5. Results and discussion
5.3. In vitro/in vivo correlations (II, IV)
No level-A in vitro/in vivo correlation relating to enteric-coated matrix granules was observed when in vitro dissolution curves and in vivo cumulative absorption curves were superimposed (II, Fig. 7). The enteric polymers used dissolve relatively fast at pH 6.8. Drug absorption in vivo took place more slowly than drug release in vitro at pH 6.8 because the pH at the stomach during fasting is 1–2. Within this pH range dissolution of the enteric polymers was negligible, as would have been expected. Level-A in vitro/in vivo correlations could be established through use of the equation of Brockmeier and Luckow (II, Fig. 8). The correlations were formulation-specific.
Level-A in vitro/in vivo correlations relating to two enteric-coated tablet formulations are shown in Figure 4. Times relating to in vivo results were divided by 3. The in vitro dissolution curve and the in vivo cumulative absorption curve profiles are similar for the tablet containing 15% citric acid in the tablet matrix and no citric acid in granules but the lag times are different. A level-A in vitro/in vivo correlation might be capable of being established if the circumstances of the in vitro gradient dissolution study were modified. However, the correlation is always formulation-specific.
Level-C in vitro/in vivo correlations were studied in enteric-coated matrix tablets containing different amounts of citric acid in the tablet matrices or granule cores (Fig. 5). Correlation between the in vitro and in vivo parameters was poor. Neither the in vitro t50% value nor the in vitro lag time would have allowed prediction of the in vivo lag time. As discussed above, the rate of drug release did not decrease further when tablets contained more than 11.7% citric acid in the tablet matrix. However absorption of drug from tablets of the kinds described became delayed as the amount of citric acid was gradually increased.
Figure 4. Level-A in vitro/in vivo correlations for enteric-coated multiple-unit tablets containing 2.5% citric acid in the granules and 10% citric acid in the tablet matrix ( , ), and no citric acid in the granules and 15%
citric acid in the tablet matrix ( , ). In vitro result = open symbol, in vivo result = closed symbol. In vivo times were divided by 3.
0 20 40 60 80 100
0 2 4 6 8
time in vitro / time in vivo/3 (h)
released/absorbed(%)
0 20 40 60 80 100
0 2 4 6 8
time in vitro / time in vivo/3 (h)
released/absorbed(%)
pH 6.8
Figure 5. Level-C in vitro/in vivo correlations relating to enteric-coated multiple-unit tablets containing different percentages (0, 10, 11.7, 13.3, 15) of citric acid in the tablet matrix and no citric acid in the granules (top) or containing various percentages of citric acid in the granules (0, 2.5, 10) and 10% citric acid in the tablet matrix (bottom). Tlag relating to absorption was used as the in vivo parameter and tlag relating to dissolution or the t50% -value was used as the in vitro parameter. Dissolution media pH -values were; 6.8 ( , line) and 7.4 ( , broken line).
6. Conclusions
The main objective in relation to this study was development of an oral multiple-unit colon-specific formulation. The intention was to prepare a formulation, using enteric polymers as excipients that allowed drug liberation and absorption after a lag time of about 4–5 hours in the fasting state. The formulation developed also had to prevent drug liberation at the stomach.
It was found that enteric-coated matrix granules that also contained enteric polymers as matrix formers are not appropriate for use in preparing colon-specific formulations. Drug liberation in the stomach can be prevented by enteric coating but after gastric emptying drug release occurred too rapidly, in the small intestine. The pH at which the enteric polymer used for coating of the granules dissolved affected the lag time in relation to commencement of drug absorption. Through inclusion of an organic acid in the granules drug dissolution can be modified in vitro.
However, preparation of colon-specific formulations through use of enteric-coated matrix granules that contained an organic acid as excipients proved impossible.
Drug release and absorption can be targeted on the colon through use of enteric polymers and citric acid as excipients in multiple-unit tablets. Lag times of some 2–4 hours in relation to commencement absorption of ibuprofen can be achieved by incorporation of different amounts of citric acid in the tablet matrix and the granules. It is important to include citric acid in the tablet matrix itself if lengthy lag times are required. Percentages of citric acid of between 10 and 15 would be appropriate for colon-specific formulations. Drug release takes place after a lag time especially once the percentage of citric acid in the tablet matrix exceeds 10. Citric acid can be incorporated in the granules to adjust drug release after the lag time. It may be unnecessary to include citric acid in granule cores if citric acid has been incorporated in the tablet matrix.
This kind of multiple-unit tablet developed is more likely than granules to remain entire in the upper gastrointestinal tract. Accordingly, drug
the tablet matrix the tablet is likely to remain entire for longer. In this way drug release at the end of the small intestine might be prevented even though pH levels exceed 7. In the colon the formulation can disintegrate into granules. These can then distribute themselves throughout the colon.
It was concluded that in vitro/in vivo correlation relating to the kinds of tablets studied was poor. It is therefore important to undertake bioavailability testing at all stages of development. For colon-specific formulations it might be possible to establish a level-A in vitro/in vivo correlation by adjustment of the circumstances relating to the in vitro gradient dissolution study.
Acknowledgements
The work described was carried out in the Division of Biopharmaceutics and Pharmacokinetics, Department of Pharmacy, University of Helsinki.
I am most grateful to Professor Martti Marvola for suggesting the topic of the studies. His support, patience and ideas made completion of this study possible.
I also thank Professor Jouko Yliruusi for providing excellent tableting and film-coating facilities. I am grateful to Docent Jyrki Heinämäki for excellent guidance regarding use of the film-coating equipment.
Professor Peep Veski, head of the Department of Pharmacy, University of Tartu, is thanked for his cooperation.
The reviewers of the thesis, Professor Kristiina Järvinen and Docent Sari Eerikäinen are sincerely thanked for their constructive criticisms, and suggestions for its improvement.
Particular thanks are due to Erja Piitulainen B.Sc.(Pharm.), Susanna Oravisto B.Sc.(Pharm.), Karin Krogars M.Sc.(Pharm.), Mia Säkkinen Lic.Sc.(Pharm.), Minna-Liisa Aaltonen M.Sc.(Pharm.), Susanna Lempää M.Sc.(Pharm.) and Taina Sten M.Sc.(Pharm.) for their excellent technical assistance and friendship.
I am most grateful to all of my colleagues in the Division of Biopharmaceutics and Pharmacokinetics for their friendship, support and fruitful discussions.
Finally, my warmest thanks go to my dear husband Eerik for his love, humour and never-ending optimism. I also thank our little son Henri for being my sunshine and for sharing my interest in writing and reading. His
Financial support from the Finnish Cultural Foundation and the Pharmacal Research Foundation, Finland, is gratefully acknowledged.
Pirjo Nykänen
Helsinki, August 2003
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