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

"The patent describes a controlled-release Galenical preparation of the drug Dilfiazem, which can be taken once a day for blood pressure control. The preparation is designed to release the drug slowly and evenly over a period of time, providing a consistent level in the blood. The release rate is measured using a specific method, and the preparation is tested in humans to ensure that it works properly. The preparation can be made in tablet or capsule form, and may contain microgranules or pellets to achieve the controlled release. The microporous membrane used in the preparation helps to maintain the solubility of the drug and is hydrated by the gastrointestinal tract. The technical effect of this patent is to provide a reliable and effective treatment for blood pressure control with a single daily dose of Dilfiazem."

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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