Pharmaceutical Research

, Volume 12, Issue 7, pp 1049–1054 | Cite as

Oral Solid Controlled Release Dosage Forms: Role of GI-Mechanical Destructive Forces and Colonic Release in Drug Absorption Under Fasted and Fed Conditions in Humans

  • Mohammed Shameem
  • Noriko Katori
  • Nobuo Aoyagi
  • Shigeo Kojima


Purpose. This study was undertaken to examine the effects of mechanical destructive forces on drug release from controlled release (CR) dosage forms in vitro and in vivo and their colonic release, using two CR tablets of acetaminophen A and B, showing slower and faster erosion rates, respectively.

Methods. In vitro release rates were determined by several official methods. Tablets were administered to healthy volunteers under fasting and fed conditions.

Results. Both tablets showed similar release rates under mild destructive conditions (e.g., paddle method at 10 rpm) but CR-B showed faster release under highly destructive conditions (e.g., rotating basket method at 150 rpm), where the tablet was eroded. The in vivo release from CR-B was faster than from CR-A, possibly because of enhanced erosion. The variable in vivo release from CR-B indicated large inter-subject differences in destructive GI forces. The fastest in vivo release from CR-B among individuals was approximated by the in vitro dissolution determined by destructive methods such as the rotating basket at 150 rpm. The slowest in vivo release from tablets A and B was lower than the dissolution by the paddle method at 10 rpm. The release from both tablets was markedly reduced at 3–4 hrs after dosing irrespective of feeding conditions which can be attributed to release inhibition in the colon.

Conclusions. Effects of GI destructive forces on the tablet erosion and the release inhibition in the colon must be considered in the development of CR dosage forms.

