Sustained release formulations of lorazepam

Abstract

A pharmaceutical composition for delivering lorazepam in a prolonged fashion is achieved with prolonged release lorazepam pharmaceutical beads. The composition typically contains sustained release lorazepam beads and delayed sustained release lorazepam beads. The composition can provide once daily dosing that maintains 24 hour therapeutic effect under steady state conditions.

Description

[0001]The present application claims the benefit of priority under 35 U.S.C. §119(e) from prior U.S. provisional patent application No. 61 / 750,797, filed on Jan. 9, 2013 and from prior U.S. provisional patent application No. 61 / 762,833, filed on Feb. 8, 2013; the entire contents of each provisional application being incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]The present invention relates to sustained release formulations of lorazepam and to methods of treating patients with a once-a-day dose of lorazepam.[0003]Lorazepam is the generic name for the active pharmaceutical ingredient ±7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one, which has the following structure:Like other benzodiazepines, lorazepam has CNS activity and has proven to be a useful treatment for anxiety related disorders, such as: General Anxiety Disorder or Anxiety associated with Major Depression and others. It is almost insoluble in water. This compound was disclos...

AI Technical Summary

Benefits of technology

[0009]Another aspect of the invention relates to a sustained release lorazepam pharmaceutical composition, which comprises lorazepam prolonged release beads in sufficient amount and duration that in a single dose pharmacokinetic study, said composition has a pharmacokinetic profile that comprises a Tmax at 4 hours or longer and continued absorption of lorazepam beyond 20 hours, preferably for at least 24 hours, more preferably for at least 28 hours, and still more preferably for at least 30 hours; said composition being an oral dosage form containing 0.5 to 10 mg of lorazepam. The composition when administered once daily to a patient, maintains a therapeutic effect for at least 24 hours By providing a prolonged release dosage form that achieves prolonged absorption, lorazepam can accumulate in the blood plasma and provide favorable steady state pharmacokinetic profiles.

Problems solved by technology

While the immediate release tablets of lorazepam, with a multi-dose per day regimen, have been available for several decades, thus far no once-a-day dosage form has been commercially introduced.

But the relative bioavailability was reduced in the sustained release tablet such that after 30 hours the AUC was only about 85% of the AUC achieved with the immediate release tablets.

Abrams et al. also noted that “the [serum] concentrations of both formulations were similar between 10 and 30 h[ours].” Thus, despite providing some delay in the rise of lorazepam serum concentrations and a lower Cmax, the sustained release tablet apparently did not serve to extend the therapeutic duration of lorazepam beyond that achieved with immediate release tablets.

But administering a complete daily dose in a single immediate release dosage form would increase the Cmax and the peak-trough variations (concentration differences between Cmax and Cmin) beyond those attained in conventional b.i.d. administration (i.e., twice-daily dosing), and thus would likely increase the risk of drug related adverse events, i.e., side effects.

Using a sustained release formulation can reduce the rate of increase in plasma drug concentration and the value of Cmax, but runs the risk of sub-therapeutic plasma concentration levels, especially near the end of the dosing cycle, and / or lower overall drug exposure than the current b.i.d. immediate release tablet regimen.

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