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

Authors


Sharma Division of Gastroenterology, University of Arkansas for Medical Sciences, Slot 567, 4301 W. Markham Street, Little Rock, AR 72205-7199, USA.

Abstract

Background:

Because of its acid-labile nature, lansoprazole 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 gastrostomy, 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 fl. 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 (< 0.0001). Median intragastric pH rose from 1.5 to 5.2 (< 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% (< 0.0001 for each comparison).

Conclusion:

Lansoprazole can effectively suppress intragastric acidity when given through a gastrostomy as intact, non-encapsulated granules in orange juice.

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 oesophagitis.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 benefit 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 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 affiliated 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 medications. Patients did not receive any prokinetic agents or other acid-suppressing medicines, including anticholinergics, 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 Briefly, 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 fl. 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 fl. 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 (Flexiflo 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 gastrostomy tube within the gastric lumen. We did not confirm the electrode position radiologically, but obtained consistently good pH recordings. We repeated the 24-h intragastric pH study under identical conditions 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 briefly 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 significant. 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 (< 0.0001). The effect of lansoprazole 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 (< 0.0001).

Figure 1.

.  Individual mean pH values on 24-h intragastric pH monitoring before and after lansoprazole granules 30 mg daily for 7 days.

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 lansoprazole to 81.1 ± 11% on day 7 (< 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 (< 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 (< 0.0001).

Figure 2. Proportion (%) of 2.

Figure 2. Proportion (%) of 2.

4-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 (*< 0.0001 vs. baseline).

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 comparability 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 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 efficacious in healing duodenal ulceration in patients with a gastrostomy 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 efficacious 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. (Deerfield, IL) supplied the lansoprazole and provided additional financial support for this study.

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