Fosinopril tablet formulations

Shelf stable tablets containing fosinopril sodium are prepared by employing either sodium stearyl fumarate or hydrogenated vegetable oil as the lubricant. The tablets can contain conventional excipients such as fillers, binders, and disintegrants as well as an optional diuretic.

BACKGROUND OF THE INVENTION 
The sodium salt of fosinopril, 
(4S)-4-cyclohexyl-1-[[[(RS)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)phosp 
hinyl]acetyl]-L-proline, propionate (ester) sodium salt, is currently 
undergoing clinical evaluation as an antihypertensive agent. 
Fosinopril, its ability to inhibit the angiotensin converting enzyme and 
thus lower blood pressure in humans, and formulations of fosinopril 
including combinations with various diuretics are described by Petrillo, 
Jr., in U.S. Pat. Nos. 4,337,201 and 4,384,123. 
SUMMARY OF THE INVENTION 
This invention is directed to the discovery that the shelf life and 
stability of fosinopril sodium formulated as tablets is increased when the 
lubricant employed is sodium stearyl fumarate or hydrogenated vegetable 
oil as compared to tablets employing magnesium stearate as the lubricant. 
In addition to the fosinopril sodium, the tablet formulation can also 
include a diuretic, preferably chlorthalidone, a filler, a disintegrant, a 
binder, a lubricant, and other commonly employed pharmaceutically 
acceptable agents. The tablet can include a color agent or the tablets can 
be color film coated. The tablets can be prepared in a variety of shapes 
and can be scored for the convenience of the user. 
DETAILED DESCRIPTION OF THE INVENTION 
Fosinopril sodium having the chemical formula 
##STR1## 
is an angiotensin converting enzyme inhibitor currently being clinically 
evaluated as an antihypertensive agent. 
Fosinopril sodium bulk material has a relatively low bulk density, exhibits 
poor flow characteristics, and adheres to metal surfaces during tableting. 
Previously, fosinopril sodium was tableted by a wet granulation process in 
which the tablet binder material was added to a solvent to form a solution 
of about 20% on a weight to weight basis. The fosinopril sodium and a 
portion of the tablet filler and disintegrant were then added. The mix was 
granulated and dried to less than 1% by weight of volatiles. The remainder 
of the tablet excipients were added and the final blend was obtained by 
lubrication with magnesium stearate. It was found that tablets produced 
from this blend were moisture sensitive and only marginally stable. In 
order to have a useful shelf life these tablets required the use of a 
protective package. 
This invention is directed to the discovery that by eliminating magnesium 
stearate as the lubricant during the tableting of fosinopril sodium and 
instead employing either sodium stearyl fumarate or hydrogenated vegetable 
oil, tablets having improved stability are obtained. The tablets thus 
prepared are significantly less moisture sensitive and have a useful shelf 
life without the need for protective packaging. Sodium stearyl fumarate is 
the preferred lubricant since hydrogenated vegetable oil can cause 
processing problems of sticking to the punch tips during long tableting 
runs. 
As discussed by Petrillo, Jr. in U.S. Pat. Nos. 4,337,201 and 4,384,123, 
various diuretics can be combined with fosinopril sodium for the treatment 
of hypertension. Suitable diuretics include chlorthalidone, the thiazide 
diuretics such as chlorothiazide, hydrochlorothiazide, flumethiazide, 
bendroflumethiazide, etc., ethacrynic acid, ticrynafen, furosemide, 
musolimine, bumetanide, triameterene, amiloride, spironolactone, and salts 
thereof with chlorthalidone and hydrochlorothiazide being preferred. 
Tablets prepared according to this invention contain from about 5 mg. to 
about 50 mg. of fosinopril sodium as the sole active agent or from about 
10 mg. to about 75 mg. of a combination of fosinopril sodium and diuretic 
in a ratio of from about 1:5 to about 5:1 on a weight basis. 
