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⁺,K⁺-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.

Description

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 H2 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 (or as a product for reconstitution), and are prescribed for short-term treatment of active duodenal ulcers,...

AI Technical Summary

Benefits of technology

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 and / or after the intravenous administration of the proton pump inhibitor.

Problems solved by technology

These above-listed conditions commonly arise in healthy or critically ill patients, and may be accompanied by significant upper gastrointestinal bleeding.

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.

H2-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.

Regardless of the risk type, stress-related mucosal damage results in significant morbidity and mortality.

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.

Controversy remains regarding pharmacologic intervention to prevent stress-related bleeding 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, H2-antagonists fall short of being the optimal pharmacotherapeutic agents for preventing of stress-related mucosal bleeding.

ENGL. J. MED., 317: 1376-1382 1987)), but data on critical care patients with head injury, trauma, or burns are limited.

In an attempt to identify optimal therapy, cost of care becomes an issue.

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.

Although these drugs are stable at alkaline pH, they are destroyed rapidly as pH falls (e.g., by gastric acid).

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.

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.

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.

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.

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.

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.

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 ingestion of large amounts of sodium bicarbonate is inconsistent with this advice.

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.

Fifth, excessive antacid intake (such as sodium bicarbonate) can result in drug interactions that produce serious adverse effects.

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.

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.

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.

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