Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1995-06-06
2001-10-09
Kumar, Shailendra (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S440000, C514S565000, C514S556000, C562S575000
Reexamination Certificate
active
06300362
ABSTRACT:
The presents invention relates to the use of certain acid donors as stabilizers in pharmaceutical compositions, and to the stabilized pharmaceutical compositions resulting therefrom.
BACKGROUND OF THE INVENTION
There are a number of pharmaceutical compositions which suffer from instability problems due to the fact that the active component is susceptible to certain types of degradation, thereby diminishing their attractiveness and, in some cases, rendering them unsuitable from a commercial standpoint. For example, several ACE (Angiotensin Converting Enzyme) inhibitor-containing compositions suffer from this drawback since certain ACE inhibitors degrade readily in pharmaceutical dosage forms. More particularly, and as is the case with other ACE inhibitors such as Quinapril and Enalapril, Spirapril degrades readily in dosage forms to the diketo piperazine (the internal cyclization product) and the diacid (the ester hydrolysis product). Accordingly, in view of their usefulness in treating hypertension, a number of research endeavors have been directed to overcoming the instability problem associated with ACE inhibitor-containing compositions, without appreciable success.
DESCRIPTION OF THE PRIOR ART
European Patent Application 264,888 is directed to the stabilization of ACE inhibitor-containing pharmaceutical compositions employing ascorbic acid alone or a combination of ascorbic acid with fumaric acid, maleic acid and/or citric acid as the stabilizing component(s).
U.S. Pat. No. 4,743,450 is also directed to the stabilization of ACE inhibitor-containing pharmaceutical compositions employing, as the stabilizer component, a combination of an alkali or alkaline earth metal salt (preferably, magnesium carbonate) and a saccharide (preferably, mannitol or lactose).
Although each of the above patents represents an attempt to overcome the instability problems associated with ACE inhibitor-containing compositions, there still exists a dire need for ACE inhibitor-containing compositions exhibiting improved stability, especially in the presence of moisture. To this end, the present invention is directed to pharmaceutical compositions, particularly ACE inhibitor-containing compositions, exhibiting improved stability.
OBJECTS OF THE INVENTION
It is, therefore, an object of the present invention to provide new stabilized pharmaceutical compositions.
It is another object of the present invention to provide new stabilized pharmaceutical compositions comprising a select group of acid donors as the stabilizing component thereof.
It is still another object of the present invention to provide new stabilized ACE inhibitor-containing pharmaceutical compositions.
It is yet still another object of the present invention to provide new stabilized ACE inhibitor-containing pharmaceutical compositions comprising a select group of acid donors as the stabilizing component thereof.
ADVANTAGES OF THE INVENTION
The stabilized pharmaceutical compositions of the instant invention exhibit a number of advantages as follows:
1) The active component, e.g., an ACE inhibitor, is virtually preserved from any type of degradation.
2) They exhibit an extended shelf-life under normal storage conditions.
3) They are insensitive to moisture and, in fact, the stability improves with an increase in moisture.
4) They exhibit minimal, if any, discoloration over a significant period of time.
5) They exhibit minimal, if any, instability when employed in the presence of colorants.
DESCRIPTION OF THE INVENTION
The attainment of the above objects and advantages is made possible by the use of certain acid donors and, more particularly, a select group of hydrochloric acid donors. In comparison to certain acidifiers which have previously been employed as stabilizers in pharmaceutical compositions, e.g., citric acid, maleic acid, ascorbic acid, etc., the acid donors of the present invention release the more volatile hydrochloric acid and, therefore, effect a greater diffusion through the dosage form matrix. Although any compounds which produce hydrochloric acid would be suitable in the practice of the instant invention, preferred acid donors include amino acid hydrochlorides and Lewis acid chlorides. The preferred amino acid hydrochlorides are glycine hydrochloride, glutamic acid hydrochloride, betaine hydrochloride, alanine hydrochloride, valine hydrochloride, lysine hydrochloride, arginine hydrochloride and aspartic acid hydrochloride, whereas the preferred Lewis acid chlorides are ferric chloride, zinc chloride and aluminum chloride. The more preferred amino acid hydrochlorides are glycine hydrochloride, glutamic acid hydrochloride and betaine hydrochloride, whereas the more preferred Lewis acid chloride is ferric chloride. The most preferred acid donor is glycine hydrochloride.
Although, in general, the hydrochloric acid donor can be employed in any amount which will prevent degradation of the active component, e.g., an ACE inhibitor, the amount of the hydrochloric acid donor employed is between 1% and 25%, preferably between 1% and 20%, more preferably between 1% and 15%, most preferably between 1 and 10%, based on the total weight of the pharmaceutical composition.
Although the essence of the instant invention, viz., the use of a select group of hydrochloric acid donors as stabilizers in pharmaceutical compositions, would apply to all pharmaceutical compositions where buffering to a low pH for required stability is essential, it has particularly been found useful when applied to ACE inhibitor-containing pharmaceutical compositions since, as indicated above, many ACE inhibitors degrade readily in pharmaceutical dosage forms. In general, all ACE inhibitor-containing pharmaceutical compositions wherein the ACE inhibitor employed is prone to form diketopiperazine degradation products would benefit from the use of a select group of hydrochloric acid donors as stabilizers therefor. For example, one class of ACE inhibitors to which the instant invention would apply are compounds of formula I:
wherein R
1
and R
2
, independently, are hydrogen or a group —OC
n
H
2n+1
, where n is 1 to 5; and R
3
is hydrogen or a group —C
n
H
2n+1
, where n is as defined above.
In the above formula, preferred compounds are those where R
1
and R
2
have the same significance. More preferred compounds of the above formula are those where R
1
and R
2
are both hydrogen or methoxy and R
3
is hydrogen or methyl. The most preferred compound of the above formula is Quinapril having the formula
All of the above compounds are known, having been previously described in U.S. Pat. No. 4,344,949. Moreover, their usefulness in treating hypertension as well as methods for their preparation are set forth therein.
Another class of ACE inhibitors to which the invention would apply are compounds of formula II:
wherein R is C
1
-C
6
alkyl, benzyl, benzylthio, benzyloxy, phenylthio or phenoxy;
R
1
is hydroxy or C
1
-C
6
alkoxy;
and R
2
is hydrogen, C
1
-C
6
alkyl or C
1
-C
6
aminoalkyl.
In the above formula, preferred compounds are those wherein R is benzyl, R
1
is C
1
-C
6
alkoxy and R
2
is hydrogen, methyl or aminobutyl. More preferred compounds of the above formula are those wherein R is benzyl, R
1
is C
1
-C
4
alkoxy and R
2
is hydrogen or methyl. The even more preferred compounds of the above formula are those wherein R is benzyl, R
1
is ethoxy and R
2
is methyl. The most preferred compound of the above formula is Enalapril having the formula
All of the above compounds of formula II are known, having been previously described in European Patent 12,401. Moreover, their usefulness in treating hypertension as well as methods for their preparation are set forth therein.
A particularly preferred class of ACE inhibitors to which the instant invention would apply are compounds of formula III:
wherein R, R
1
and R
2
have the significances indicated above regarding the compounds of formula II.
The preferred, more preferred and even more preferred compounds of the above formula are as set forth above regarding the compounds of formula II. The most prefe
Ross Bruce A.
Vivilecchia Richard V.
Borovian Joseph J.
Kumar Shailendra
Novartis AG (formerly Sandoz Ltd.)
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