patients at risk and, therefore, it was thought
to be unethical to include a placebo group in this study. No
clinically significant upper gastrointestinal bleeding occurred
during omeprazole solution therapy. Gastric pH was maintained above
4 on omeprazole 20 mg/day in seventy-three of seventy-five
patients. No adverse events or drug interaction associated with
omeprazole were encountered.
12TABLE 2 Mech Major Head Renal Multiple Acid/ Liver Vent Surgery
Multitrauma Injury Hypotension Failure Sepsis Operation Base Coma
Failure Burn 75 61 35 16 14 14 14 12 10 4 2 2 Risk factors present
in patients in this study (n = 75)
[0230]
13 TABLE 3 Per day RANITIDINE (day-9) Rantidine 150 mg/24 hr 6.15
Ancillary Product (1) Piggyback (60%) 0.75 Ancillary Product (2)
micro tubing (etc.) 2.00 Ancillary Product (3) filter .40 Sterile
Prep required yes R.N. time ($24/hr) 20 minutes/day (includes pH
8.00 monitoring) R.Ph. time, hood maint. 3 minutes ($40/hr) 2.00
Pump cost $29/24 hrs .times. 50%) 14.50 TOTAL for 9 days
.quadrature. 304.20 RANITIDINE Cost per day .quadrature. 33.80
CIMETIDINE (day 1-9) Cimetidine 900 mg/24 hr 3.96 Ancillary Product
(1) Piggyback 1.25 Ancillary Product (2) micro tubing (etc.) 2.00
Ancillary Product (3) filter .40 Sterile Prep required yes R.N.
time ($24/hr) 20 minutes/day (includes pH 8.00 monitoring) R.Ph.
time, hood maint. 3 minutes ($40/hr) 2.00 Pump cost $29/24 hrs
.times. 50%) 14.50 TOTAL for 9 days .quadrature. 288.99 CIMETIDINE
Cost per day .quadrature. 32.11 SUCRALFATE (day 1-9) Sucralfate 1
Gm .times. 4 2.40 Ancillary Product (1) syringe .20 Sterile Prep
required no R.N. time ($24/hr) 30 minutes/day (includes pH 12.00
monitoring) TOTAL for 9 days .quadrature. 131.40 SUCRALFATE Cost
per day .quadrature. 14.60 Note: Does not include the cost of
failure and/or adverse effect. Acquisition, preparation and
delivery costs of traditional agents.
[0231]
14TABLE 4 The average length of treatment was 9 days. Cost of care
was calculated from these date Per Day Total OMEPRAZOLE (day 1)
Product acquisition cost 40 mg load .times. 2 5.66/dose) 11.32
11.32 Ancillary product materials for solution preparation 0.41
0.41 Ancillary product syringe w/needle 0.20 0.40 Sterile
preparation required no SOS preparation time (R.N.) 6 minutes 2.40
4.80 R.N. time ($24/hr) 21 minutes/day (includes pH monitoring)
8.40 8.40 OMEPRAZOLE (days 2-9) Product acqusition cost 20 mg per
day 2.80 22.65 Ancillary product materials for solution preparation
0.41 0.82 Ancillary product syringe w/needle 0.20 1.60 Sterile
preparation required no SOS preparation time (R.N.) 6 minutes 2.40
4.80 R.N. time ($24/hr) 18 minutes/day (includes pH monitoring)
8.40 57.60 2/75 patient require 40 mg simplified omeparzole
solution per day (days 2-9) 0.63 No additional cost for adverse
effects or for failure TOTAL.quadrature. 113.43 Simplified
Omerprazole Solution cost per day .quadrature. 12.60
Pharmacoeconomic evaluation of omeprazole cost of care
[0232]
15 TABLE 5 Time Control 1 hour 24 hour 2 day 7 day 14 day Conc
(mg/ml) 2.01 2.07 1.94 1.96 1.97 1.98 Stability of Simplified
Omeprazole Solution at room temperature (25.degree. C.) Values are
the mean of three samples
EXAMPLE X
[0233] Bacteriostatic and Fungistatic Effects of Omeprazole
Solution
[0234] The antimicrobial or bacteriostatic effects of the
omeprazole solution were analyzed by applicant. An omeprazole
solution (2 mg/ml of 8.4% sodium bicarbonate) made according to the
present invention was stored at room temperature for four weeks and
then was analyzed for fungal and bacterial growth. Following four
weeks of storage at room temperature, no bacterial or fungal growth
was detected.
[0235] An omeprazole solution (2 mg/ml of 8.4% sodium bicarbonate)
made in accordance with the present invention was stored at room
temperature for twelve weeks and then was analyzed for fungal and
bacterial growth. After twelve weeks of incubation at room
temperature, no fungal or bacterial growth was detected.