As discussed above, in addition to the actives, fosinopril sodium and the 
optional diuretic, and the lubricant, tablets prepared according to this 
invention will include excipients such as a filler, a disintegrant, and a 
binder. The preferred filler is lactose or lactose and microcrystalline 
cellulose. The preferred disintegrants are selected from sodium 
carboxymethyl starch, cross linked sodium carboxymethyl starch, 
crospovidone, i.e., 1-ethenyl-2-pyrrolidinone homopolymer, cross linked 
sodium carboxymethylcellulose (AcDiSol or Croscarmellose Sodium), sodium 
starch glycolate, and mixtures thereof. The preferred binders are selected 
from povidone, i.e., 2-pyrrolidinone, 1-ethenyl-, homopolymer, 
hydroxypropyl cellulose, and mixtures thereof. Alternatively, a single 
agent such as pregelatinzed starch can be employed as both disintegrant 
and binder. Other ingredients commonly employed in tableting 
pharmaceutical products can also be included such as coloring agents. 
On a weight percentage basis, the above ingredients will preferably be 
present in the final tablets as follows: 
______________________________________ 
Preferred percentage 
Ingredient by weight 
______________________________________ 
Fosinopril sodium about 1 to about 25 
diuretic, (preferably 
from 0 up to about 25 
chlorthalidone or 
hydrochlorothiazide) 
filler (preferably about 30 to about 90 
lactose or lactose 
combined with micro- 
crystalline cellulose) 
disintegrant (preferably 
about 2 to about 10 
sodium carboxymethyl starch 
and its cross linkaged form 
and/or crospovidone and/or 
crosslinked sodium carboxy- 
methylcellulose and/or sodium 
starch glycolate) 
binder (preferably about 1 to about 5 
povidone and/or hydroxy- 
propyl cellulose) 
combined binder and about 5 to about 15 
disintegrant (preferably 
pregelatinized starch) 
lubricant (preferably 
about 0.3 to about 4 
sodium stearyl fumarate) 
______________________________________ 
The fosinopril sodium tablets of this invention can be prepared by 
conventional tablet forming techniques such as, for example, wet 
granulation and dry granulation. In the wet granulation process, the 
active ingredient or ingredients are mixed with portions of the filler and 
disintegrant. This blend is then wet granulated with a solution of the 
binder in a solvent. The solution will preferably be from about 5% to 20% 
by weight of solvent and the preferred solvents include ethanol, 
isopropanol, and water. The resultant wet granulation is then dried and 
milled. The dried granulation is then mixed with the balance of the filler 
and disintegrant. The resulting blend is mixed with sodium stearyl 
fumarate, which is preferred, or hydrogenated vegetable oil to produce the 
final mix which is then compressed into tablets. 
In the dry granulation process, the active ingredient or ingredients and 
the filler, disintegrant and binder are blended in a mixer (planetary or 
high shear) for several minutes. The blend is then milled and mixed with 
sodium stearyl fumarate, which is preferred, or hydrogenated vegetable oil 
to produce the final mix which is then compressed into tablets. 
The wet granulation process employing water as the solvent and the dry 
granulation process have the added advantage of avoiding the use of an 
organic solvent. This results in a cost savings as well as a safer process 
needing fewer environmental controls.

EXAMPLE 1 
Tablets were prepared containing: 
______________________________________ 
Ingredient Weight (mg.) 
______________________________________ 
Fosinopril sodium 40.0 
Chlorthalidone 15.0 
Lactose 318.00 
Povidone 9.0 
Crospovidone 14.0 
Sodium stearyl fumarate 
4.0 
Water q.s. 
