Stabilization of quinapril using magnesium oxide

Details Stabilization of quinapril using magnesium oxide Stabilization of quinapril using magnesium oxide

2000-11-20

2002-07-09

Fay, Zohreh (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S562000, C514S423000, C424S440000, C424S465000

Reexamination Certificate

active

06417196

ABSTRACT:

FIELD OF THE INVENTION
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
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 coloration.
U.S. Pat. No. 4,743,450 discloses that stable compositions containing ACE inhibitors of the type discussed above can be produced using certain additives as stabilizers. Specifically, this patent discloses that the inorganic salts of metals of Group I and II of the Periodic Table act as stabilizers of ACE inhibitor-containing formulations susceptible to certain types of degradation. Magnesium carbonate is taught to be a preferred stabilizer.
One ACE inhibitor, quinapril HCl, is sold commercially under the tradename, ACCUPRIL®, and employs magnesium carbonate hydroxide in its formulations. Magnesium carbonate hydroxide contains approximately 40% to 42% magnesium oxide.
While magnesium carbonate hydroxide acts as an effective stabilizer of quinapril, its use in pharmaceutical formulations represents certain disadvantages. Magnesium carbonate hydroxide is a white, bulky powder which is difficult to formulate into tablets because of its poor compressibility, moldability, and flowability. The difficulties encountered by the use of magnesium carbonate hydroxide to formulate ACE inhibitor-containing compositions is accentuated when the compositions are manufactured using a wet granulation process.
The preparation of granulations for tableting by wet granulation is the oldest and still the most widely used. Before dry compaction became a viable process, wet granulation was—for all practical purposes—the only method available. However, it is laborious, involving considerable material handling, as well as several processing steps, and therefore it is costly. In general, the technique involves no more than the incorporation of a granulating fluid into the mixed, powdery tablet ingredients (including at least some tableting aids) in such an amount and manner as to convert them into a uniform, moist, coherent, non-pasty mass, which then is formed into moist granules of fairly uniform size, usually by forcing the mass through a screen. Thereafter, the moist granules are dried and rescreened to break down agglomerates, and finally blended with other tableting aids so as thus to arrive at the granulation ready for tableting.
It will be noted that in wet granulation, the tablet ingredients besides the active matter also conventionally include other, pharmacologically inert materials, certainly tableting aids and perhaps also bulking agents. Some of such tableting aids may be included in the mixed, powdery ingredients before the granulating fluid is incorporated therein, while further tableting aids may be applied to the surfaces of the granules, and in between them, after the granules have been formed and before the granulate is passed to the tableting machine.
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. Manufacturers have experienced several rate-limiting steps when processing magnesium carbonate hydroxide: batch sizes limited due to the lower density of magnesium carbonate hydroxide blends; granulation times of 15 minutes or longer; variability in granulation times of 15 to 37 minutes when using different lots of magnesium carbonate hydroxide; need for high amounts of water to achieve granulation end points and potentially long drying times based upon initial loss on drying in the range of 23 to 29% (loss on drying or “LOD” is a moisture determination test using heat to determine how much water or solvent is in a product); and limitations in flowability.
Magnesium carbonate hydroxide is also problematic to manufacturers because of sourcing concerns.
It can be understood that it would be an improvement to the art if one could improve the wet granulation processing conditions of an ACE inhibitor-containing formulation without sacrificing the stabilizing effects of a compound like magnesium carbonate hydroxide.
SUMMARY OF THE INVENTION
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.
In another embodiment, a process is disclosed for preparing stabilized ACE inhibitor-containing compositions with magnesium oxide. The process comprises the steps of contacting the ACE inhibitor with a suitable amount of a stabilizer consisting essentially of magnesium oxide and one or more hydrolysis-minimizing agents, such as saccharides, to minimize hydrolysis. In a preferred embodiment, the process comprises the steps of contacting quinapril HCl with a suitable amount of a stabilizer consisting essentially of magnesium oxide and one or more saccharides to form a mixture; and subjecting the mixture to wet granulation processing.
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.
In addition to having greater storage stability, the formulations of the present inventions are rendered more suitable for use in drug combinations.
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 minut

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