Effective Gastric Acid Suppression After

Oral Administration of Enteric-Coated

Omeprazole Granules

MUHAMMAD A. MOHIUDDIN, MD, K.G. PURSNANI, MD, DAVID A. KATZKA, MD,

R.M. GIDEON, JUNE A. CASTELL, MS, and DONALD O. CASTELL, MD

Omeprazole is inactivated by exposure to gastric acid and is formulated as a gelatin capsulecontaining enteric-coated granules that release the drug in alkaline medium. In clinicalsituations where patients are unable to take the capsule orally, the optimum means ofadministrat ion is uncertain . Eleven normal volunteers were given omeprazole 20 mg everyday for one week before breakfast in random order as either a 20-mg capsule with water orfree enteric-coated granules with either 8 oz of orange juice, 8 oz of water with 2 Alka-Seltzerantacid tablets (aspirin free), or 1 teaspoon of apple sauce. On day 7 of each regimen, an 8-hrintragastric pH study was performed following omeprazole 20 mg and standard breakfast.The median percentage of time of gastric acid pH . 4 after an omeprazole capsule was 68.5(25± 100); after granules with orange juice 59 (43± 100); after granules in Alka-Seltzer solution63 (31± 100), and after granules in apple sauce 65 (30 ± 99), with no signi® cant differences(ANOVA). The time for the gastric pH to reach , 4 9 after having been above was also similarfor all four regimens (ANOVA). Omeprazole granules administered orally in a variety ofways achieve gastric acid suppression as effectively as the intact capsule.

KEY WORDS: omeprazole; acid suppression; gastric secretion.

Omeprazole is a potent inhibitor of gastric acid se-

cretion with prolonged action (1, 2). Exposure to

gastric acid may lead to premature degradation and

inactivation resulting in poor bioavai labilit y (3).

Therefore it is given as enteric-coated granules in a

gelatin capsule and is dif® cult to administer in pa-

tients who are unable to swallow the intact capsule.

Administration of granules removed from the capsule

will potentially expose the drug to gastric acid (4, 5).

However, if the integrity of the enteric coating is

maintained, the acid suppressing effect should persist.

It has been shown that crushing the granules prior to

administration causes degradation and that omepra-

zole should not be given in this fashion (4, 5). We

conducted this study to compare the ef® cacy of the

intact capsule to omeprazole granules removed from

the capsule and given orally by different means of

administration.

MATERIALS AND METHODS

Fourteen healthy volunteers, eight women and six men,mean age 31 years (range 23± 41) were enrolled in the study.These subjects had no history of gastrointestinal or systemicdisease or current use of any medication that might affectgastric acid secretion. For females of child-bearing age, anaccepted method of birth control had to be documentedbefore enrollment in the study.

Manuscript received September 4, 1996; revised manuscript re-ceived December 12, 1996; accepted December 19, 1996.

From the Graduate Hospital, Department of Medicine, Phila-delphia, Pennsylvania.

Supported by a grant from Astra Merck.Presented at the annual meeting of the American College of

Gastroenterology, Seattle, Washington, October 1996.Address for reprint requests: Dr. Donald O. Castell, Department

of Medicine, The Graduate Hospital, Suite 501, Pepper Pavilion,1800 Lombard Street, Philadelphia, Pennsylvania 19146.

Digestive Diseases and Sciences, Vol. 42, No. 4 (April 1997), pp. 715± 719

715Digestive Diseases and Sciences, Vol. 42, No. 4 (April 1997)

0163-2116/97/0400-0715$12.50/0 Ñ 1997 Plenum Publishing Corporation

Subjects were instructed to take omeprazole 20 mg daily

before breakfast for a total of four weeks, including one-

week trials given in random order in the following manner:omeprazole capsule with 8 oz of water or omeprazole

granules mixed in 8 oz of orange juice, 8 oz of water in

which two tablets of Gold Alka-Seltzer antacid effervescent

tablets had been dissolved (Bayer Corp.) 1 teaspoon ofapple sauce (AS).