[0236] The results of these experiments illustrate the
bacteriostatic and fungistatic characteristics of the omeprazole
solution of the present invention.
EXAMPLE XI
[0237] Bioequivalency Study
[0238] Healthy male and female study participants over the age of
18 will be randomized to receive omeprazole in the following
forms:
[0239] (a) 20 mg of a liquid formulation of approximately 20 mg
omeprazole in 4.8 mEq sodium bicarbonate qs to 10 ml with
water;
[0240] (b) 20 mg of a liquid formulation of approximately 2 mg
omeprazole per 1 ml of 8.4% sodium bicarbonate.
[0241] (c) Prilosec.RTM. (omeprazole) 20 mg capsule;
[0242] (d) Capsule prepared by inserting the contents of an
omeprazole 20 mg capsule into a #4 empty gelatin capsule (Lilly)
uniformly dispersed in 240 mg of sodium bicarbonate powder USP to
form an inner capsule. The inner capsule is then inserted into a
#00 empty gelatin capsule (Lilly) together with a homogeneous
mixture of 600 mg sodium bicarbonate USP and 110 mg pregelatinized
starch NF.
[0243] METHODOLOGY:
[0244] After appropriate screening and consent, healthy volunteers
will be randomized to receive one of the following four regimens as
randomly assigned by Latin Square. Each subject will be crossed to
each regimen according to the randomization sequence until all
subjects have received all four regimens (with one week separating
each regimen).
[0245] Regimen A (20 mg omeprazole in 4.8 mEq sodium bicarbonate in
10 ml volume); Regimen B (20 mg omeprazole in 10 ml 8.4% sodium
bicarbonate in 10 ml volume); Regimen C (an intact 20 mg omeprazole
capsule); Regimen D (Capsule in capsule formulation, see above).
For each dose/week, subjects will have an i.v. saline lock placed
for blood sampling. For each regimen, blood samples will be taken
over 24 hours a total of 16 times (with the last two specimens
obtained 12 hours and 24 hours after drug administration).
[0246] Patient Eligibility
[0247] Four healthy females and four healthy males will be
consented for the study.
[0248] Inclusion Criteria
[0249] Signed informed consent.
[0250] Exclusion Criteria
[0251] 1. Currently taking H.sub.2-receptor antagonist, antacid, or
sucralfate.
[0252] 2. Recent (within 7 days) therapy with lansoprazole,
omeprazole, or other proton pump inhibitor.
[0253] 3. Recent (within 7 days) therapy with warfarin.
[0254] 4. History of variceal bleeding.
[0255] 5. History of peptic ulcer disease or currently active G.I.
bleed.
[0256] 6. History of vagotomy or pyloroplasty.
[0257] 7. Patient has received an investigational drug within 30
days.
[0258] 8. Treatment with ketoconazole or itraconazole.
[0259] 9. Patient has an allergy to omeprazole.
[0260] Pharmocokinetic Evaluation and Statistical Analysis
[0261] Blood samples will be centrifuged within 2 hours of
collection and the plasma will then separated and frozen at
-10.degree. C. (or lower) until assayed. Pharmacokinetic variables
will include: time to peak concentration, mean peak concentration,
AUC (0-t) and (0-infinity). Analysis of variance will be used to
detect statistical difference. Bioavailability will be assessed by
the 90% confidence interval of the two one-sided tests on the
natural logarithm of AUC.
[0262] HPLC Analysis
[0263] Omeprazole and internal standard (H168/24) will be used.
Omeprazole and internal standard will be measured by modification
of the procedure described by Amantea and Narang. (Amantea M A,
Narang P K. Improved Procedure for Quantification of Omeprazole and
Metabolites Using Reversed-Phased High Performance Liquid
Chromotography. J. CHROMATOGRAPHY 426; 216-222. 1988). Briefly, 20
ul of omeprazole 2 mg/ml NaHCO.sub.3 or Choco-Base omeprazole
suspension and 100 ul of the internal standard are vortexed with
150 ul of carbonate buffer (pH=9.8), 5 ml of dichloroethane, 5 ml
of hexane, and 980 ul of sterile water. After the sample is
centrifuged, the organic layer is extracted and dried over a
nitrogen stream. Each pellet is reconstituted with 150 ul of mobile
phase (40% methanol, 52% 0.025 phosphate buffer, 8% acetonitrile,
pH=7.4). Of the reconstituted sample, 75 ul is injected onto a
C.sub.18 5 U column equilibrated with the same mobile phase at 1.1
ml/min. Under these conditions, omeprazole is eluted at
approximately 5 minutes, and the internal standard at approximately
7.5 minutes. The standard curve is linear over the concentration
range 0-3 mg/ml (in previous work with SOS), and the between-day
coefficient of variation has been <8% at all concentrations. The
typical mean R2 for the standard curve has been 0.98 in prior work
with SOS (omeprazole 2 mg/ml NaHCO.sub.3 8.4%).
