The pharmacodynamics of lansoprazole administered viagastrostomy as intact, non-encapsulated granules

V. K. SHARMA, E. A. UGHEOKE, R. VASUDEVA & C. W. HOWDEN

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

Carolina, USA

Accepted for publication 13 July 1998

INTRODUCTION

The proton pump inhibitor lansoprazole is a potent,

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

controlled clinical trials, it has been shown to be

superior to H2-receptor antagonists in healing peptic

ulcers2, 3 and erosive oesophagitis.4 Compared to

omeprazole 20 mg, lansoprazole 30 mg is at least as

effective in healing duodenal ulcers5 or erosive oeso-

phagitis.6

Like other proton pump inhibitors, lansoprazole 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 which have a higher

pH.

Patients with a gastrostomy may need proton pump

inhibitor treatment because of erosive oesophagitis or

peptic ulcer disease. However, such patients may be

unable to swallow intact capsules and may previously

have been denied the therapeutic bene®t of a proton

pump inhibitor. We have previously shown that

omeprazole can be safely and effectively administered

via a gastrostomy as intact granules in orange juice.7

For lansoprazole, pharmacokinetic studies have shown

SUMMARY

Background: Because of its acid-labile nature, lansopra-

zole is usually administered as encapsulated enteric-

coated granules. The gelatin capsule and acid-resistant

coating of the granules have been considered essential

for effective drug absorption and optimal bioavailability.

Lansoprazole may attain effective plasma levels when

given as non-encapsulated intact granules, but effects

on intragastric acidity are unknown.

Aim: To test the effectiveness of non-encapsulated,

intact lansoprazole granules in suppressing intragastric

acidity when administered through a gastrostomy.

Methods: Eight men, each with an established gastro-

stomy, underwent baseline 24 h intragastric pH

monitoring while off any acid-suppressing medication.

Via the gastrostomy, they then received 7 days of once-

daily dosing with 30 mg lansoprazole as intact granules

in 3 ¯. oz. of orange juice. Intragastric pH monitoring

was repeated on day 7.

Results: Mean intragastric pH pre-dosing was 1.96 �

0.5 (s.d.). This increased to 4.7 � 0.6 on day 7

(P < 0.0001). Median intragastric pH rose from 1.5 to

5.2 (P < 0.0001). Before lansoprazole, the proportions

of time when intragastric pH was above 3, 4 and 5 were

23.2, 13.5 and 7.5%, respectively. Corresponding

values after 7 days of lansoprazole were 81.1, 70.2

and 52.3% (P < 0.0001 for each comparison).

Conclusion: Lansoprazole can effectively suppress

intragastric acidity when given through a gastro-

stomy as intact, non-encapsulated granules in orange

juice.

Correspondence to: Dr V. K. Sharma, Division of Gastroenterology, Uni-

versity of Arkansas for Medical Sciences, Slot 567, 4301 W. MarkhamStreet, Little Rock, AR 72205-7199, USA.

Aliment Pharmacol Ther 1998; 12: 1171±1174.

Ó 1998 Blackwell Science Ltd 1171

comparable serum levels after administration of intact,

non-encapsulated granules in apple juice or apple sauce

as with the customary capsule formulation.8, 9 The

present study was designed to evaluate the effect on

24-h intragastric acidity of intact, non-encapsulated

lansoprazole granules administered via a gastrostomy.

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 lansoprazole.

Informed consent was obtained from the patient or his

legal representative prior to enrolment in the study.

Patients receiving treatment with a proton pump

inhibitor or an H2-receptor antagonist were considered

eligible for inclusion if, in the opinion of the investigator

and the patient's primary physician, these medications

could be safely discontinued for at least 1 week prior to

the study. Before the study, two patients had been

receiving a proton pump inhibitor and two had been

receiving an H2-receptor antagonist via gastrostomy.

None of the patients had been receiving oral medica-

tions. Patients did not receive any prokinetic agents or

other acid-suppressing medicines, including anticholi-

nergics, during the study. Other prescribed medicines

necessary for patient care were continued during the

study.