Subjects were instructed to let the granules stand in

orange juice (OJ) or Alka-Seltzer (ALK) for at least 15 minprior to drinking. The granules are sticky when wet andsubjects were told to ingest the granules mixed with OJ orALK as follows; 4 oz used to mix the granules in a cup anddrink it, 2 oz to rinse the cup used for any leftover mixture,and 2 oz as a chaser to ensure that all the drug was taken.

On day 7 for each regimen, subjects underwent gastricpH study as described below. Before insertion of a pHprobe, the position of the lower esophageal sphincter (LES)was determined from previous manometric study if avail-able or by the station pull-through technique using a solid-state esophageal manometry catheter (Konigsberg Instru-ments, Pasadena, California) connected to a Synecticspolygram. This study was approved by the InstitutionalReview Board at the Graduate Hospital.

pH Monitoring. Ambulatory pH monitoring was per-formed for an 8-hr period using a portable, monocrystallineantimony pH electrode and portable Digitrapper (SynecticsMedical, Irving, Texas). All electrodes were initially cali-brated in buffer solutions of pH 7 and pH 1. The pHelectrode was positioned with the tip in the stomach, 10 cmbelow the proximal margin of the LES.

After intubation with the pH probe, each subject took thedose of omeprazole in the same form as it was given for thepast week. A standard breakfast consisting of a muf® n, andan 8-oz cup of milk mixed with Carnation Instant Breakfastwas ingested within 15 min of taking the medication.

All subjects were instructed to pursue their normal activ-ities for the next 8 hr. Food and drinks, other than thestandard breakfast, were not allowed during the pH moni-toring. Alcohol and smoking were also not permitted. Thesame standard breakfast was provided on each of the fourstudy days.

Five subjects also had a similar gastric pH study per-formed prior to the four-week study after one dose ofomeprazole 20 mg without the one-week loading dose. Twoof these subjects took an omeprazole capsule, one subjectwas given omeprazole granules in OJ, and two receivedomeprazole granules in Alka-Seltzer solution. The samestandard breakfast and conditions were followed during pHmonitoring both after the single dose or one week ofloading dose.

Data Analysis. Data from the Digitrapper were loadedinto a computer and analyzed using the Synectics Esopha-gram program. In addition to computed analysis, eachtracing was reviewed by a physician blinded to the form ofomeprazole administration who assessed the time fromomeprazole ingestion until the ® rst point at which gastricpH returned to a sustained level below 4 after having beenabove 4.

Comparisons among the different regimens of omepra-zole were made using ANOVA (Newman-Keuls). The wil-coxon signed rank test was used to compare the results of

the pH study after loading dose to that of the single dose ofomeprazole.

RESULTS

Eleven volunteers completed the study. Three sub-

jects were eliminated because of noncompliance. Two

volunteers reported minor headaches and myalgias;

however, these resolved on continuat ion of the med-

ication, and they went on to complete the study.

The individual percentage of time of gastric pH .4 for each form of omeprazole administration is

shown in Figure 1. There was considerab le intersub-

ject variability in the gastric acid response to omepra-

zole, with 8-hr percentage of time of pH . 4 varying

from as low as 25± 30% to as high as 100%. This effect

has been previously reported in studies of normal

subjects in our laboratory (6). However, the intrasu-

bject variation was considerab ly tighter, with the re-

sponse to the four dosing regimens being quite simi-

lar. In only two subjects did gastric acid response to

one form of administrat ion vary by more than 100%

from the other three. Interestingly, this occurred with

the capsule on both occasions, but the response was

greater in one subject and smaller in the other. There

was no signi® cant difference in median values for acid

suppression between any of the four regimens

(ANOVA). These values are shown in Table 1.

Figure 2 shows individual time in minutes for the

gastric pH to reach below 4 after taking the four

dosing forms of omeprazole and breakfast. As with

percentage of time of pH . 4, there is wide intersub-

ject variability and much less variation in response by

the same subject. Median and range values for time to

intragastric pH , 4 for each form of administrat ion

are shown in Table 1. There were no signi® cant

differences between these time periods (ANOVA).

