Captopril formulation providing increased duration of activity

A formulation comprising captopril within an enteric or delayed release coated pH stable core combined with additional captopril that is available for immediate release following administration.

BACKGROUND OF THE INVENTION 
Captopril, 1-[(2S)-3-mercapto-2-methyl-1-oxopropyl]-L-proline, is an 
angiotensin converting enzyme inhibitor approved for use as an 
antihypertensive agent for the treatment of congestive heart failure. 
Other indications are currently being evaluated. 
Captopril is available in the United States from E. R. Squibb & Sons, Inc., 
in a tablet form in amounts of 12.5 mg., 25 mg., 50 mg., and 100 mg. of 
active ingredient. In addition, the combination of captopril and 
hydrochlorothiazide is available in the United States from E. R. Squibb & 
Sons, Inc. in tablets containing 25 mg. of captopril and 15 mg. or 25 mg. 
of hydrochlorothiazide and tablets containing 50 mg. of captopril and 15 
or 25 mg. of hydrochlorothiazide. 
In addition, captopril is available in Japan from Sankyo in a capsule 
containing an oil formulation of captopril which includes a fatty acid and 
ascorbic acid. 
Joshi et al. in U.S. Pat. No. 4,808,413 disclose a controlled release 
formulation in the form of beadlets of a medicament such as captopril. The 
beadlets are formed of the medicament, a non-lipophilic binder-excipient, 
and an organic carboxylic acid such as citric acid at from at least 5%, 
preferably at least 10%, by weight of the formulation. The beadlets may 
also optionally include one or more auxilliary binders, one or more 
fillers or excipients, one or more lubricants, water, and/or other 
conventional additives. 
Drost et al. in U.S. Pat. No. 4,756,911 disclose a controlled release 
formulation in the form of a coated tablet containing a core portion from 
which medicament is slowly released. The core includes hydroxypropylmethyl 
cellulose having a particular methoxyl content and viscosity as the 
primary gelling agent. Suitable medicaments are disclosed as including 
angiotensin converting enzyme inhibitors such as captopril. 
Mehta et al. in U.S. Pat. Nos. 4,728,512 and 4,794,001 disclose 
formulations providing three distinct releases of medicament. The 
formulation consists of three groups of spheroids containing an active 
medicinal substance. The first group of spheroids is uncoated and rapidly 
disintegrates upon ingestion to release an initial dose of medicinal 
substance a second group of spheroids is coated with a pH sensitive coat 
to provide a second dose and a third group of spheroids is coated with a 
pH independent coat to provide a third dose. A powder blend of active 
medicinal substance may be substituted for the first group of uncoated 
spheroids. The therapeutic preparation may be utilized as a mixture of 
groups of spheroids in a capsule. 
SUMMARY OF THE INVENTION 
This invention is directed to captopril formulations having an increased 
duration of activity. The formulations include captopril in a pH 
stabilized core having an enteric or delayed release coating which 
protects the captopril until release in the colon. The coated pH 
stabilized core can be in the form of beads or core tablets. This coated 
core is then combined with additional captopril to give the final 
compositions which have a given amount of captopril available for 
immediate release following oral administration and an additional amount 
of pH stabilized captopril available for release in the colon. 
The pH stabilized core in addition to containing captopril also includes 
one or more chelating agents, one or more antioxidants, and one or more 
binding agents. Other optional ingredients can be included within the core 
such as fillers, plasticizers, lubricants, as well as additional active 
ingredients such as a diuretic. The core is coated with an enteric coating 
which is selected to release the core contents when exposed to the lower 
part of the intestine or a delayed release coating which is selected to 
slowly release the core contents throughout the gastrointestinal tract.

DETAILED DESCRIPTION OF THE INVENTION 
Captopril has been shown to be poorly absorbed in the colon (Hu et al., 
Journal of Pharmaceutical Sciences, Vol. 77, p. 1007-1011, 1988). It is 
believed that this is because captopril at the pH of the colon which 
varies from about 5 to 7.5 is converted into metabolites such as the 
disulfide and mixed disulfides. Thus, a captopril formulation in which at 
least a portion of the captopril is available in a pH stabilized form upon 
release into the colon will result in improved bioavailability and longer 
duration of activity. 
This invention is directed to formulations for oral administration having a 
portion of the captopril in a pH stabilized core. The core can be in the 
form of beads or a tablet. The core is coated with an enteric or delayed 
release coating. This coated core is then compressed into tablets along 
with a powder mixture containing additional captopril or is then 
overcoated with a solution containing additional captopril or is then 
filled along with uncoated captopril beads into a capsule shell. As a 
result, the final compositions of this invention provide an amount of 
captopril for immediate release following oral administration and an 
additional amount of captopril in a pH stabilized environment available 
for release upon passage of the contents of the core through the digestive 
system into the colon. 
