Administration of CREON® pancrelipase pellets via gastrostomy tube is feasible with no loss of gastric resistance or lipase activity: an in vitro study.

BACKGROUND AND OBJECTIVES: In clinical practice, the need sometimes arises to administer pancreatic enzyme replacement therapy via gastrostomy tube (G-tube) by mixing the pellets contained in the capsules with soft food. The objective of this study was to identify G-tubes that allow administration of pancrelipase gastro-resistant pellets without clogging, sticking, pellet damage or loss of enteric coating integrity. METHODS: In this in vitro study, CREON® (pancrelipase) Delayed-Release Capsules were opened and the pellets sprinkled onto a small amount of baby food of pH <4.5 (applesauce and bananas manufactured by both Gerber and Beech-Nut). The mixture was stirred gently and after 15 minutes poured into a 35 mL syringe and pushed slowly (~15 mL in 10-15 seconds) through a G-tube. Pellets were collected and the tube flushed with water. G-tubes were inspected visually for clogging/sticking and damage to pellets was assessed. If there was none with all four foods, pellet integrity (gastric resistance and lipase activity) was assessed by an in vitro dissolution method with a 2-hour gastric simulation step. The activity required to confirm integrity was ≥80% of actual US Pharmacopeia lipase activity per capsule. G-tubes initially tested were Kimberly-Clark MIC Bolus® size 14 French (Fr) and upwards and Kimberly-Clark MIC-KEY® 14 Fr and upwards. Following successful testing, assessment of Bard® Tri-Funnel 18 Fr and Bard® Button 18 Fr G-tubes was carried out. RESULTS: Based on the absence of clogging, sticking and visible damage to pellets, and the maintenance of pellet integrity, administration of CREON® pancrelipase pellets was feasible through the following G-tubes: Kimberly-Clark MIC Bolus® size 18 Fr, Kimberly-Clark MIC-KEY® 16 Fr, Bard® Tri-Funnel 18 Fr and Bard® Button 18 Fr. Lipase activity met the predetermined specification and was ≥90% for all four tubes and all four foods, with no differences versus untreated pellets (i.e. pellets not mixed with baby food or pushed through a G-tube). These data apply to all CREON® pancrelipase capsule formulations, regardless of their strength in lipase units, as pellet composition, size and quality are identical. CONCLUSION: CREON® pancrelipase pellets can be mixed with baby food of pH <4.5 and administered via the following G-tubes without clogging, sticking or visible pellet damage, and with no loss of gastric resistance or lipase activity: Kimberly-Clark MIC Bolus® size 18 Fr and larger, Kimberly-Clark MIC-KEY® 16 Fr and larger, Bard® Tri-Funnel 18 Fr and larger and Bard® Button 18 Fr and larger.

In vitro comparative study of three pancreatic enzyme preparations: dissolution profiles, active enzyme release and acid stability.

BACKGROUND: Various pancreatic enzyme preparations are used for the treatment of pancreatic insufficiency but their bioequivalence is often unknown. AIM: To determine in vitro the pH-dependent release and acid resistance of enzymes from three commercially available pancreatin capsules, two containing enteric-coated (Creon 25000; Eurobiol 25000) and one uncoated (Eurobiol 12500) microspheres. METHODS: Dissolution experiments were performed at pH values ranging from 4.0 to 5.8. Lipase, chymotrypsin and amylase activities were measured in the solution as a function of time. RESULTS: Eurobiol 25000 started to release its enzymes significantly at pH 5.0 (t(1/2) = 71 min), whereas the enzymes from Creon 25000 were only released at higher pH value (5.4; t(1/2) = 49.2 min). Unlike chymotrypsin, lipase and amylase were highly sensitive to acidic conditions at the lowest pH values tested. Both enzymes were also found to be sensitive to proteolytic inactivation at the highest pH values tested. Overall, Eurobiol 25000 released higher amounts of active amylase and lipase than Creon 25000 at the pH values usually found in duodenal contents. The uncoated Eurobiol 12500 preparation was, however, the only one that could immediately release rather high levels of active chymotrypsin and lipase at low pH (4.5). CONCLUSION: These findings suggest that pH-sensitive enteric-coated pancreatin products containing similar amounts of enzymes might not be bioequivalent depending on the pH of duodenal contents.

Enzyme content and acid stability of enteric-coated pancreatic enzyme products in vitro.

OBJECTIVES: Pancreatic enzymes are prescribed routinely for pancreatic insufficiency. In the current health care environment, drug substitution is commonly performed although there is no proof of therapeutic or bioequivalence for these products. The purpose of this in vitro, prospective study was to evaluate the enzyme contents and dissolution of various capsules of pancreatic enzyme using current United States Pharmacopoeia (USP) methodology. METHODS: Nine different pancreatic enzyme products were purchased on the market and supplied to Irvine Analytical Laboratories (IAL) (Irvine, CA). All test products were maintained in the laboratory environment, at room temperature, throughout the testing period by IAL. USP procedures for assay and dissolution testing of pancrelipase delayed-release capsules, as described in the latest USP supplement were observed during product testing, including determination of amylase, lipase, and protease activity. In addition, a point assay with measurement of lipase after dissolution in simulated gastric fluid pH of 1.0 for 1 hour and then dissolution in pH 6 phosphate buffer for 30 minutes performed in accordance with USP guidelines. RESULTS: Assay results of amylase, protease, and lipase from the 9 tested products are within USP specified limits. The percentage of label claim for these enzymes was higher than depicted in their label except for one drug batch. However, the percentage of lipase activity after dissolution varied with 2 of 3 batches of 1 drug not dissolving, and 1 batch of another drug, revealing only 8% lipase activity in the USP dissolution test. CONCLUSION: While assay of pancreatic enzymes reveal they were equal to their USP claims regarding their enzyme content, not all pancreatic enzyme replacements are equal in their release of lipase activity according to USP requirements. The findings maybe clinically seen with therapeutic failures of enzyme products. The FDA has recently decreed that all pancreatic enzyme products will require an approved NDA as differences in pharmaceutical quality have been identified in this product. Thus, it is considered that substitution of these products maybe questionable. Things are seldom what they seem- not all pancreatic enzyme replacements are equal. Further studies are warranted to investigate dissolution characteristics.

The enzyme levels in blood are not affected by oral administration of a pancreatic enzyme preparation (Creon 10,000) in pancreas-insufficient pigs.

After oral intake, small amounts of intact protein may be absorbed into the blood circulation. The current study investigated whether orally administered pancreatic enzymes were absorbed from the intestine. The study included 28 pigs; 3 control pigs with intact pancreatic function and 25 pigs that were made exocrine pancreas insufficient by duct ligation (20 pigs) or total pancreatectomy (5 pigs). The pigs received a pancreatic enzyme preparation (0, 2, 4, or 8 g of Creon 10,000) together with the feed. The blood plasma was analyzed for pancreatic lipase activity with a [3H]-triolein substrate assay, while (pro)colipase and cationic trypsin(ogen) levels were measured with enzyme-linked immunosorbent assay (ELISA). Administration of Creon (0-8 g) caused no significant changes in plasma (pro)colipase or cationic trypsin(ogen) levels. Lipase activity peaks in plasma samples were found, but they did not correspond to the administration of Creon. The potential source of these plasma lipase activity peaks is discussed. The results showed no absorption into blood of pancreatic enzymes after oral administration (0, 2, 4, or 8 g of Creon mixed with 100 g of feed) to pancreas-insufficient pigs.