Fig 1. Individual total percentage of time of gastric pH . 4 for 11

subjects after different forms of administration of omeprazole 20mg daily. CAP 5 capsule, OJ 5 granules mixed with orange juice,

ALK 5 granules in Alka-Seltzer solution, AS 5 granules mixed inapplesauce.

MOHIUDDIN ET AL

716 Digestive Diseases and Sciences, Vol. 42, No. 4 (April 1997)

Median percent times of intragastric pH . 4 ac-

cording to study days (ie, days 1± 4) regardless of the

means of omeprazole administrat ion were also eval-

uated and showed remarkable similarity (day 1 563%; day 2 5 49%; day 3 5 64%, and day 4 5 65%).

No signi® cant differences were observed (ANOVA).

Thus, there appeared to be no evidence of either

cumulative response or development of tolerance

during this four-week omeprazole study.

Comparison of the ef® cacy of omeprazole (20 mg)

after the single dose to that after one week of loading

when given by the same method of administration in

® ve subjects is shown in Figure 3. In all ® ve subjects

gastric acid suppression (percentage of time of pH .4) was greater after a one-week loading dose as

compared to a single dose, and median values were

signi® cantly different (P 5 0.03).

DISCUSSION

Omeprazole is a lipophilic , weak base with a pK of

4. It is absorbed in the intestines and reaches the

parietal cells of the stomach through the bloodstream

(7). At pH 7 it is uncharged and can cross cell mem-

branes. However, in the secretory canaliculi of the

parietal cells, it is exposed to pH , 2, where it

becomes protonated, trapped, and concentrated. It is

converted to a sulfenamide form that binds covalently

and inhibit s the H1

, K1

-ATPase, a membrane-

spanning enzyme of the gastric parietal cells (8, 9).

Exposure to gastric acid degrades omeprazole.

Therefore, to circumvent this problem, the drug is

supplied as delayed release capsules containing ome-

prazole in the form of enteric-coated granules. These

granules are pH sensitive and release omeprazole

only when pH is above 6 to avoid degradation by

gastric acid and allow absorption to begin after the

drug leaves the stomach. This increases the bioavail-

ability to about 50% (3). Absorption is rapid and peak

plasma concentrations occur in 0.5± 3.5 hr (10).

After oral administrat ion, onset of action occurs

within 1 hr, and it has a half-life of 0.5± 1 hr (11). Two

hours after a single dose of 20 mg and 40 mg, maxi-

mum inhibition of acid secretion is about 51% and

86%, respectively (12). Omeprazole is dif® cult to ad-

minister in patients who are unable to take the cap-

sule orally. Oral administrat ion of crushed capsules

exposes the drug to gastric acid.

Various modes of administrat ion have been sug-

gested in clinical situations where ingestion of the

capsule is not possible. These include buffered and

nonbuffered suspensions (13, 14) and intravenous so-

lutions (15). It has also been documented that an

alkalinized omeprazole solution in critically ill pa-

tients provides effective prophylaxis against stress-

related mucosal damage (16). However, none of these

formulations are commercially available in the

United States. Omeprazole granules were found to be

TABLE 1. MEDIAN AND RANGE VALUES FOR GASTRIC ACID

CONTROL FOR EIGHT HOURS AFTER OMEPRAZOLE (20 MG)

Form of Administration

Capsule

Granules in

juice

Granules in

Alka-Seltzer

Granules in

applesauce

Percent time gastric

pH . 4.0Median (%) 68 59 63 65

Range (%) 25± 100 43± 100 31± 100 29± 99Time until gastric

pH falls , 4.0Median (min) 289 251 284 240

Range (min) 70± 490 120± 486 145± 491 110± 492

Fig 2. Individual time in minutes for 11 volunteers until the ® rstpoint at which gastric pH stayed below 4 after having risen above 4

following ingestion of omeprazole with different forms of admin-istration. Abbreviations as in Figure 1.

