Stabilization of quinapril using magnesium oxide

Abstract

The present invention is directed to ACE inhibitor-containing compositions stabilized by the presence of magnesium oxide. Preferably, the ACE inhibitor, quinapril, is protected from certain forms of degradation when prepared in a pharmaceutical composition consisting essentially of magnesium oxide as the stabilizing agent. The presence of magnesium oxide also lends itself to favorable processing conditions during the manufacture of ACE inhibitor-containing compositions, especially processing by wet granulation.

Description

FIELD OF THE INVENTION [0001] The present invention is directed to ACE inhibitor-containing compositions stabilized by the presence of magnesium oxide. Preferably, the ACE inhibitor, quinapril, is protected from certain forms of degradation when prepared in a pharmaceutical composition consisting essentially of magnesium oxide as the stabilizing agent. The presence of magnesium oxide also lends itself to favorable processing conditions during the manufacture of ACE inhibitor-containing compositions, especially processing by wet granulation. BACKGROUND OF THE INVENTION [0002] Certain ACE (Angiotensin Converting Enzyme) inhibitors, which are useful as antihypertensives, are susceptible to certain types of degradation. Specifically, quinapril and structurally-related drugs can degrade via (1) cyclization via internal nucleophilic attack to form substituted diketopiperazines, (2) hydrolysis of the side-chain ester group, and (3) oxidation to form products having often unwanted coloratio...

AI Technical Summary

Benefits of technology

[0011] It has been discovered that stable compositions containing ACE inhibitors of the type discussed above can be produced using magnesium oxide as the primary cyclization stabilizer. In one embodiment, a pharmaceutical composition is prepared by combining the ACE inhibitor, quinapril HCl, with a stabilizing agent consisting essentially of magnesium oxide. Use of magnesium oxide not only minimizes the cyclization degradation of ACE inhibitors, but also improves the formulation of ACE inhibitors into pharmaceutical compositions by the wet granulation technique. In a preferred embodiment, a pharmaceutical composition is prepared by combining the ACE inhibitor with not only a stabilizing agent consisting essentially of magnesium oxide, but also an agent that minimizes the hydrolysis of the ACE inhibitor, such as a saccharide, a diuretic, dicalcium phosphate or commonly known fillers having hydrolysis minimizing effects on the ACE inhibitor. In a more preferred, a pharmaceutical composition is prepared by combining 5.8% by weight of magnesium oxide with 5.8% weight of quinapril hydrochloride with the inclusion of 88.3% weight of lactose to yield a composition which withstands oxidative, hydrolytic, and cyclization degradation at 60° C. for 10 days.

[0013] The compositions of the invention have several advantages over compositions which do not contain the stabilizing additive. Principally, the active ingredients or drugs contained therein are virtually protected from cyclization and hydrolysis. In addition, the discoloration which sometimes occurs when ACE inhibitors of this class are formulated and allowed to stand for significant periods of time is minimized or eliminated completely. Thus, a stable tabletted quinapril formulation can be produced which will undergo no detectable oxidative discoloration.

[0014] In addition to having greater storage stability, the formulations of the present inventions are rendered more suitable for use in drug combinations.

[0015] The instant formulations are further advantageous due to the fact that the presence of magnesium carbonate hydroxide, and all of its inherent disadvantages, is unnecessary. Preparation of ACE inhibitor-containing compositions with magnesium oxide as the principal stabilizer results in improved processing by a wet granulation technique. Improvements that decrease the cost and labor include, but are not limited to an increase in batch sizes due to the high density of magnesium oxide formulations; granulation times of 4.5 to 5 minutes or less; decreased variability in granulation times (between 0.5 to 1 minute) when using different lots of magnesium oxide; decreased amounts of water to achieve granulation end points and shorter drying times based upon initial loss on drying (LOD) values in the range of 5% to 8% and improved flowability.

Problems solved by technology

Certain ACE (Angiotensin Converting Enzyme) inhibitors, which are useful as antihypertensives, are susceptible to certain types of degradation.

Magnesium carbonate hydroxide is a white, bulky powder which is difficult to formulate into tablets because of its poor compressibility, moldability, and flowability.

However, it is laborious, involving considerable material handling, as well as several processing steps, and therefore it is costly.

The labor and cost so characteristic of wet granulation processes are common when compounds like magnesium carbonate hydroxide are mixed with ACE inhibitors like quinapril HCl.

Magnesium carbonate hydroxide is also problematic to manufacturers because of sourcing concerns.

Images