Tablet weight 400 
______________________________________ 
100,000 tablets of the above formulation were prepared as follows. A blend 
was prepared of fosinopril sodium (4000 g.), chlorthalidone (1500 g.), 
lactose (17,900 g.), and crospovidone (700 g.) in a suitable mixer such as 
planetary mixer or high shear mixer for 5 to 10 minutes. Povidone (900 g.) 
was dissolved in water (7 liters) and the above blend was wet granulated 
with the entire povidone solution. The wet granulation was dried at 
45.degree.-70.degree. C. in a suitable dryer such as a tray drying oven or 
a fluid bed dryer until the volatile content of the wet granulation was 
less than 3% by weight. The dried granulation was passed through a hammer 
mill fitted with 0.03-0.07 inch screen operating at medium to fast speed, 
knives forward. The screened granulation was then mixed with lactose 
(13,900 g.) and crospovidone (700 g.) in the mixer (planetary or high 
shear) for 5 to 10 minutes. Sodium stearyl fumarate (400 g.) was then 
added to the above blend and mixing was continued for 1 to 3 minutes. The 
final blend was then compressed into 400 mg. tablets using a rotary tablet 
press. 
EXAMPLES 2 TO 5 
Following the procedure of Example 1, the following tablets were obtained. 
______________________________________ 
Weight (mg.) 
Ingredient 2 3 4 5 
______________________________________ 
Fosinopril sodium 
20.0 10.0 5.0 5.0 
Chlorthalidone 15.0 15.0 25.0 5.0 
Lactose 244.75 161.0 62.5 82.5 
Povidone 6.75 4.5 3.0 3.0 
Crospovidone 10.50 7.5 3.5 3.5 
Sodium stearyl fumarate 
3.0 2.0 1.0 1.0 
Water q.s. q.s. q.s. q.s. 
Tablet weight 300 200 100 100 
______________________________________ 
EXAMPLES 6 TO 9 
Following the procedure of Examples 1 to 5, the following tablets were 
obtained. 
______________________________________ 
Weight (mg.) 
Ingredient 6 7 8 9 
______________________________________ 
Fosinopril sodium 
20.0 10.0 20.0 10.0 
Hydrochlorthiazide 
12.5 12.5 12.5 12.5 
Lactose 237.5 157.5 112.5 123.5 
Avicel (Microcrystalline 
-- -- 40.0 40.0 
cellulose 
Povidone 6.0 4.0 4.0 4.0 
Croscarmellose Sodium 
15.0 10.0 -- -- 
(cross linked sodium 
carboxymethylcellulose) 
Sodium starch glycolate 
-- -- 7.0 7.0 
Sodium stearyl fumarate 
9.0 6.0 4.0 3.0 
Water q.s. q.s. q.s. q.s. 
Tablet weight 300 200 200 200 
______________________________________ 
EXAMPLES 10 AND 11 
The following tablets were prepared by a modification of the procedures of 
Examples 1 to 9. 
______________________________________ 
Weight (mg.) 
Ingredients 10 11 
______________________________________ 
Fosinopril sodium 20.0 10.0 
Hydrochlorothiazide 
12.5 12.5 
Lactose 107.5 118.5 
Avicel (micro- 40.00 40.00 
crystalline cellulose) 
Pregelatinized starch 
16.0 16.0 
Sodium stearyl fumarate 
4.0 3.0 
Water q.s. q.s. 
Tablet weight 200 200 
______________________________________ 
In the preparation of the tablets of Examples 10 and 11, a portion of the 
pregelatinized starch was added before the wet granulation step and the 
remainder was added to the dried granulation. 
EXAMPLE 12 
Tablets were prepared containing the following: 
______________________________________ 
Ingredient Weight (mg.) 
______________________________________ 
Fosinopril sodium 5.0 
Lactose 139.5 
Avicel (microcrystalline 
40.0 
cellulose) 
Crospovidone 7.0 
Povidone 4.5 
Sodium stearyl fumarate 
4.0 
Alcohol (used for processing, 
q.s. 
not present in tablet) 
Tablet Weight 200 
______________________________________ 
200,000 tablets of the above formulation were prepared as follows. 
