Release characteristics and in vitro-in vivo correlation of pulsatile pattern for a pulsatile drug delivery system activated by membrane rupture via osmotic pressure and swelling.
This study attempted to characterize the influence of core and coating formulations on the release profiles to establish in vitro/in vivo correlations of pulsatile pattern for a pulsatile drug delivery system activated by membrane rupture based on three core tablet formulations (A-core: HPMC 50+4000 cps, B-core: E10M, and C-core: K100M) coated with various thicknesses of a semipermeable ethylcellulose membrane plasticized with HPMC 606 (Pharmacoat 606) at different ratios with/without adding various amounts of water to dissolve it in the coating solution. Drug release behaviors were investigated using apparatus II in four media of pH 1.2 solution, pH 6.8 buffer, deionized water, and a NaCl solution rotated at 75, 100, and 150 rpm. Pilot studies of the in vivo pharmacokinetics were conducted as well for comparison with the in vitro results. Results demonstrated that drug release from the three kinds of core tablets in deionized water increased with an increasing stirring rate, and decreased with an increasing viscosity grade of HPMC used in the core formulations. A significant promotion of drug release from core tablets was observed for the three levels of NaCl media in comparison with that in deionized water. Results further demonstrated that a slightly slower release rate in pH 1.2 solution and a faster release rate in pH 6.8 buffer than that in deionized water were observed for the A-core and B-core tablets, with the former being slower than the latter. However, similar release rates in the three kinds of media were observed for C-core tablets, but they were slower than those for the A- and B-core tablets. Dissolution of coated tablets showed that the controlling membrane was ruptured by osmotic pressure and swelling which activated drug release with a lag time. The lag time was not influenced by the pH value of the release medium or by the rotation speeds. The lag time increased with a higher coating level, but decreased with the addition of the hydrophilic plasticizer, Pharmacoat 606, and of the water amount in the coating solution. The lag time also increased with a higher concentration of NaCl in the medium. The release rate after the lag time was determined by the extent of retardation of gelation of HPMC in the core tablet based on the ionic strength of the medium. Results of the three pilot crossover studies for the exemplified pulsatile systems indicated that the lag time for the in vivo plasma profile was well correlated with that determined from the in vitro release profile in pH 1.2 solution and the in vivo release rate was better reflected by that performed in pH 6.8 buffer.
Lin
Hong-Liang
HL
College of Pharmacy, Taipei Medical University, Taiwan, ROC.
Lin
Shyr-Yi
SY
Lin
Ying-Ku
YK
Ho
Hsiu-O
HO
Lo
Yo-Wen
YW
Sheu
Ming-Thau
MT
D000284:Administration, Oral; D000328:Adult; D002482:Cellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D017292:Doxazosin / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D004337:Drug Carriers; D006801:Humans; D006863:Hydrogen-Ion Concentration; D065347:Hypromellose Derivatives; D008567:Membranes, Artificial; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D008954:Models, Biological; D009997:Osmotic Pressure; D010539:Permeability; D010865:Pilot Projects; D020551:Pulse Therapy, Drug; D012965:Sodium Chloride / Q000737:chemistry; D012995:Solubility; D013607:Tablets; D014783:Viscosity; D014867:Water / Q000737:chemistry
D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008567:Membranes, Artificial; D013607:Tablets; D014867:Water; D065347:Hypromellose Derivatives; D012965:Sodium Chloride; C013517:ethyl cellulose; D002482:Cellulose; D008747:Methylcellulose; D017292:Doxazosin