Substituted benzimidazole dosage forms and method of using same

Details Substituted benzimidazole dosage forms and method of using same Substituted benzimidazole dosage forms and method of using same

2001-07-09

2003-11-11

Fan, Jane (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S273700, C548S307100, C514S395000

Reexamination Certificate

active

06645988

ABSTRACT:

TECHNICAL FIELD
The present invention relates to pharmaceutical preparations comprising substituted benzimidazole proton pump inhibitors.
BACKGROUND OF THE INVENTION
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
2
histamine antagonist properties. Drugs of this class suppress gastric acid secretion by the specific inhibition of the H
+
,K
+
-ATPase enzyme system (proton pump) at the secretory surface of the gastric parietal cell.
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 (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 symptomatic 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.
H
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
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.
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.
Omeprazole (Prilosec®), lansoprazole (Prevacid®) and other PPIs reduce gastric acid production by inhibiting H
+
,K
+
-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
+
,K
+
-
ATPase
, Nature, 290:159-161(1981); Wallmark et al,
The Relationship Between Gastric Acid Secretion and Gastric H
+
,K
+
-
ATPase Activity
, J. Biol.Chem., 260: 13681-13684 (1985); Fryklund et al.,
Function and Structure of Parietal Cells After H
+
,K
+
-ATPase Blockade
, Am. J. Physiol., 254 (3 PT 1); G399-407 (1988)).
PPIs contain a sulfinyl group in a bridge between substituted benzimidazole and pyridine rings, as illustrated below.
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
+
,K
+
-ATPase (Hardman et al.,
Goodman
&
Gilman's The Pharmacological Basis of Therapeutics,
p. 907 (9
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
+
,K
+
-ATPase; (b) the requirement for acidic conditions to catalyze generation of the reactive inhibitor; and (c) the trapping of the protonated drug and the cationic sulfenamide within the acidic canaliculi and adjacent to the target enzyme. (Hardman et al., 1996).
Omeprazole and lansoprazole are available for oral administration as enteric-coated granules in gelatin capsules. Other proton pump inhibitors such as rabeprazole and pantoprazole are supplied as enteric-coated dosage forms. The enteric dosage forms of the prior art have been employed because they are acid labile; thus, it is important that these drugs not be exposed to low pH 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 micro-encapsulation or the enteric coating is disrupted (e.g., trituration to compound a liquid, or chewing the capsule), the dosage forms of the prior art will be exposed to degradation by the gastric acid in the stomach.
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

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