Formulation, release characteristics and bioavailability of novel monolithic hydroxypropylmethylcellulose matrix tablets containing acetaminophen.
Effect of incorporating pharmaceutical excipients on the in vitro release profiles and the release mechanism of monolithic hydroxypropylmethylcellulose (4000 cps) matrix tablets (m-HPMC tablets) in terms of mimicking the dual drug release character of bi-layered Tylenol ER tablets was studied. We also compared the in vitro release profiles of optimized m-HPMC matrix tablet and Tylenol ER tablet in water, pH 1.2 gastric fluid, and pH 6.8 intestinal fluid, and in vivo drug bioavailabilities in healthy human volunteers. Acetaminophen was used as the model drug. The m-HPMC tablets were prepared using a wet granulation method followed by direct compression. Release profiles and swelling rates of m-HPMC tablets were found to be highly influenced by the types and amounts of pharmaceutical excipients incorporated. Starch 1500 (Prejel) and sodium lauryl sulfate (SLS) played a key role in determining the dissolution rate of m-HPMC tablets. Additional excipients, i.e., microcrystalline cellulose (Avicel PH101) and NaH2PO4 were used to tune the release profiles of m-HPMC tablets. The effect of pharmaceutical excipients on drug release from HPMC-based matrix tablets was found to be mainly due to a change in hydrophilic gel expansion and on physical interactions between the drug and HPMC. The optimized m-HPMC tablet with a balanced ratio of Prejel, SLS, Avicel PH101, and NaH2PO4 in the formulation showed dual release profiles in water, pH 1.2 gastric fluid, and pH 6.8 intestinal fluid in vitro. Dual release was defined as immediate drug release within few minutes followed by extended release over 8 h. The similarity factors of m-HPMC tablets and bi-layered Tylenol ER tablets were 79.8, 66.1, and 82.7 in water, gastric fluid and intestinal fluid, respectively, indicating the equivalence of the two release profiles. No significant in vivo bioavailability differences were observed in healthy human volunteers. The developed m-HPMC tablet with dual release characteristics can be easily prepared using a conventional high-speed tablet machine and could provide an alternative to commercially available bilayered Tylenol ER tablets.
Cao
Qing-Ri
QR
National Research Laboratory for Bioavailability Control, College of Pharmacy, Kangwon National University, Chuncheon, Republic of Korea.
Choi
Yun-Woong
YW
Cui
Jing-Hao
JH
Lee
Beom-Jin
BJ
D000082:Acetaminophen / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D005079:Excipients; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D007700:Kinetics; D007785:Lactose / Q000031:analogs & derivatives; D008297:Male; D008747:Methylcellulose / Q000031:analogs & derivatives; D010078:Oxazines; D012995:Solubility; D013501:Surface-Active Agents; D013607:Tablets; D014867:Water / Q000737:chemistry
D018712:Analgesics, Non-Narcotic; D005079:Excipients; D007202:Indicators and Reagents; D010078:Oxazines; D013501:Surface-Active Agents; D013607:Tablets; D014867:Water; D000082:Acetaminophen; D008747:Methylcellulose; C071191:MK 458; D007785:Lactose