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.

Description

FIELD OF INVENTION[0001]This invention relates to once daily preparations comprising Diltiazem and pharmaceutically acceptable salts thereof, such as the hydrochloride salt, suitable for evening administration to patients suffering hypertension and / or angina. This invention also relates to a method for evening administration of such once daily preparations to patients for the treatment and prevention of the patients' myocardial ischemia and angina.BACKGROUND OF THE INVENTION[0002]Diltiazem, a benzothiazepine, is an orally active calcium channel blocker (calcium-antagonist) with relatively high selectivity for vascular smooth muscle that is effective in the treatment of hypertension and angina pectoris. Today, persons having these conditions take prescribed once daily preparations of Diltiazem generally to maintain constant levels of the drug in the body over a 24-hour period. Until recently the timing of the taking of the medicine wasn't considered an important consideration by the ...

AI Technical Summary

Benefits of technology

[0035]Where the preparation comprises microgranules or pellets (for example) in the capsule or tablet (made, for example, by compressing the microgranules (with preferably wax placebo beads)), the central core may comprise Diltiazem or a pharmaceutically acceptable salt thereof associated with a wetting agent. The Diltiazem may be mixed (in whole or in part) with the wetting agent or may not be mixed with the wetting agent. The wetting agent assists to maintain the solubility. of the Diltiazem in each microgranule, ensuring that the solubility of the Diltiazem is unaffected by the pH of the gastrointestinal tract or other adverse conditions which each of the microgranules of the preparation will meet in the gastrointestinal tract.

[0039]Instead of the wetting agent, any other suitable dissolution agent may be used to assist the release of the Diltiazem from the preparation. For example, instead of the preferred surface active (wetting) agent (surfactant), an organic acid (such as adipic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid, tartaric acid and the like) may be incorporated in the core. In this regard, the presence of the organic acid in the core permits the diltiazem in the core to dissolve when the composition passes into the higher pH regions of the gastrointestinal tract of the intestine at which pH diltiazem is much less soluble.

[0043]According to another aspect of the invention, there is provided a controlled-release Galenical preparation (such as a tablet and a capsule) of pharmaceutically acceptable Diltiazem including the pharmaceutically acceptable salts thereof, such as the hydrochloride salt, suitable for evening dosing every 24 hours containing from about 120 mg to about 540 mg or more (as desired) 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 15 hours (preferably about 11-about 13 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 bioavailabibty 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 food (such as a standardized FDA breakfast) and without food according to the same FDA guidelines or criteria.

[0099]a covered vessel made of glass or other inert, transparent material1; a motor; a metallic drive shaft; and a cylindrical basket. The vessel is partially immersed in a suitable water bath of any convenient size that permits holding the temperature inside the vessel at 37±0.5° during the test and keeping the bath fluid in constant, smooth motion. No part of the assembly, including the environment in which the assembly is placed, contributes significant motion, agitation, or vibration beyond that due to the smoothly rotating stirring element Apparatus that permits observation of the specimen and stirring element during the test is preferable. The vessel is cylindrical, with a hemispherical bottom. It is 160 to 175 mm high, its inside diameter is 98 to 106 mm, and its nominal capacity is 1000 mL. Its sides are flanged at the top. A fitted cover may be used to retard evaporation.2 The shaft is positioned so that its axis is not more than 2 mm at any point from the vertical axis of the vessel and rotates smoothly and without significant wobble. A speed-regulating device is used that allows the shaft rotation speed to be selected and maintained at the rate specified in the individual monograph, within ±4%. 1The materials should not sorb, react, or interfere with the specimen being tested.2 If a cover is used, it provides sufficient openings to allow ready insertion of the thermometer and withdrawal of specimens.

[0106]a covered vessel made of glass or other inert, transparent material1; a motor; a metallic drive shaft; and a cylindrical basket. The vessel is partially immersed in a suitable water bath of any convenient size that permits holding the temperature inside the vessel at 37±0.5° during the test and keeping the bath fluid in constant, smooth motion. No part of the assembly, including the environment in which the assembly is placed, contributes significant motion, agitation, or vibration beyond that due to the smoothly rotating stirring element. Apparatus that permits observation of the specimen and stirring element during the test is preferable. The vessel is cylindrical, with a hemispherical bottom. It is 160 to 175 mm high, its inside diameter is 98 to 106 mm, and its nominal capacity is 1000 mL. Its sides are flanged at the top. A fitted cover may be used to retard evaporation.2 The shaft is positioned so that its axis is not more than 2 mm at any point from the vertical axis of the vessel and rotates smoothly and without significant wobble. A speed-regulating device is used that allows the shaft rotation speed to be selected and maintained at the rate specified in the individual monograph, within ±4%. 1 The materials should not sorb, react, or interfere with the specimen being tested.2 If a cover is used, it provides sufficient openings to allow ready insertion of the thermometer and withdrawal of specimens.

Problems solved by technology

However a careful review of the report shows inconsistencies which cannot support the authors' conclusions.

Moreover at page 82, the authors themselves acknowledge the study cannot lead to reliable conclusions “because the number of patients was too small”.

Further, an immediate release portion of the dosage in the order of 15% is not desirable for evening administration.

When the blood pressure is naturally at its lowest, not only is there no need for further reduction at that time, but such reduction can harm the patient.

Particularly, if the blood pressure is reduced below a minimum the patient is put at a greater risk for cardiovascular accidents including stroke.

Further, the 15% immediate release diltiazem is no longer available when needed.

According to Searle Canada, simply changing the time you take the drug your physician has prescribed will not provide the same safety and effectiveness that is designed specially for chronotherapy using veraparnil.

According to Searle Canada, the prior formulations do not take into account the natural circadian variations in the body's physiological functions.

They appear not to give the benefits meant to be achieved by chronotherapy.

Nothing in these patents teach formulations suitable as chronotherapeutics.

Unfortunately, the proposed system covers only the period from 2:00 a.m. to 8:00 a.m.

Moreover, this formulation when given at night leads to significantly lower bioavailability than if given in the morning.

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