controlled release colonic release drug absorption 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    N. Katori, N. Aoyagi, and T. Terao. Estimation of agitation intensity in the GI tract in human and dog based on in vitro/in vivo correlation. Pharm. Res. 12: 245–251 (1995).Google Scholar
  2. 2.
    J. C. Bain, S. B. Tan, D. Ganderton, and M. C. Solomon. A discrepancy between pharmacopoeial dissolution tests and bioavailability. Pharm. Tech. Int. 2: 36–40 (1990).Google Scholar
  3. 3.
    S. Aoki, H. Ando, K. Tatsuishi, K. Uesugi, and H. Ozawa. Determination of the mechanical impact force in the in vitro dissolution test and evaluation of the correlation between in vivo and in vitro release. Int. J. Pharm. 95: 67–75 (1993).Google Scholar
  4. 4.
    C. G. Wilson, N. Washington, J. L. Greaves, F. Kamali, J. A. Rees, A. K. Sempik, and J. F. Lampard. Bimodal release of ibuprofen in a sustained-release formulation: A scintigraphic and pharmacokinetic open study in healthy volunteers under different condition of food intake. Int. J. Pharm. 50: 155–161 (1989).Google Scholar
  5. 5.
    C. G. Wilson, N. Washington, J. L. Greaves, C. Washington, I. R. Wilding, T. Hoadley, and E. E. Sims. Predictive modeling of the behavior of a controlled release buflomedil HCl formulation using scintigraphic and pharmacokinetic data. Int. J. Pharm. 72: 79–86 (1991).Google Scholar
  6. 6.
    B. Abrahamsson, M. Alpsten, M. Hugosson, U. E. Jonsson, M. Sundgren, A. Svenheden, and J. Tolli. Absorption, gastrointestinal transit and tablet erosion of felodipine extended-release tablets. Pharm. Res. 10: 709–714 (1993).Google Scholar
  7. 7.
    K. Wingstrand, B. Abrahamsson, and B. Edgar. Bioavailability from felodipine extended-release tablets with different dissolution properties. Int. J. Pharm. 60: 151–156 (1990).Google Scholar
  8. 8.
    K. Sako, T. Mizumoto, T. Kajiyama, and T. Omura. In vitro and in vivo release behavior of erodable and non-erodable sustain release tablets of acetaminophen. Proceedings of the 6th Conference of the Academy of Pharmaceutical Society. and Technology, Japan. p. 25–27 (1990).Google Scholar
  9. 9.
    A. Adithan and J. Thangam. A comparative study of saliva and serum paracetamol levels using simple spectrophotometric method. Br. J. Clin. Pharmacol. 14: 107–109 (1982).Google Scholar
  10. 10.
    D. Verotta. An Inequality-constrained least squares deconvolution method. J. Pharmacokinet. Biopharm. 17: 269–289 (1986).Google Scholar
  11. 11.
    K. Yamaoka, T. Tanigawara, T. Nakagawa, and T. Uno. A pharmacokinetic analysis program (MULTI) for microcomputer. J. Pharmacobio-Dyn. 4: 879–885 (1981).Google Scholar
  12. 12.
    H. Ogata, T. Shibazaki, T. Inoue, and A. Ejima. Dissolution system for chloramphenicol tablet bioavailability. J. Pharm. Sci. 68: 712–715 (1979).Google Scholar
  13. 13.
    H. Ogata, N. Aoyagi, N. Kaniwa, and A. Ejima. Effect of food on the bioavailability of metronidazole from sugar coated tablets having different dissolution rates in subjects with low gastric acidity. Int. J. Clin. Pharmacol. Ther. Toxicol. 24: 279–282 (1986).Google Scholar
  14. 14.
    S. K. El-Arini, G. K. Shiu, and J. P. Skelly. Theophylline controlled release preparations and fatty food: An in vitro study using rotating dialysis cell method. Pharm. Res. 7: 1134–1140 (1990).Google Scholar
  15. 15.
    T. Mizumoto, K. Sako and M. Fukui. In vitro/in vivo correlation of single unit CR dosage forms. Abstract of 111th Conference of Pharmaceutical Society of Japan. No.4: p.105 (1991)Google Scholar
  16. 16.
    S.S. Davis, J.G. Hardy and J.W. Fara. Transit of pharmaceutical dosage forms through the small intestine. Gut. 27: 885–892 (1986).Google Scholar
  17. 17.
    N. Aoyagi, N. Kaniwa, Y. Takeda and M. Uchiyama. The purpose of dissolution test in Japanese Pharmacopoeia and its application principles. J P Forum. 3: 46 (1994).Google Scholar
  18. 18.
    Z. Hussain and M. Friedman. Release and absorption characteristics of novel theophylline sustained-release formulations-In vitro-in vivo correlation. Pharm. Res. 7: 1167–1171 (1990).Google Scholar
  19. 19.
    H. Ogata, N. Aoyagi, N. Kaniwa, T. Shibazaki, A. Ejima, N. Takasugi, E. Mafune, T. Hayashi, and K. Suwa. Bioavailability of nalidixic acid from uncoated tablets in humans. Part I: Correlation with the dissolution rates of the tablets. Int. J. Clin. Pharmacol.Ther.Toxicol. 22: 175–183 (1984).Google Scholar
  20. 20.
    R. Dietrich, R. Brausse, G. Benedikt and V.W. Steinijans. Feasibility of in vitro/in vivo correlation in the case of a new sustained-release theophylline pellet formulation. Arzneim-Forsch. 38: 1229–1237 (1988).Google Scholar
  21. 21.
    N. Kaniwa, H. Ogata, N. Aoyagi, T. Shibazaki, A. Ejima, Y. Watanabe, K. Motohashi, K. Sasahara, E. Nakajima, T. Morioka, and T. Nitanai. The bioavailability of flufenamic acid and its dissolution from capsules. Int. J. Clin. Pharmacol. Ther. Toxicol. 21: 56–63 (1983).Google Scholar
  22. 22.
    T. Kimura, K. Sudo, Y. Kanezaki, K. Miki, Y. Takeichi, Y. Kurosaki and T. Nakayama: Drug absorption from large intestine: Physicochemical factors governing drug absorption. Biol. Pharm. Bull. 17: 327–333 (1994).Google Scholar
  23. 23.
    H. Nakajima, K. Sako, T. Sawada, A. Okada and M. Fukui. Continuously absorbable oral delivery systems using acetaminophen. Abstract of 114th Conference of Pharmaceutical Society of Japan. No.4: p.37 (1994).Google Scholar

Copyright information

© Plenum Publishing Corporation 1995

Authors and Affiliations

  • Mohammed Shameem
    • 1
  • Noriko Katori
    • 1
  • Nobuo Aoyagi
    • 1
  • Shigeo Kojima
    • 1
  1. 1.Division of DrugsNational Institute of Health SciencesSetagaya-ku, TokyoJapan

Personalised recommendations