The effects on intragastric acidity of per-gastrostomy administrationof an alkaline suspension of omeprazole

V. K. SHARMA, R. VASUDEVA & C. W. HOWDEN

Division of Digestive Diseases and Nutrition, Department of Internal Medicine, University of South Carolina School of

Medicine, Columbia, SC, USA

Accepted for publication 5 April 1999

INTRODUCTION

The proton pump inhibitor omeprazole is a non-

competitive inhibitor of gastric H+,K+-ATPase.1 Like

other proton pump inhibitors, omeprazole is a lipophilic

weak base and is unstable in an acid environment. It is

therefore usually administered as capsules of enteric-

coated, acid-resistant granules. The capsules release the

drug in the neutral or alkaline environment of the

duodenum.1 The gelatin capsule prevents premature

dissolution of the acid-resistant enteric coating by water

or saliva that have a higher pH.

Patients with a gastrostomy may need treatment for

gastro-oesophageal re¯ux disease or peptic ulcer. Since

such patients are typically unable to swallow intact

capsules, they may be denied the bene®ts of proton

pump inhibitor treatment. We have previously shown

that omeprazole and lansoprazole can be safely and

effectively administered via a gastrostomy as intact,

non-encapsulated granules in orange juice.2, 3 How-

ever, there may still be perceived dif®culties with

administering granules through a gastrostomy or

nasogastric tube of size smaller than 18 Fr because of

concerns with tube blockage interfering adversely with

drug delivery. We therefore studied the effect on

intragastric acidity of a liquid formulation of omeprazole

administered via gastrostomy. This has previously been

termed `simpli®ed omeprazole suspension' (SOS).4±6

This formulation has been used in critically ill pa-

tients.4, 6 However, this is the ®rst study to speci®cally

examine its pharmacodynamics in patients who were

not critically ill.

SUMMARY

Background: It may be dif®cult to administer proton

pump inhibitors via gastrostomy. Previous studies have

examined the effect of intact proton pump inhibitor

granules in orange juice. This study examined the effect

of an alkaline suspension of omeprazole (simpli®ed

omeprazole suspension (SOS)) on 24-h intragastric

acidity.

Methods: Six men with an established gastrostomy had

a baseline 24-h intragastric pH study using methodol-

ogy we have previously described. They then received

20 mg SOS o.d. for 7 days and had a repeat pH study at

the end of this period. Four of the patients then received

20 mg SOS with 30 cc of liquid antacid (Mylanta, TM)

per gastrostomy o.d. for a further 7 days and then

underwent a third pH study.

Results: SOS raised mean pH from 2.2 to 4.1. Intragas-

tric pH was above 3, 4 and 5 for 35, 28 and 17% of the

24-h period at baseline, respectively; corresponding

values after SOS were 63, 51 and 39%, respectively.

Addition of liquid antacid to SOS did not further

increase its pH-controlling effect.

Conclusions: We found a statistically signi®cant effect of

o.d. SOS on intragastric pH when administered via

gastrostomy. We found no additional bene®t of admin-

istering SOS with liquid antacid.

Correspondence to: Dr Colin W. Howden, Division of Digestive Diseases,

Rush-Presbyterian-St. Luke's Medical Center, 1725 West Harrison Street,Suite 206, Chicago, IL 60612, USA.

Aliment Pharmacol Ther 1999; 13: 1091±1095.

Ó 1999 Blackwell Science Ltd 1091

PATIENTS AND METHODS

This was an open-label study with each patient serving

as his own control. All patients with a gastrostomy who

were resident in the WJB Dorn Veterans' Affairs Medical

Center (Columbia, SC) or its af®liated nursing home were

considered eligible for the study. We excluded patients

with a history of upper gastrointestinal tract surgery,

acute illness or known sensitivity to omeprazole.

Informed consent was obtained from each patient or

his legal representative before enrolment in the study.

Patients did not receive any other acid-suppressing

medicines, anticholinergics, or prokinetic agents for

1 week before starting, and during, the study. Other

prescribed medicines that were considered necessary for

patient care were continued during the study.

We have previously described the procedure for

measurement of intragastric pH via the gastrostomy.2, 3

Brie¯y, baseline 24-h intragastric pH data were ob-

tained using a Zinetics 24 single sensor internal

reference monocrystalline antimony pH probe (Zinectics

Medical Inc., Salt Lake City, UT) and Digitrapper Mark

III (Synectic Medical Inc., Irving, TX). The probe was

passed through the gastrostomy tube (Flexi¯o Magna-

PortTM, Ross Laboratories, Columbus, OH) to a pre-

determined length of 42 cm. It was secured to the

external end of the gastrostomy tube with adhesive tape

so that the electrode was 2±3 cm from the internal

bumper of the gastrostomy tube within the gastric

lumen. As in previous studies,2, 3 we did not con®rm the

electrode position radiologically. However, we consis-

tently obtained good pH recordings.

