Pharmaceutical Technology: Controlled Drug Release, Volume 2

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CH. 7] A NEW IBUPROFEN PULSED RELEASE ORAL DOSAGE FORM 85 Fig. 4—ibuprofen plasma levels following administration of the following: , ibuprofen 300 mg conventional marketed tablets; ■, ibuprofen (d vs =11:5 µm) 300 mg conventional tablets; ■, ibuprofen (d vs =5 µm) 300 mg conventional tablets. Each curve is the mean of the data from two subjects. The lag time evident in the dissolution profile of the second dose is determined by the progressive gelation of the intermediate barrier; in addition, since the dissolution medium permeates the barrier very slowly and wets the third layer, the disintegrant efficiency could be reduced, thus resulting in a significant decrease of drug dissolution rate. In vivo experiments Preliminary plasma levels obtained in a few subjects in order to verify the dependence of the in vivo pattern on the structure of the whole system and on the type, amount and characteristics of the drug and the polymers used are very promising. Fig. 4 shows the plasma profiles obtained after oral administration of two plain tablets of 300 mg of ibuprofen prepared with two different batches of active principle, having differing particle size distributions (d vs =11.5 µm and 5 µm), compared with a conventional marketed ibuprofen tablet. The plasma levels are strongly dependent on the specific surface area of the ibuprofen powder. The differences in absorption rate and bioavailability between the tablets prepared with the differing batches of ibuprofen are clearly evident despite the fact that their in vitro dissolution profiles can be practically superimposed when tested according to the USP XXI ibuprofen Tablets monograph. Fig. 5 shows an example of the plasma levels after administration of the pulsed release system to two volunteers. As can be seen from Fig. 5, in both cases there are two peaks. The first peak is 20µg ml −1 after about 1h, and the second is 16–20 µg ml −1 after 4.5–5 h; there is an evident delay in the absorption of the second dose which appears to correlate quite well with the in vitro performance of the pulsed system.
86 MATRIX FORMULATIONS [CH. 7 Fig. 5—ibuprofen plasma levels following administration of pulsed release system to two subjects: , first subject; ■. second subject. CONCLUSIONS The in vitro disintegration and dissolution tests of the pulsed system, obtained with a suitable blend of polymers and appropriate processing, are in good agreement with the in vivo blood levels and pattern. Despite the problems posed by the pharmacokinetic and physicochemical characteristics of ibuprofen (small therapeutic window, erratic absorption owing to its poor solubility, etc.), this pulsed release system results in good separation of the two plasma peaks (indicating that there is in fact delayed release of the second drug dose) at the desired concentrations. These preliminary results, which substantiate the initial hypothesis, show the system to be very promising. ACKNOWLEDGEMENTS This work was supported by a grant from FARMARESA (Research Contract 1986/ 87). The authors are grateful to Mrs. M.C.Sacchi for assistance in text and figure preparation. REFERENCES 1 [] U.Conte, P.Columbo, C.Caramella and A.La Manna, Proc. Symp. on Polymers in Medicine, Plenum, New York, 1983, p. 179. 2 [] U.Conte, P.Colombo, C.Caramella, G.P.Bettinetti, F.Giodano and A.La Manna, Farmaco, Ed. Prat., 39, 67 (1984). 3 [] P.Colombo, U.Conte, C.Caramella, A.Gazzaniga and A.La Manna, J. Control. <strong>Release</strong>, 1, 283 (1985). 4 [] A.La Manna, U.Conte, P.Colombo, A.Gazzaniga, G.C.Santus and M.E. Sangalli, Italian Patent Appl. 20708 A/ 86, 28 2May, 1986. 5 [] A.Gazzaniga, U.Conte, P.Colombo, M.E.Sangalli, C.Caramella and A.La Manna, Polymers in Medicine III, Elsevier, Amsterdam, 1988, p. 201.
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PHARMACEUTICAL TECHNOLOGY Controlle
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136 CH. 12] BIODEGRADABLE POLYMERS
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184 CH. 17] SILICON MATRIX SYSTEMS
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194 INDEX dry granulation, 43 elect
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Pharmaceutical Technology: Controlled Drug Release, Volume 2

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