Fosinopril sodium (1,000 g.), lactose (16,500 g.), Avicel (1,000 g.) and 
crospovidone (700 g.) were mixed in a suitable mixer (planetary or high 
shear) for 5 to 10 minutes. Povidone (800 g.) was dissolved in denatured 
alcohol (4 liters) and blended with the above mixture forming a wet 
granulate. This wet granulate was dried at 45.degree.-70.degree. C. in 
suitable dryer such as a tray drying oven or a fluid bed dryer until the 
volatile content of the wet granulation was less than 3% by weight. The 
dried granulation was passed through a hammer mill fitted with a 0.03-0.07 
inch screen operating at medium to fast speed, knives forward. The 
screened granulation was mixed with lactose (12,100 g.), Avicel (7,000 g.) 
and crospovidone (700 g.) in a suitable mixer (planetary or high shear) 
for 5 to 10 minutes. Sodium stearyl fumarate was added to the above blend 
and mixed for 1 to 3 minutes in the same mixer. This final blend was then 
compressed into 200 mg. tablets using a rotary tablet press. 
EXAMPLE 13 AND 14 
Following the procedure of Example 12, the following tablets were obtained. 
______________________________________ 
Weight (mg.) 
Ingredient 13 14 
______________________________________ 
Fosinopril sodium 10.0 20.0 
Lactose 134.5 124.5 
Avicel (microcrystalline 
40.0 40.0 
cellulose) 
Crospovidone 7.0 7.0 
Povidone 4.5 4.5 
Sodium stearyl 4.0 4.0 
fumarate 
Alcohol (used for q.s. q.s. 
processing, not 
present in tablet) 
Tablet Weight 200 200 
______________________________________ 
EXAMPLE 15 
Tablets were prepared containing the following: 
______________________________________ 
Ingredient Weight (mg.) 
______________________________________ 
Fosinopril sodium 5.0 
Lactose 143 
Avicel (microcrystalline cellulose) 
40.0 
Crospovidone 7.0 
Povidone 4.0 
Sodium stearyl fumarate 1.0 
Tablet weight 200 mg. 
______________________________________ 
200,000 tablets of the above formulation were prepared as follows. 
Fosinopril sodium (1,000 g.), lactose (28,600 g.), Avicel (8,000 g.), 
crospovidone (1400 g.) and povidone (800 g.) were mixed in a suitable 
mixer (planetary or high shear) for 5 to 10 minutes. The blend was then 
passed through a hammer mill equipped with a 0.04-0.08 inch size round 
hole screen operating at medium speed, knives forward. Sodium stearyl 
fumarate (200 g.) was added to the above blend and mixed for 1 to 3 
minutes in the same mixer. This final blend was then compressed into 200 
mg. tablets using a rotary tablet press. 
Following the procedures of Examples 1 to 5 and 12 to 15, similar tablets 
were prepared substituting hydrogenated vegetable oil for the sodium 
stearyl fumarate. 
EXAMPLE 16 
Following the procedure of Example 12 fosinopril sodium tablets were 
prepared utilizing sodium stearyl fumarate, hydrogenated vegetable oil, 
and magnesium fumarate as the lubricant. The initial amount of fosinopril 
sodium was measured and similar measurements were made after 10 days and 
25 days storage under varying conditions. 
______________________________________ 
Weight of Fosinopril Sodium 
Sodium stearyl 
Hydrogenated Magnesium 
Storage fumarate vegetable oil 
stearate 
condition 
formulation formulation formulation 
______________________________________ 
Initial 4.99 mg. 4.86 mg. 4.95 mg. 
10 days at 
4.36 mg. 4.71 mg. 3.44 mg. 
75.degree. C. in 
closed 
containers 
10 days at 
4.87 mg. 4.60 mg. 3.44 mg. 
50.degree. C., 75% 
relative 
humidity 
in open 
containers 
10 days at 
4.36 mg. 3.92 mg. 0.90 mg. 
60.degree. C., 75% 
relative 
humidity 
in open 
containers 
25 days at 
4.25 mg. 4.37 mg. 3.39 mg. 
75.degree. C., in 
closed 
containers 
25 days at 
4.69 mg. 4.31 mg. 1.83 mg. 
50.degree. C., 75% 
relative 
humidity 
in open 
containers 
______________________________________