The captopril formulations of this invention contain from about 12.5 mg. to 
about 100 mg. of total weight of captopril. The amount of captopril in the 
pH stabilized core will range from about 25% to about 75% by weight of the 
total captopril content, i.e., from about 3 mg. to about 75 mg., and will 
be present at from about 5% to about 50% by weight of the core. The core 
in addition to the captopril contains one or more chelating agents, one or 
more antioxidants, and one or more binders as well as other optional 
ingredients. 
Suitable chelating agents for inclusion within the core include disodium 
edetate, capric and caprylic acid, the sodium salts of capric and caprylic 
acid, bile salts, and surfactants such as polysorbate 80. The chelating 
agent is included within the core at from about 1% to about 20% by weight 
of the core. The preferred chelating agent is disodium edetate. 
Suitable antioxidants for inclusion within the core include ascorbic acid, 
erythorbic acid, and sodium erythorbate alone or in combination with a 
buffering agent such as sodium ascorbate. The anti-oxidant alone or with 
buffering agent are included at from about 10% to about 70% by weight of 
the core. The preferred antioxidant is ascorbic acid plus sodium 
ascorbate. 
The core also includes one or more binding agents at from about 5% to about 
30% by weight of the core. A suitable binder is microcrystalline cellulose 
which also functions as a spheronizing aid when the core is formulated as 
beads. Other suitable binders include povidone, gelatin, carbopol, sodium 
carboxymethylcellullose and cornstarch. 
The enteric coating composition is formed from polymeric materials known to 
be insoluble below pH of 5. Suitable materials include methacrylic acid 
copolymers such as Eudragit L and S available from Rohm Pharma, 
hydroxypropyl methylcellulose phthalate such as HPMCP available from 
Eastman Kodak, and cellulose acetates such as cellulose acetate 
trimellitate available from Eastman Kodak as C-A-T, cellulose acetate 
phthalate available from Eastman Kodak as C-A-P, and blends of cellulose 
acetate trimellitate and cellulose acetate phthalate. The delayed release 
coating composition is formed from polymeric materials known to be 
water-insoluble but permeable to water and dissolved drugs. Suitable 
materials include ethylcellulose available as a dispersion from FMC and 
methacrylic acid copolymers such as Eudragit RS and RL available from Rohm 
Pharma. The enteric or delayed release coating composition can also 
include a plasticizer such as acetyltri-n-butyl citrate, triethyl citrate, 
acetyltriethyl citrate, tri-n-butyl citrate, castor oil, polyethylene 
glycol, or dibutyl phthalate. Talc or other glidants such as microfine 
silicas or metallic stearates can also be included in the enteric or 
delayed release coating composition. 
The enteric or delayed release coated pH stabilized core in bead form can 
be prepared by any known sheronization techniques including the use of an 
extrusion/spheronization system, the use of a highshear mixer/granulator, 
the use of a rotating pan, the use of rotary fluidized-bed granulation, 
and the use of an agglomerator/powder applicator. For example, if the 
extrusion/spheronization system is employed, the beads would be prepared 
by mixing the captopril, chelating agent, antioxidant, binder, and any 
other optional ingredients in a planetary or high shear mixer for several 
minutes. Water is then added at from about 10% to 40% by weight of the 
mixture and granulation is continued. The granulated mass is then extruded 
through a screen. The extrudate is then processed in a spheronizer at a 
rotational speed of about 600 to 1000 rpm for about one to five minutes. 
The resulting spheres are dried and then coated with a solvent solution or 
dispersion of the enteric or delayed release polymeric coating composition 
in a fluidized-bed coater. The resulting enteric or delayed release coated 
pH stabilized core beads are then dried at 25.degree. to 75.degree. C. in 
either an oven-tray drier or a fluidized-bed drier. 
The resulting pH stabilized enteric or delayed release coated beads can 
then be combined with captopril beads prepared without the coating step 
and filled into capsule shells. 
Alternatively, the pH stabilized enteric or delayed release coated beads 
can be compressed into tablets with a powder mixture of captopril. The 
powder mixture in addition to the captopril can include a binder such as 
microcrystalline cellulose, a disintegrant such as cornstarch or 
croscarmellose, a lubricant such as stearic acid or magnesium stearate, 
and a glidant such as talc, microcrystalline cellulose, or magnesium 
stearate. 
The pH stabilized core can also be prepared as a tablet which is then 
enteric or delayed release coated and finally overcoated with a coating 
solution containing additional captopril. The core tablet can be prepared 
by mixing the captopril, chelating agent, antioxidant and binder along 
with optional ingredients such as a lubricant, disintegrant, and glidant. 
Suitable lubricants include stearic acid and magnesium stearate, suitable 
disintegrants include cornstarch, and suitable glidants include talc. The 
resulting mixture is then compressed in a tablet forming press. This 
tablet is then coated with a solvent solution or dispersion of the enteric 
or delayed release polymeric coating composition and overcoated with a 
solution of captopril and a water soluble polymer. Suitable water soluble 
polymers include cellulose derivatives such as hydroxypropylcellulose, 
hydroxypropylmethyl cellulose, and blends thereof. A plasticizer such as 
polyethylene glycol, i.e., polyethylene glycol 3350 or 8000, can also be 
included in the outer coating. 