Fig 3. Total percentage of time of gastric pH . 4 for ® ve individualsubjects after a single dose of omeprazole 20 mg compared with

one week of same loading dose of omeprazole. Greater gastric acidsuppression occurred after the loading dose (P 5 0.03).

GASTRIC ACID SUPPRESSION BY OMEPRAZOLE

717Digestive Diseases and Sciences, Vol. 42, No. 4 (April 1997)

as effective as the capsule for acid suppression when

given in water via a nasogastric tube. However, the

granules tended to be very sticky when wet and re-

quired repeated ¯ ushing of the tube (17).

In the current study, we compared the ef® cacy of

omeprazole provided either as capsule or as enteric-

coated granules given orally by different means, on

gastric acid secretion measured by continuous intra-

gastric pH. Our data show that omeprazole granules

can be taken out of the capsule and given in various

ways for effective acid suppression.

We let the subjects mix the omeprazole granules in

OJ or ALK and let it stand for at least 15 min. The pH

of OJ is 3.1, and with two effervescent tablets of

(aspirin-free) ALK in 8 oz of water pH is 6.7. ALK

contains sodium bicarbonat e, citric acid, and potas-

sium bicarbonate. These agents act as buffers. Ome-

prazole granules release the drug in an alkaline envi-

ronment when the pH is above 6 (10). The stability of

the drug in buffered solution is strongly dependent on

the pH of the buffer pH; the half-life of degradation

is less than 10 min at pH , 4 and 18 hr at pH 6.5 (18).

We observed that the granules dissolved completely

in ALK solution on standing while they ¯ oated on the

surface of OJ. Therefore, theoretically, we had ome-

prazole in an alkaline buffered solution. When the

median percentage of times of gastric pH . 4 were

compared for granules in ALK solution it was equally

effective. Therefore, it seems likely that when the

granules dissolved releasing the drug, it was protected

from the acid in the stomach by the buffering action

of ALK solution . Furthermore, since omeprazole

does not effect the gastric emptying time (19) and

since the gastric t1/2 for liquids is short in normal

individuals, omeprazole in ALK solution probably

remained in the stomach for only a short time and in

a buffered form it escaped acid degradation .

In this study, we found considerable individual

variation in response to all forms of administration of

omeprazole , as previously reported for our laboratory

(6). This may be due to the genetic polymorph ism in

the hepatic cytochrome P-450 system involved in the

metabolism of omeprazole (20). While one female

subject showed consistent near 100% acid suppres-

sion, male subject failed to achieve 50% acid suppres-

sion on all four regimens, as measured by pH moni-

toring.

We also found that in most individual s the effect of

omeprazole 20 mg in the morning did not last for 24

hr, as is commonly believed. The basal gastric pH at

the start of pH monitoring after six days on omepra-

zole before the next dose was to be given was between

2 and 2.5. Only one subject showed pH . 4 through-

out the study. We have previously shown that the

median time of gastric acid suppression (pH . 4.0) in

normal individuals taking omeprazole 20 mg twice a

day to be about 7 hr (21). When we compared the

effect of a single dose to one week of loading, our data

substantiat es previous ® ndings that the ef® cacy of the

drug increases after multiple doses as compared to a

single dose (22).

Our study shows that omeprazole granules can be

given orally in an acidic solution such as orange juice,

in an alkaline solution such as Alka-Seltzer, or when

mixed with a semisolid such as applesauce and pro-

duce acid suppression comparable to the intact cap-

sule. Further studies will be needed to con® rm these

effects in patients and with administrat ion through a

tube. With these means of administration of omepra-

zole, we have attempted to establish regimens that

can be utilized when the whole capsule cannot be

given. As all of these means of administrat ion are

equally effective, they should be tailored to particular

clinical situations and the limitations of individual

patients depending on whether liquids or semisolids

can be swallowed.

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719Digestive Diseases and Sciences, Vol. 42, No. 4 (April 1997)