Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-03-16
2004-07-27
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S451000, C424S452000, C424S456000, C424S464000, C424S465000
Reexamination Certificate
active
06767556
ABSTRACT:
FIELD OF INVENTION
This invention relates to solid pharmaceutical compositions comprising a stable salt of moexipril, specifically the magnesium salt, moexipril magnesium.
BACKGROUND
Some ACE (Angiotensin Converting Enzyme) inhibitors, which are useful as antihypertensives, are susceptible to degradation by cyclization, hydrolysis or oxidation. Such ACE inhibitors include enalapril, quinapril and moexipril, and acid addition salts thereof.
Enalapril and its acid addition salts and their use as ACE inhibitors, is disclosed in U.S. Pat. No. 4,374,829.
Quinapril and moexipril and their acid addition salts are disclosed in U.S. Pat. No. 4,344,949.
Various methods of improving the stability of these compounds are disclosed in the prior art.
Enalapril and its acid addition salts are more easily stabilized than moexipril and its acid addition salts. There are thus some methods in the prior art that are satisfactory for the stabilization of enalapril and its acid addition salts, but not moexipril and its acid addition salts.
U.S. Pat. No. 5,562,921 discloses that stable tablets can be made comprising enalapril maleate by restricting the inactive ingredients used in the tablets to certain ones found not to cause degradation. However, because moexipril and its acid addition salts are less stable than enalapril maleate, this approach does not work with moexipril and its acid addition salts.
U.S. Pat. Nos. 5,350,582 and 5,573,780 both disclose that stable tablets can be made by reacting enalapril maleate with an alkaline sodium compound to convert the enalapril maleate to enalapril sodium. Enalapril sodium is found to be much more stable than enalapril maleate.
U.S. Pat. No. 4,830,853 discloses that certain ACE inhibitors, and in particular quinapril, can be stabilized against oxidation and discoloration by including ascorbic acid or sodium ascorbate in the composition. However, it appears that this approach does not stabilize moexipril or its addition salts sufficiently to be commercially useful, as products presently being marketed do not use this approach.
Finally, U.S. Pat. No. 4,743,450 discloses that certain ACE inhibitors can be stabilized by making solid compositions that include an alkaline compound as stabilizer. Magnesium, calcium and sodium compounds are said to be preferred, and magnesium is most preferred. The examples in this patent all relate to solid dosage forms comprising quinapril hydrochloride as active drug and magnesium carbonate as stabilizer.
There is also a relevant publication by Gu et al, “Drug-Excipient Incompatibility Studies of the Dipeptide Angiotensin Converting Enzyme Inhibitor, Moexipril Hydrochloride: Dry Powder vs Wet Granulation”, Pharm Res. 7(4):370-383. This publication discloses that moexipril hydrochloride can be stabilized by making compositions comprising moexipril hydrochloride and an alkaline stabilizing agent selected from sodium bicarbonate, sodium carbonate and calcium carbonate. It is stated that the stabilization is accomplished only when the compositions are made by a wet granulation process. In the conclusion of the publication, it is postulated that the stabilization results from the neutralization of the acidic drug by the basic excipient at the outer surface of the granulated material. It is also stated that it is possible that a portion of the moexipril was converted to alkaline salts via granulation. It thus appears clear that Gu, et al teaches that only a portion (if any) of the drug, and only that portion at the outer surface of the granules, may be converted to the alkaline salt, and that the stable product thus results entirely or primarily not from conversion to alkaline salts, but from stabilization of the moexipril hydrochloride by the presence of the alkaline stabilizing compound in the final product.
Gu, et al is thus consistent with the teaching of U.S. Pat. No. 4,743,450, which, as aforesaid, teaches stable compositions comprising the unstable drug, stabilized by the presence of an alkaline compound in the final composition.
Tablets containing moexipril hydrochloride are sold in the United States and elsewhere under the tradename Univasc® by Schwarz Pharma. The labeling of these tablets indicates that the tablets contain moexipril hydrochloride and magnesium oxide. This indicates that these tablets are compositions in accordance with the teaching of U.S. Pat. No. 4,743,450.
There are certain problems inherent in the teaching of U.S. Pat. No. 4,743,450. In particular:
1. The examples of U.S. Pat. No. 4,743,450 indicate a ratio of magnesium carbonate to active drug from about 5.8 to about 16.5 by weight, so that it appears that the amount of magnesium compound required is large and substantially exceeds the amount of the active drug.
2. Using the approach of U.S. Pat. No. 4,743,450, it is difficult to precisely control the exact final ingredients in the composition. The moexipril hydrochloride and magnesium compound are capable of an acid-base reaction. It is difficult to control the process so as to completely avoid an acid-base reaction in the making of the composition. The exact composition of the final product is thus uncertain and probably variable, if the teaching of U.S. Pat. No. 4,743,450 is followed.
In light of the prior art, the object of the present invention is to enable a stable composition comprising a moexipril salt which overcomes these limitations of the prior art.
DESCRIPTION OF THE INVENTION
Improved stability is achieved by producing a dosage form which comprises moexipril magnesium.
It has been found that the magnesium salt of moexipril (i.e. moexipril magnesium) is sufficiently stable to enable stable solid compositions, without the presence of an alkaline stabilizing compound in the final composition. It has also been found that stable solid compositions comprising moexipril magnesium can be made using moexipril or an acid addition salt thereof, by reacting the moexipril or acid addition salt with an alkaline magnesium compound, so as to convert most or all (i.e. more than half) of the moexipril or acid addition salt to moexipril magnesium.
Since the purpose of the present invention is to eliminate the unstable moexipril or acid addition salt thereof and replace it with stable moexipril magnesium, it will be understood that it is desirable that the preparation of the moexipril or acid addition salt converted and moexipril magnesium be as high as possible. Hence the amount converted will preferably be more than 70%, more preferably more than 80%, even more preferably more than 90%, and most preferably 100% or virtually 100%.
The moexipril or acid addition salt thereof used in the process will preferably be moexipril hydrochloride.
The alkaline magnesium compound will preferably be magnesium hydroxide or the magnesium salt of a weak acid such as, for example, magnesium carbonate. Magnesium oxide may be used in place of magnesium hydroxide, as magnesium oxide will convert to magnesium hydroxide in the presence of water.
The molecular formula for moexipril hydrochloride is C
27
H
34
N
2
O
7
.HCl and the molecular weight is 535.04 g.
The molecular equations, for converting moexipril hydrochloride to moexipril magnesium plus magnesium chloride, by reacting with magnesium hydroxide and magnesium carbonate are as follows:
1) Using magnesium hydroxide:
2C
27
H
34
N
2
O
7
.HCl+2Mg(OH)
2
→Mg(C
27
H
33
N
2
O
7
)
2
+MgCl
2
+4H
2
O.
2) Using magnesium carbonate:
2C
29
H
34
N
2
O
7
.HCl+2MgCO
3
→Mg(C
27
H
33
N
2
O
7
)
2
+MgCl
2
+2H
2
O+2CO
2
.
It can be seen that a complete conversion of moexipril hydrochloride to moexipril magnesium plus magnesium chloride requires for each mole (535 g) of moexipril hydrochloride, the following minimum amount of alkaline magnesium compound:
i) If magnesium hydroxide is used, one mole, which is 58.3 g.
ii) If magnesium carbonate is used, one mole, which is 84.3 g.
If only the minimum amount of alkaline magnesium compound, so calculated, is used, it is possible that the reaction may not go to completion, leaving some of the moexipril or
Hughes Ivor M.
Hughes Neil H.
Page Thurman K.
Sarkis Marcelo
Sheikh Humera N.
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