New insight into modified release pellets - Internal structure and drug release mechanism.
The aim of the study was to explore the drug release mechanism from pellets, coated with blends of poly(vinyl acetate) (PVAc) and polyvinyl alcohol-polyethylene glycol graft copolymer (PVA-PEG). Water influx and drug solubilization inside the pellets were investigated in correlation to drug release. The highly soluble drug Chlorpheniramine maleate (CPM) was used as a model compound. Modified release pellets were manufactured by fluid bed drug layering and film coating of starter beads. The pellets were characterized using cross section EDX mapping, confirming location and homogeneity of the different layers. A film coat of 23%, containing PVAc/PVA-PEG in 9:1 ratio, resulted in a sigmoid shaped release curve with 2 h lag-time, followed by 3 h of continuous drug release. Using NMR analysis, water influx and drug solubilization inside the pellets were detected within 20 min. Additionally, dissolution of PVA-PEG after several minutes and drug release after the lag-time were measurable. A fast water influx into PVAc/PVA-PEG film coated pellets did not result in a fast drug release. Despite a fast drug solubilization within the pellets, drug release was initiated after 2 h, suggesting a one way stream of water during the observed lag-time.
Ensslin
Simon
S
Technical Research & Development; Novartis Pharma AG, 4056 Basel, Switzerland.
Moll
Klaus Peter
KP
Paulus
Kurt
K
Mäder
Karsten
K
D001682:Biological Availability; D002482:Cellulose / Q000737:chemistry; D002713:Chlorine / Q000032:analysis; D002744:Chlorpheniramine / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations / Q000138:chemical synthesis / Q000737:chemistry*; D017666:Deuterium Oxide / Q000737:chemistry; D004343:Drug Implants / Q000138:chemical synthesis / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D065347:Hypromellose Derivatives; D008274:Magnesium / Q000032:analysis; D009682:Magnetic Resonance Spectroscopy; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D010100:Oxygen / Q000032:analysis; D011092:Polyethylene Glycols / Q000737:chemistry; D011142:Polyvinyl Alcohol / Q000737:chemistry; D011145:Polyvinyls / Q000737:chemistry; D012825:Silicon / Q000032:analysis; D013052:Spectrometry, X-Ray Emission; D013627:Talc / Q000737:chemistry; D014025:Titanium / Q000032:analysis / Q000737:chemistry; D014867:Water / Q000737:chemistry
D003692:Delayed-Action Preparations; D004343:Drug Implants; C519734:Kollicoat IR; D011145:Polyvinyls; D014867:Water; D013627:Talc; C009495:titanium dioxide; C013215:polyvinyl acetate; D065347:Hypromellose Derivatives; D002744:Chlorpheniramine; D011092:Polyethylene Glycols; D002713:Chlorine; D011142:Polyvinyl Alcohol; D002482:Cellulose; D008747:Methylcellulose; D014025:Titanium; D008274:Magnesium; D017666:Deuterium Oxide; D010100:Oxygen; D012825:Silicon