Patients were given lansoprazole 30 mg as intact

granules at 08.00 hours every morning. Lansoprazole

granules were administered according to the method we

have previously described for omeprazole.7 Brie¯y,

lansoprazole granules were obtained by opening a

standard 30 mg capsule. The granules were poured

into an open 30 mL catheter-tipped syringe that was

attached to the patient's gastrostomy tube. To this, we

added about 1.5 ¯. oz. of orange juice (pH 3.5 � 0.1) to

wash the granules through the gastrostomy and into

the gastric lumen. We then injected a further 1.5 ¯. oz.

of orange juice via the syringe to ensure that all

granules were delivered into the stomach. The patients

had previously been receiving continuous feeding via

their gastrostomy. However, we discontinued feeding

for 2 h before and 1 h after administration of the

lansoprazole granules.

Baseline 24-h intragastric pH data were obtained

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). We passed the probe

through the gastrostomy tube (Flexi¯o Magna-Port,

Ross Laboratories, Columbus, OH) to a predetermined

length of 42 cm and secured it with adhesive tape so

that the electrode lay in the gastric lumen. The electrode

was 2±3 cm from the internal bumper of the gastro-

stomy tube within the gastric lumen. We did not

con®rm the electrode position radiologically, but

obtained consistently good pH recordings. We repeated

the 24-h intragastric pH study under identical condi-

tions after 7 days of once daily dosing with lansoprazole

granules 30 mg.

On the days of the intragastric pH studies, patients

received bolus rather than continuous feeding via their

gastrostomy (Osmalite-HN, two cans three times daily).

If required, we brie¯y removed the probe for tube

feedings or for the administration of any prescribed,

non-study medications. The times of removal of the

probe and the duration of the probe being outside the

stomach were identical during both 24-h pH studies.

The probe was then repositioned at 42 cm. 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 lansoprazole using a paired Student's t-test

(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 Dorn VA/University of

South Carolina School of Medicine Human Studies

Subcommittee.

RESULTS

We initially enrolled 10 patients. We excluded two who

had achlorhydria during the baseline intragastric pH

study. Eight men (mean age 63.4 years; range 48±

75 years) completed the study. All patients tolerated

lansoprazole well; no adverse events were observed

during the study.

Mean 24-h intragastric pH before administration of

lansoprazole was 1.96 (s.d. 0.5). This rose to 4.7 (s.d.

0.6) on day 7 (P < 0.0001). The effect of lansoprazole

1172 V. K. SHARMA et al.

Ó 1998 Blackwell Science Ltd, Aliment Pharmacol Ther 12, 1171±1174

was consistent among the different patients studied,

with an appreciable increase in mean intragastric pH

seen in all. These data are depicted in Figure 1. Median

24-h intragastric pH rose from 1.5 to 5.2 with

lansoprazole (P < 0.0001).

The proportions of the 24-h recording periods during

which intragastric pH was maintained above 3, 4 and 5

are depicted in Figure 2. The mean proportion of the

24 h recording period during which the intragastric pH

was above 3 rose from 23.2 � 13.4% before lansopra-

zole to 81.1 � 11% on day 7 (P < 0.0001). Intragastric

pH was above 4 for 13.5 � 8.9% of the recording period

at baseline. This rose to 70.2 � 12.4% on lansoprazole

(P < 0.0001). Intragastric pH was above 5 for

7.5 � 6.1% of the recording period during the baseline

study. This rose to 52.3 � 17.8% on lansoprazole

(P < 0.0001).

DISCUSSION

Lansoprazole is a lipophilic weak base. It is acid labile,

and is usually administered by mouth as a delayed-

release capsule of enteric-coated granules. The acid-

resistant enteric coating is activated at pH > 6.0. The

gelatin capsule prevents the enteric-coated granules

from coming into contact with water or saliva that might

activate the coating prematurely. Gastric acid dissolves

the gelatin capsule, releasing enteric-coated lansoprazole

granules into the gastric lumen, where dissolution does

not occur in the acidic pH in the stomach. The more

alkaline environment of the small intestine dissolves the

coating to release the drug for absorption.1

Intraluminal gastric acid could protonate the drug

before absorption, thereby decreasing its bioavailability.