Following the baseline 24-h intragastric pH study, six

patients were given 7 days of o.d. dosing with SOS

20 mg. To prepare the SOS, a 20-mg capsule of

omeprazole was opened and its contents poured into a

standard 15 cc syringe. Following that, 10 cc of 8.4%

sodium bicarbonate solution was drawn into the

syringe. The syringe was gently shaken for 10±

15 min until a white suspension of omeprazole had

been obtained. This freshly prepared suspension was

administered through the gastrostomy tube and ¯ushed

into the gastric lumen using an additional 10±15 cc of

tap water. A 24-h intragastric pH study, identical to the

baseline study, was repeated after 7 days of o.d. dosing

with SOS.

Following the second intragastric pH study, four of the

patients received an additional 7 days of o.d. dosing

with SOS 20 mg given with 30 cc of a liquid antacid

(Mylanta TM), via the gastrostomy. This was performed

to see if the addition of a liquid antacid would have any

additional pH-raising effect over SOS alone. A third 24-

h intragastric pH study, identical to the ®rst two, was

performed at the end of this 7-day dosing period.

During the study, patients received continuous feeding

via their gastrostomy on the days when intragastric pH

was not measured. However, feedings were brie¯y

discontinued for 2 h before and for 1 h after adminis-

tration of SOS. On the days of the intragastric pH

studies, patients received bolus rather than continuous

feeding via their gastrostomy (Osmalite-HN, 2 cans

t.d.s.). If required, the probe was brie¯y removed for

tube feedings or for the administration of any prescribed

non-study medications. The probe was then re-posi-

tioned at the 42 cm mark. The times of removal of the

probe, and the duration of the probe being outside the

stomach were similar during each 24-h pH study. Other

prescribed medicines were given at the same time as the

feedings to minimize the time that the probe was outside

the stomach.

Intragastric pH data are summarized as mean �

standard deviation. Results at baseline were compared

to those on SOS alone and to those on SOS and liquid

antacid using paired Student's t-tests (two-tailed). P-

values of 0.05 or less were regarded as statistically

signi®cant. SPSS 7.1 for Windows (SPSS Inc., Chicago,

IL) was used for data analysis.

This study was approved by the WJB Dorn Veterans

Affairs Medical Center/University of South Carolina

School of Medicine Human Studies Subcommittee.

RESULTS

Six men (mean age 69.2; s.d. 9.8) met the enrolment

criteria and were included in the study. Each success-

fully completed 7 days of o.d. dosing with SOS. Two

patients who completed this ®rst part of the study were

discharged before they could complete the second phase

of the study, which consisted of SOS and liquid antacid.

SOS was well tolerated whether given with or without

the liquid antacid; no adverse events were observed

during the study.

Mean (� s.d.) 24-h intragastric pH was 2.2 + 0.8 at

baseline. This rose to 4.1 + 1.5 after 7 days of dosing

with SOS 20 mg (P < 0.01). The effect of SOS was

highly consistent with an appreciable rise in mean

intragastric pH seen in all patients. These data are

depicted in Figure 1.

1092 V. K. SHARMA et al.

Ó 1999 Blackwell Science Ltd, Aliment Pharmacol Ther 13, 1091±1095

In the four individuals who went on to receive 7 days

of dosing with SOS 20 mg and liquid antacid, mean

(� s.d.) 24-h intragastric pH was 2.0 � 0.7 at baseline.

This rose to 3.8 � 0.5 after SOS alone, and was

4.1 � 0.5 after SOS and liquid antacid (P < 0.01 vs.

baseline; P > 0.05 vs. SOS alone).

During the baseline study, intragastric pH was held

above 3, 4 and 5 for 35%, 28% and 17%, respectively,

of the recording period. Following 7 days of o.d. dosing

with SOS 20 mg, the corresponding ®gures were 63%,

51% and 39% (P < 0.05 for each comparison with

baseline). After 7 days of o.d. dosing with SOS 20 mg

and liquid antacid, the corresponding ®gures were 64%,

56% and 42% (P < 0.05 for each comparison with

baseline; P > 0.05 for each comparison with SOS

20 mg alone). These data are depicted in Figure 2.

DISCUSSION

Omeprazole is a lipophilic weak base that is acid-labile.

It is usually administered by mouth as enteric-coated

granules contained in a gelatin capsule. The acid-

resistant enteric coating of the granules is activated at a

pH of 6.0 or above. The gelatin capsule prevents the

enteric-coated granules from coming into contact with

water or saliva that might activate the coating prema-

turely. Gastric acid dissolves the gelatin capsule releas-

ing omeprazole granules into the gastric lumen. The

acidic pH in the stomach prevents dissolution of the

enteric coating. The more alkaline environment of the

small intestine dissolves the coating to release the drug

for absorption.1 Acid could protonate the drug within

the gastric lumen and thereby reduce its absorption.

Disruption of the enteric coating of the granules, for

example, by crushing them, might render the medica-

tion ineffective by exposing it to gastric acid.

