United States Patent:   5,980,951

Assignee:  Merck & Co., Inc. (Rahway, NJ)

Filed:  April 8, 1997

An oral drug dosage unit, for administration to a patient, having active drug, and an effective diameter and surface composition sufficient for the unit to be transported from the stomach into the duodenum following substantially complete emptying of chyme from the stomach into the intestine and prior to release of active drug from the unit, wherein the active drug has an absorption rate that is substantially affected by the coinciding presence of food in the stomach, the effective diameter of the unit prevents gastric emptying of the unit prior to gastric emptying of chyme, and the surface composition is an enteric coating which prevents release of the active drug in the stomach and allows release of the active drug in the intestine.

SUMMARY OF THE INVENTION

The invention is an oral, coated pharmaceutical composition suitable for administration to a patient. The coated compositions comprise an active drug, suitable solid oral dosage form pharmaceutical excipients, and a suitable protective enteric coating surrounding the active drug and pharmaceutical excipients. The suitable coating prevents release from the composition of active drug while the coated composition is located in the stomach, and provides for release of the active drug following transfer of the composition from the stomach to the intestine.

The compositions have sufficient effective diameter to prevent gastric emptying of the composition from the stomach into the duodenum until gastric emptying of chyme from the stomach is completed.

The compositions are specifically designed to prevent interaction of the active drug with food. While the compositions remain in the stomach, food is converted in the stomach to chyme and then transported to the duodenum. Only after gastric emptying of the chyme does the composition leave the stomach and enter the duodenum. The active drug is then released from the coated composition into the intestine.

The compositions include a coated medicament having releasability of the active drug only in the intestine having an inner core and an outer coating, wherein the inner core comprises active drug and one or more suitable pharmaceutically acceptable excipients, and wherein the outer coating does not substantially dissolve in the stomach and does substantially dissolve in the intestine.

The invention also includes a method for preventing interaction between food and an active drug whose absorption is affected by the presence of food, which comprises administering to the patient an oral, coated pharmaceutical composition of the invention which releases the active drug into the intestine after food has been digested.

The active drug can be a fibrinogen receptor antagonist suitable for administration to a patient in need of therapy for inhibiting platelet aggregation. The coated compositions of the invention thus may comprise an inhibitor of fibrinogen binding to the GP IIb/IIIa receptor, suitable solid oral dosage form pharmaceutical excipients, and a suitable protective enteric coating surrounding the inhibitor and pharmaceutical excipients. The suitable coating prevents release from the composition of the fibrinogen receptor antagonist while the coated composition is located in the stomach, and provides for release of the fibrinogen receptor antagonist following transfer of the composition from the stomach to the intestine. This only occurs after the food has been digested and eliminated from the stomach.

The invention also includes the use of a composition of the invention in the manufacture of a medicament for reducing the risk of acute coronary ischemic syndrome in patients at risk to acute coronary ischemic syndrome, in a mammal.

The compositions are particularly useful for reducing the risk of acute coronary ischemic syndrome in patients at risk to acute coronary ischemic syndrome. The compositions minimize the risk associated with oral fibrinogen receptor antagonists that interact with food, and provide a safer means for treating patients in need of fibrinogen receptor antagonists.

The invention also includes a composition in the manufacture of a medicament for preventing, in a patient, interaction between food and an active drug, the absorption rate of which drug is substantially affected by the coinciding presence of food in the stomach.

Claim 1 of 8 Claims

1. An oral dosage unit, for administration to a patient, having a therapeutically effective amount of a fibrinogen receptor antagonist, and an effective diameter and surface composition sufficient for the oral drug dosage unit to be transported from the stomach into the duodenum following substantially complete emptying of chyme from the stomach into the duodenum and prior to release of fibrinogen receptor antagonist from the oral drug dosage unit, wherein:

a) the fibrinogen receptor antagonist has an absorption rate that is affected by the coinciding presence of food in the stomach;

b) the effective diameter of the oral drug dosage unit prevents gastric emptying of the oral drug dosage unit prior to gastric emptying of chyme; and

c) the surface composition is an enteric coating which prevents release of the fibrinogen receptor antagonist in the stomach and allows release of the fibrinogen receptor antagonist in the intestine,

wherein the fibrinogen receptor antagonist is selected from the group consisting of 2(S)-[(p-Toluenesulfonyl)amino]-3-[[[5,6,7,8-tetrahydro-4-oxo-5-[2-(piperi din -4-yl)ethyl]-4H -pyrazolo-[1,5-.alpha.][1,4]diazepin-2-yl]carbonyl]amino]propionic acid, (R)-methyl-3-[[[3-[4-(aminoiminomethyl)phenyl]-4,5-dihydro-5-isoxazolyl]ac etyl]amino]-N-butoxycarbonyl)-L-alanine monoacetate and Ethyl 3-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino-4-pentynoat e and pharmaceutically acceptable salts thereof.

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