An additional active ingredient particularly a diuretic such as 
hydrochlorothiazide can be included within the pH stabilized enteric or 
delayed release coated core or within the additional captopril powder, 
beads or coating or within both. 
Coloring agents can be included within the enteric or delayed release 
coating or outer captopril overcoating. 
The following examples are illustrative of the invention and exemplify 
preferred embodiments. 
EXAMPLE 1 
Enteric and delayed release coated pH stabilized core beads are prepared 
from the following ingredients: 
______________________________________ 
Composition of the beads 
Captopril 60 mg. 
Disodium edetate 45 mg. 
Ascorbic acid 330 mg. 
Sodium ascorbate 24 mg. 
Avicel .RTM. RC 581 65 mg. 
(contains 11% by weight of sodium 
carboxymethylcellulose and 89% 
by weight of microcrystalline 
cellulose) 
Composition of the enteric or delayed 
release coating 
Methacrylic acid copolymer* 
120 mg. 
Acetyltri-n-butyl citrate 
30 mg. 
Talc 30 mg. 
Composition of powder mixture 
Captopril 40 mg. 
Microcrystalline cellulose 
150 mg. 
Cornstarch 10 mg. 
Stearic acid 6 mg. 
______________________________________ 
*By employing Eudragit L from Rohm Pharma an enteric coating is obtained 
and by employing Eudragit RS from Rohm Pharma a delayed release coating i 
obtained. 
The above core ingredients are mixed for 5 minutes in a planetary mixer 
(Hobart Co.) at about 60 rpm. A sufficient amount of purified water is 
added to the mixing powder in the same planetary mixer and granulated 
until a wet mass of suitable consistency is obtained. This granulated mass 
is passed through an extruder equipped with a 1.0 mm. screen. The 
extrudate is then processed in a spheronizer (Caleva, Model 15) at a 
rotational speed of about 850 rpm for two minutes. 
The resulting spheres are transferred to a fluidized bed coater/drier, 
dried at 60.degree. C. and then coated with a solution of the above 
enteric coating composition in acetone/isopropyl alcohol (6:4). The 
resulting coated spheres are then dried in a fluidized bed at 50.degree. 
C. for 15 minutes. 
The above powder mixture is prepared by blending the captopril, 
microcrystalline cellulose, and cornstarch in a Hobart mixer for 10 
minutes. The coated beads are blended with the powder mixture for 5 
minutes, the stearic acid is then added, and mixing is continued for an 
additional 5 minutes. This mixture is then compressed into tablets in a 
conventional rotary press. 
EXAMPLE 2 
Enteric or delayed release coated and uncoated core beads are prepared from 
the following ingredients: 
______________________________________ 
Composition of the beads to be coated 
Captopril 50 mg. 
Disodium edetate 45 mg. 
Ascorbic acid 121 mg. 
Sodium ascorbate 9 mg. 
Avicel .RTM. RC 581 60 mg. 
Composition of the enteric or 
delayed release coating 
Methacrylic acid copolymer* 
60 mg. 
Acetyltri-n-butyl citrate 
15 mg. 
Talc 15 mg. 
Composition of uncoated core beads 
Captopril 50 mg. 
Lactose 37 mg. 
Microcrystalline cellulose 
80 mg. 
Citric acid 18 mg. 
______________________________________ 
*See explanation in Example 1. 
The uncoated beads and the enteric or delayed release coated core beads of 
above ingredients are prepared according to the procedure of Example 1. 
A mixture of the coated and uncoated core beads is filled into a gelatin 
capsule shell. 
EXAMPLE 3 
A pH stabilized core tablet having an interior coating and an outer 
captopril containing overcoating is prepared from the following 
ingredients: 
______________________________________ 
Composition of the core tablets 
Captopril 25 mg. 
Disodium edetate 22 mg. 
Ascorbic acid 125 mg. 
Sodium ascorbate 18 mg. 
Microcrystalline cellulose 
50 mg. 
Stearic acid 3 mg. 
Cornstarch 20 mg. 
Composition of interior coating 
Methacrylic acid copolymer* 
40 mg. 
Acetyltri-n-butyl citrate 
10 mg. 
Talc 10 mg. 
Composition of overcoat 
Captopril 25 mg. 
Hydroxypropylcellulose 
15 mg. 
______________________________________ 
*See explanation in Example 1. 
The pH stabilized core tablet is prepared by mixing the above ingredients 
in a planetary mixer for 5 minutes and then compressing in a tablet press. 
The resulting core tablet is then coated with the above enteric or delayed 
release coating composition in acetone/isopropyl alcohol (6:4). 
The enteric or delayed release coated core tablet is then overcoated with 
the above captopril composition in methanol and dried at 40.degree. C.