We have previously shown that both omeprazole and

lansoprazole can be safely and effectively administered

via gastrostomy when given as intact granules in

orange juice.2, 3 After 7 days of o.d. dosing, omeprazole

20 mg as intact granules suspended in orange juice

raised mean intragastric pH from 1.8 to 4.9

(P < 0.0001) in 14 gastrostomy patients.2 Presumably,

the orange juice maintained a suf®ciently acidic milieu

around the granules until they reached the duodenum

where the enteric coating dissolved and the drugs were

absorbed as usual. This method of administration

prevented any premature activation of the enteric

coating and any inactivation of either drug by gastric

acid. Administering the granules in orange juice also

prevented clumping in the gastrostomy tube and

avoided possible blockage. SOS 20 mg actually pro-

duced a quantitatively smaller effect on intragastric pH

than the same dose of non-encapsulated intact ome-

prazole granules in a similar patient population.2

SOS is a relatively novel formulation obtained by

suspending omeprazole granules in 8.4% sodium bicar-

Figure 1. Mean 24-h intragastric pH at baseline, following 7 days

of o.d. dosing with SOS 20 mg (n � 6), and following 7 days of

o.d. dosing with SOS 20 mg and Mylanta TM 30 cc (n � 4).

Figure 2. Proportion (%) of 24-h recording period during which

the intragastric pH was maintained above 3,4 and 5 at baseline,

following 7 days of o.d. dosing with SOS 20 mg (n � 6), and

following 7 days of o.d. dosing with SOS 20 mg and Mylanta TM

30 cc (n � 4).

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Ó 1999 Blackwell Science Ltd, Aliment Pharmacol Ther 13, 1091±1095

bonate solution.4±6 However, there is no agreed stan-

dard method for preparing SOS. Given the lack of

published data concerning the stability of this formula-

tion, we prepared SOS freshly for each patient and each

administration. This alkaline suspension neutralizes

gastric acid with which omeprazole might come into

contact. It maintains a neutral milieu around the

omeprazole and so prevents its intraluminal protona-

tion. Omeprazole can then be absorbed from the small

intestine and transported to the parietal cells where it

irreversibly binds and inactivates canalicular H+,K+-

ATPase.

Phillips et al.4 and Lasky et al.6 studied SOS in critically

ill patients in an attempt to limit bleeding from stress-

related gastric mucosal disease. SOS was given via

nasogastric tube as two doses of 40 mg, 8 h apart,

followed by 20 mg each morning for the duration of the

study; pH data were obtained by nasogastric aspiration.

The mean baseline values for intragastric pH in these

studies were 3.5 and 3.3, respectively; with SOS these

increased to 7.1 and 6.7 (P < 0.005). The higher

baseline pH seen in these critically ill patients compared

to our patients probably resulted in less intragastric

degradation and greater bioavailability of the ®rst dose

of omeprazole. Furthermore, the use of a larger loading

dose of omeprazole may have contributed to their

results, showing an apparently greater antisecretory

effect of SOS than we found. No patients in these

uncontrolled studies developed evidence of clinically

signi®cant upper gastrointestinal bleeding.

Mohiuddin and colleagues studied the effects of 7 days

of oral administration of omeprazole in sodium bicar-

bonate (two Alka Seltzer Gold TM tablets dissolved in

240 cc of water).7 This formulation of omeprazole

raised intragastric pH above 4 for 65.1% of an 8-h

recording period. This was not signi®cantly different

from the effect of 7 days of dosing with omeprazole

20 mg o.d. as intact capsules, which kept the pH above

4 for 68.7% of the recording period.

In a comparative study with lansoprazole, Tolman and

colleagues administered omeprazole 20 mg o.d. as

intact capsules to 17 healthy adult men. After 5 days

of o.d. dosing, intragastric pH was maintained above 3,

4 and 5 for 61%, 50% and 40% of the day, respective-

ly.8 This corresponds very closely to our results for SOS

alone; intragastric pH was above 3, 4 and 5 for 63%,

51% and 39%, respectively, in our study. Furthermore,

our results are consistent with those of Chiverton et al.9

who administered omeprazole 20 mg as intact capsules

o.d. in the morning for 7 days to six patients with

healed duodenal ulcer. Baseline intragastric pH was 1.7

in that study and rose to 3.9 with omeprazole. We have

not compared the pharmacodynamic response of SOS

and intact omeprazole capsules in the same patients.

However, the results from these previous studies suggest

that the antisecretory effects of these two formulations

are at least comparable.

Our study has shown that SOS 20 mg per day

suppresses intragastric acidity when given via a gas-

trostomy. In a previous study, we obtained a quantita-

tively greater effect on intragastric pH with intact

omeprazole granules in orange juice.2 However, we

have not directly compared these two formulations in

the same patients. The effect of SOS 20 mg that we

obtained is similar to that previously reported with

intact omeprazole capsules.8, 9 While our results appear

to be at variance to those of Phillips et al.4 and Lasky

et al.,6 this can probably be explained by differences in

patient characteristics, dosing schedules and the meth-

ods used for intragastric pH measurement. Preliminary,

uncontrolled studies of SOS suggest that it may be more

effective than an intravenous H2-receptor antagonist

for the treatment and prophylaxis of stress-related

gastric mucosal disease.4, 6 However, data on its

effectiveness in other conditions are currently lacking.

ACKNOWLEDGEMENTS

Astra Merck (Wayne, PA) supported this study.

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Ó 1999 Blackwell Science Ltd, Aliment Pharmacol Ther 13, 1091±1095