Chronotherapeutic diltiazem formulations and the administration thereof

Abstract

A method of treating or preventing myocardial ischemia in a patient in need thereof comprising administration of a controlled-release Galenical preparation of pharmaceutically acceptable Diltiazem including the pharmaceutically acceptable salts thereof, suitable for evening dosing every 24 hours containing from about 180 mg to about 420 mg of the form of Diltiazem associated with excipients to provide controlled (sustained) release of the form of Diltiazem for providing a Cmax of diltiazem in the blood at between about 10 hours and about 17 hours after administration, the preparation comprising the form of Diltiazem in oral sustained-release dosage form in which the Diltiazem is adapted to be released after administration over a prolonged period of time and exhibits when given to humans (i) a higher bioavailability when given at night compared to when given in the morning without food according to FDA guidelines or criteria and (ii) bioequivalence when given in the morning with and without food according to the same FDA guidelines or criteria.

1 . A method of treating myocardial ischemia in a patient in need thereof comprising administration of a once daily controlled-release galenical preparation to the patient, wherein the preparation comprises from about 180 mg to about 420 mg of a pharmaceutically acceptable form of diltiazem and one or more excipients, the preparation providing controlled release of the pharmaceutically acceptable form of diltiazem such that the preparation provides a Cmax of diltiazem in the blood at between about 10 hours and about 17 hours after administration of the preparation; and wherein the pharmaceutically acceptable form of diltiazem is released from the preparation
 (i) into an aqueous medium at the following rates measured using the method of United States Pharmacopoeia No. XXIII at 100 rpm in 900 ml of water:
 (a) between about 1% and about 15% after 2 hours; 
 (b) between about 7% and about 35% after 4 hours; 
 (c) between about 30% and about 58% after 8 hours; 
 (d) between about 55% and about 80% after 14 hours; and 
 (e) and in excess of about 75% after 24 hours; or 
   (ii) into a buffered medium having a pH between about 5.5 and about 6.5 at the following rates measured using the method of United States Pharmacopoeia No. XXIII at 100 rpm in 900 ml of the buffered medium:
 (a) between about 1% and about 25% after about 2 hours; 
 (b) between about 7% and about 45% after about 4 hours; 
 (c) between about 30% and about 68% after about 8 hours; 
 (d) in excess of about 75% after about 24 hours. 
   
     
     
         2 . The method of  claim 1  wherein the pharmaceutically acceptable form of diltiazem is released from the preparation
 (i) into an aqueous medium at the following rates measured using the method of United States Pharmacopoeia No. XXIII at 100 rpm in 900 ml of water:
 (a) between about 4% and about 8% after 2 hours; 
 (b) between about 16% and about 21% after 4 hours; 
 (c) between about 44% and about 52% after 8 hours; 
 (d) between about 69% and about 76% after 14 hours; and 
 (e) in excess of about 85% after 24 hours; or 
   (ii) into a buffered medium having a pH of about 5.8 at the following rates measured using the method of United States Pharmacopoeia No. XXIII at 100 rpm in 900 ml of the buffered medium:
 (a) between about 4% and about 15% after about 2 hours; 
 (b) between about 16% and about 30% after about 4 hours; 
 (c) between about 44% and about 62% after about 8 hours; 
 (d) in excess of about 80% after 24 hours. 
   
     
     
         3 . The method of  claim 1  wherein the Cmax of diltiazem in the blood is obtained between about 11 and about 13 hours after administration of the preparation. 
     
     
         4 . The method of  claim 1  wherein the controlled release preparation exhibits, when administered to a human:
 (i) a higher bioavailability when given at night compared to when administered in the morning without food and   (ii) bioequivalence when administered in the morning with food and without food.   
     
     
         5 . The method of  claim 1  wherein the preparation releases the pharmaceutically acceptable form of diltiazem at a rate of less than about 15% of the total amount of active per hour during dissolution. 
     
     
         6 . The method of  claim 1  wherein the preparation is administered to the patient in the evening for effective treatment of the patient's myocardial ischemia the next morning. 
     
     
         7 . The method of  claim 1  wherein the preparation is administered to the patient in the evening for effective treatment of the patient's myocardial ischemia over a twenty-four hour period. 
     
     
         8 . The method of  claim 1  wherein the preparation comprises about 180 mg of Diltiazem. 
     
     
         9 . The method of  claim 1  wherein the preparation comprises about 360 mg of Diltiazem. 
     
     
         10 . The method of  claim 1  wherein the preparation comprises about 420 mg of Diltiazem. 
     
     
         11 . The method of  claim 1  wherein the method of treating myocardial ischemia in a patient in need thereof reduces the incidence of myocardial ischemia in the patient. 
     
     
         12 . The method of  claim 1  wherein the preparation is a diffusion controlled preparation. 
     
     
         13 . The method of  claim 1  wherein the preparation is in the form of a tablet. 
     
     
         14 . The method of  claim 13  wherein the tablet is uncoated. 
     
     
         15 . The method of  claim 13  wherein the tablet is coated. 
     
     
         16 . The method of  claim 15  wherein the tablet is coated with a sustained release coating. 
     
     
         17 . The method of  claim 1  wherein the preparation is in the form of a capsule. 
     
     
         18 . The method of  claim 1  wherein pharmaceutically acceptable form of diltiazem is a pharmaceutically acceptable salt of diltiazem. 
     
     
         19 . The method of  claim 1  wherein pharmaceutically acceptable form of diltiazem is diltiazem hydrochloride. 
     
     
         20 . The method of  claim 1  wherein the preparation is adapted for administration to the patient in the evening for effective treatment of the patient's myocardial ischemia the next morning.