[0264] Applicant expects that the above experiments will
demonstrate there is more rapid absorption of formulations (a), (b)
and (d) as compared to the enteric coated granules of formulation
(c). Additionally, applicant expects that although there will be a
difference in the rates of absorption among forms (a) through (d),
the extent of absorption (as measured by the area under the curve
(AUC)) should be similar among the formulations (a) through
(d).
EXAMPLE XII
[0265] Intraveneous PPI in Combination With Oral Parietal Cell
Activator
[0266] Sixteen (16) normal, healthy male and female study subjects
over the age of 18 will be randomized to receive pantoprazole as
follows:
[0267] (a) 40 mg IV over 15 to 30 minutes in combination with a 20
ml oral dose of sodium bicarbonate 8.4%; and
[0268] (b) 40 mg IV over 15 to 30 minutes in combination with a 20
ml oral dose of water.
[0269] The subjects will receive a single dose of (a) or (b) above,
and will be crossed-over to (a) and (b) in random fashion. Serum
concentrations of pantoprazole versus time after administration
data will be collected, as well as gastric pH control as measured
with an indwelling pH probe.
[0270] Further, similar studies are contemplated wherein chocolate
or other parietal cell activator is substituted for the parietal
cell activator sodium bicarbonate, and other PPIs are substituted
for pantoprazole. The parietal cell activator can be administered
either within about 5 minutes before, during or within about 5
minutes after the IV dose of PPI.
[0271] Applicant expects that these studies will demonstrate that
significantly less IV PPI is required to achieve therapeutic effect
when it is given in combination with an oral parietal cell
activator.
[0272] Additionally, administration kits of IV PPI and oral
parietal cell activator can be packaged in many various forms for
ease of administration and to optimize packing and shipping the
product. Such kits can be in unit dose or multiple dose form.
EXAMPLE XIII
[0273] Twelve (12) Month Stability of Omeprazole Solution
[0274] A solution was prepared by mixing 8.4% sodium bicarbonate
with omeprazole to produce a final concentration of 2 mg/ml to
determine the stability of omeprazole solution after 12 months. The
resultant preparation was stored in clear glass at room
temperature, refrigerated and frozen. Samples were drawn after
thorough agitation from the stored preparations at the prescribed
times. The samples were then stored at 70.degree. C. Frozen samples
remained frozen until they were analyzed. When the collection
process was completed, the samples were shipped to a laboratory
overnight on dry ice for analysis. Samples were agitated for 30
seconds and sample aliquots were analyzed by HPLC in triplicate
according to well known methods. Omeprazole and the internal
standard were measured by a modification of the procedure described
by Amantea and Narang. Amantea M A, Narang P K, Improved Procedure
For Quantitation Of Omeprazole And Metabolites Using Reverse-Phased
High-Performance Liquid Chromatography, J. Chromatography, 426:
216-222 (1988). Twenty (20) ul of the omeprazole 2 mg/ml
NaHCO.sub.3 solution and 100 ul of the internal standard solution
were vortexed with 150 ul of carbonate buffer (pH=9.8), 5 ml
dichloroethane, 5 ml hexane, and 980 ul of sterile water. The
sample was centrifuged and the organic layer was extracted and
dried over a nitrogen stream. Each pellet was reconstituted with
150 ul of mobile phase (40% methanol, 52% 0.025 phosphate buffer,
8% acetonitrile, pH=7.4). Of the reconstituted sample, 75 ul were
injected onto a C185u column equilibrated with the same mobile
phase at 1.1 ml/min. Omeprazole was eluted at .about.5 min, and the
internal standard at .about.7.5 min. The standard curve was linear
over the concentrated range 0-3 mg/ml, and between-day coefficient
of variation was <8% at all concentrations. Mean R2 for the
standard curve was 0.980.
[0275] The 12 month sample showed stability at greater than 90% of
the original concentration of 2 mg/ml. (i.e., 1.88 mg/ml, 1.94
mg/ml, 1.92 mg/ml).
[0276] Throughout this application various publications and patents
are referenced by citation and number. The disclosure of these
publications and patents in their entireties are hereby
incorporated by reference into this application in order to more
fully describe the state of the art to which this invention
pertains.
[0277] The invention has been described in an illustrative manner,
and it is to be understood the terminology used is intended to be
in the nature of description rather than of limitation. Obviously,
many modifications, equivalents, and variations of the present
invention are possible in light of the above teachings. Therefore,
it is to be understood that within the scope of the appended
claims, the invention may be practiced other than as specifically
described.
* * * * *