Correlation between in vitro dissolution profiles from enteric-coated dosage forms and in vivo absorption in rats for high-solubility and high-permeability model drugs.
We examined the in vitro dissolution-in vivo absorption correlation (IVIVC) for enteric-coated granules containing theophylline, antipyrine or acetaminophen as model drugs with high solubility and high permeability. More than 85% of each drug was released from granules coated with hypromellose acetate succinate (HPMCAS) (AS-LG grade, which dissolves at pH above 5.5) at a mean dissolution rate of more than 5 %/min after a lag time of less than 4 min in simulated intestinal fluid of pH 6.8. The lag time and the dissolution rate were significantly extended and reduced, respectively, when AS-LG was replaced with AS-HG (a grade of HPMCAS that dissolves at pH above 6.8). Enteric-coated granules were administered intraduodenally to anesthetized rats. Statistical significances of differences of in vitro lag time between AS-LG- and AS-HG-coated granules were consistent with those in vivo, for all drugs. Significant differences in dissolution rates between granules also corresponded to those in absorption rates calculated using a deconvolution method, and both parameters had comparable absolute values, except in the case of antipyrine-containing granules with relatively fast dissolution rates. Thus, a good IVIVC was generally obtained; however, the exception suggests the importance of developing a dissolution test that fully reflects the in vivo situation.
Sakuma
Shinji
S
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaokatoge-cho, Hirakata, Osaka 573-0101, Japan. sakuma@pharm.setsunan.ac.jp
Ogura
Ryoko
R
Masaoka
Yoshie
Y
Kataoka
Makoto
M
Tanno
Fumié K
FK
Kokubo
Hiroyasu
H
Yamashita
Shinji
S
D000042:Absorption; D000082:Acetaminophen / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000983:Antipyrine / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D004304:Dosage Forms; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D005079:Excipients; D006863:Hydrogen-Ion Concentration; D065347:Hypromellose Derivatives; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013806:Theophylline / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics
D004304:Dosage Forms; D004337:Drug Carriers; D005079:Excipients; D000082:Acetaminophen; D065347:Hypromellose Derivatives; D008747:Methylcellulose; D013806:Theophylline; D000983:Antipyrine