title: Interaction between fed gastric media (Ensure Plus®) and different hypromellose based caffeine controlled release tablets: comparison and mechanistic study of caffeine release in fed and fasted media versus water using the USP dissolution apparatus 3.
abstract: The aim of the study was to investigate caffeine release in fed and fasted state media from three controlled release matrix tablets containing different HPMC viscosity grades. The biorelevant in vitro dissolution methods utilize the USP 3 dissolution apparatus and biorelevant media to simulate fed and fasted gastro-intestinal dissolution conditions. The effect of tablet reciprocation rate (dip speed) in dissolution media (10 and 15 dips per minute) and media (water, fed and fasted) on caffeine release rate from - and erosion rate of - 100, 4000 and 15,000 mPa s HPMC viscosity tablets was investigated using factorial designed experiments. Furthermore, the mechanism of release in Ensure Plus(®), a nutrition drink similar in composition to the FDA standard meal, was investigated by studying tablet swelling using texture analysis. Altering dip speed has negligible effect on release and erosion rates. Using fasted media instead of water slightly decreases caffeine release from 100 and 4000 mPa s HPMC viscosity tablets as well as erosion rates, while 15,000 mPa s tablets remain unaffected. Fed compared to fasted media decreases caffeine release rate, and the food effect is greater for the 100 mPa s viscosity tablets compared to the 4000 and 15,000 mPa s viscosity tablets. The investigation using texture analysis indicates that Ensure Plus(®) becomes rate-limiting for caffeine release from HPMC tablets by forming a hydrophobic barrier around the tablets. The barrier decreases tablet water permeation, which decreases erosion rate in 100 mPa s viscosity tablets, swelling in 15,000 mPa s viscosity tablets and caffeine release from both tablets. This observed interaction between Ensure Plus(®) and the HPMC tablets may translate into decreased drug release rate in the fed stomach, which may decrease the amount of drug available for absorption in the small intestine and thus reduce systemic drug exposure and maximum plasma concentration.
authors.affiliation: Section for Pharmaceutical Design and Drug Delivery, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 København Ø, Denmark.
authors.forename: Frans
authors.initials: F
authors.lastname: Franek
authors.affiliation: Biologics and Pharmaceutical Science, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Holm
authors.affiliation: Clinical Pharmacology, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
authors.forename: Frank
authors.initials: F
authors.lastname: Larsen
authors.affiliation: Section for Pharmaceutical Design and Drug Delivery, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 København Ø, Denmark. Electronic address: bente.steffansen@sund.ku.dk.
authors.forename: Bente
authors.initials: B
authors.lastname: Steffansen
mesh_terms: D002110:Caffeine / Q000008:administration & dosage* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003692:Delayed-Action Preparations; D005079:Excipients / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D065347:Hypromellose Derivatives / Q000737:chemistry*; D012995:Solubility; D013607:Tablets; D014783:Viscosity; D014812:Vitamin K / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D003692:Delayed-Action Preparations; C029401:Ensure Plus; D005079:Excipients; D013607:Tablets; D014867:Water; D014812:Vitamin K; D002110:Caffeine; D065347:Hypromellose Derivatives
keywords: Caffeine (PubChem CID: 2519); F(i); FaSSGF; FaSSIF; FeSSIF; Food effects; HPMC; SCoF; Texture analysis; b; dips per minute; dissolution profile shape-parameter; dpm; fasted state simulated gastric fluid; fasted state simulated intestinal fluid; fed state simulated intestinal fluid; maximal resistance to probe penetration into the tablet; simulated colonic fluid; t(63); time when 63.2% of drug has been released