The acid-labile nature of lansoprazole, and the potential

for activation of the granule coating at neutral pH,

suggests that there could be premature release and

inactivation of the drug in the stomach when

administered in water through a gastrostomy. By

dissolving the coating, water might make the granules

more adherent, thereby leading to clumping in

gastrostomy tubes and possible blockage. Crushing the

granules, or any disruption to their enteric coating,

would potentially render the medication ineffective by

exposing it to gastric acid.

Chun et al. have shown comparable serum lansoprazole

levels when intact, non-encapsulated granules in apple

juice were administered via a nasogastric tube, to those

observed following oral dosing with intact capsules.9

They have also demonstrated pharmacokinetic compar-

ability when they gave lansoprazole granules orally in

apple sauce.8 However, the effect of intact lansoprazole

granules on gastric acidity has not been assessed.

We have previously shown that non-encapsulated,

intact omeprazole granules are effective in suppressing

intragastric acidity when administered in orange juice

via a gastrostomy.7 The degree of suppression of acidity

Figure 1. Individual mean pH values on 24-h intragastric pH

monitoring before and after lansoprazole granules 30 mg daily for

7 days.

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

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

and after 7 days of dosing with lansoprazole granules 30 mg once

daily (*P < 0.0001 vs. baseline).

LANSOPRAZOLE GRANULES VIA GASTROSTOMY 1173

Ó 1998 Blackwell Science Ltd, Aliment Pharmacol Ther 12, 1171±1174

obtained was comparable to that reported by other

investigators using intact capsules. In the present study,

we administered lansoprazole granules in orange juice,

as previously described for omeprazole.7 The orange

juice maintained an acidic milieu around the granules

until they reached the duodenum, where the enteric

coating dissolves and the drug disperses and is absorbed

in the usual fashion. This prevents any premature

activation of the enteric coating and any inactivation of

the drug by gastric acid. Administering the granules in

orange juice also prevents clumping in the gastrostomy

tube and avoids possible blockage.

In our patients, 7 days of dosing with lansoprazole

granules 30 mg raised mean intragastric pH from 1.96

to 4.7. This is comparable to the results of other

investigators using intact lansoprazole capsules. In a

study by Tolman et al., 5 days of once daily dosing with

lansoprazole 30 mg as intact capsules produced a mean

intragastric pH of 4.9.10 The mean intragastric pH was

> 3, 4 and 5 for about 72, 66 and 52%, respectively, of

the 24 h recording period.10

In the present study, 7 days of lansoprazole granules

30 mg daily kept the intragastric pH above 3 for 81.1%

of the 24-h recording period, which is equivalent to

19.5 h of the day. Maintenance of an intragastric pH

above 3 for approximately 20 h of the day has been

associated with optimal healing of duodenal ulcer.11 The

results from this study suggest that lansoprazole 30 mg

once daily as intact granules should be ef®cacious in

healing duodenal ulceration in patients with a gastro-

stomy if the drug is given in the manner described.

Lansoprazole granules maintained the intragastric pH

above 4 for 70.2% of the 24-h recording period, which

is equivalent to 16.9 h of the day. Maintenance of

intragastric pH above 4 appears to be important for

optimal healing of erosive oesophagitis.12 Lansoprazole

should therefore be ef®cacious in the management of

erosive oesophagitis in patients in whom the drug could

only be given via a gastrostomy as intact, non-

encapsulated granules.

In conclusion, this study has shown that lansoprazole

is effective in suppressing intragastric acidity when

given via a gastrostomy as intact, non-encapsulated

granules. Effects on intragastric acidity are comparable

to those seen with the conventional formulation and

administration. Patients with a gastrostomy who

require treatment with a proton pump inhibitor can

be given intact lansoprazole granules suspended in

orange juice and administered via the gastrostomy

tube.

ACKNOWLEDGEMENTS

TAP Pharmaceuticals Inc. (Deer®eld, IL) supplied the

lansoprazole and provided additional ®nancial support

for this study.

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