Pharmaceutical Technology: Controlled Drug Release, Volume 2

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CH. 14] COMPARISON OF TIMOLOL MALEATE RELEASE 159 Fig. 3—Timolol concentration (µg/ml) in plasma after application of one buffered (■) or unbuffered (□) matrix in each eye of a rabbit. Means±SEM of 5–9 rabbits are shown. approximately doubled. The phosphate did not affect the bulk pH in the end of experiment (Table 1). Consequently, the faster release rate of timolol from matrices with disodium phosphate is due to the higher pH on the polymer surface. Higher pH increases the rate of polymer dissolution and as a consequence drug release is accelerated. The peak timolol concentration (7.0±1.5 ng/ml) in plasma occurred at 60 min with the buffered matrices (Fig. 3). After administration of unbuffered matrix a steady state level of 1.0±0.1 ng/ml in plasma was achieved at 3 h (Fig. 3). The concentration profiles in tear fluid (Fig. 4) resemble the profiles in plasma (Fig. 3). Compared with unbuffered matrix (c max =45.2±9.4µg/ml) administration of timolol in polymer matrix with disodium phosphate resulted in a higher peak (91.5±13.7 µg/ml) in tear fluid (Fig. 4). With the unbuffered matrices, the peak levels of timolol in tear fluid were seen much later than with buffered matrices (Fig. 4). Timolol concentrations in the tear fluid and plasma suggest that compared with unbuffered matrices timolol is released more rapidly from the isopropyl ester of PVM-MA matrices with disodium phosphate in vivo. During the experiment, the buffered matrices also dissolved more rapidly in the tear fluid than the unbuffered matrices. In vivo results correspond quite well to those of the in vitro experiments although the effect of a basic additive seems to be greater in vivo. It is possible to increase the dissolution rate of PVM- MA esters in tear fluid by adding disodium phosphate or possibly other basic salts to the matrices. With basic additives it may be possible to modify drug release and polymer dissolution also in the case of other polyacids.
160 OPHTHALMIC FORMULATION [CH. 14 Fig. 4—Timolol concentration (µg/ml) in tear fluid after application of one buffered (■) or unbuffered (□) matrix in each eye of a rabbit. Means ± SEM of 11–18 eyes are shown. ACKNOWLEDGEMENTS The polymer Gantrez ® ES-335 was a generous gift from GAF (NORDEN) AB (Johanneshov, Sweden). Timolol was a generous gift from INTER x Research Corp., MSDRL (Lawrence, KS, USA). We are grateful to Mrs Lea Pirskanen for her skilful technical assistance. REFERENCES 1 [] J.Heller, R.W.Baker, R.M. Gale and J.O.Rodin, Controlled release by polymer dissolution I. Partial esters of maleic anhydride copolymers—properties and theory, J. Appl. Polym. Sci, 22, 1991 (1978). 2 [] A.Urtti, Pilocarpine release from matrices of alkyl half-esters of poly(vinyl methyl ether/maleic anhydride), Int. J. Pharm., 26, 45 (1985). 3 [] A.Urtti, L.Salminen and O.Miinalainen, Systemic absorption of ocular pilocarpine is modified by polymer matrices, Int. J. Pharm., 23, 147 (1985) 4 [] U.Finne, K.Kyyrönen and A.Urtti, Buffering of matrix modifies drug release from monoisopropyl ester of PVM/MA, Proc. Int. Symp. Control. Release Bioact. Mater., 15, 386 (1988). 5 [] K.G.Mooney, M.A.Mintun, K.J.Himmelstein and V.J.Stella, Dissolution kinetics of carboxylic acids I: effect of pH under unbuffered conditions, J. Pharm. Sci., 70, 13 (1981). 6 [] J.B.Schwartz, A.P.Simonelli and W.I.Higuchi, Drug release from wax matrices I. Analysis of data with firstorder kinetics and with the diffusion-controlled model, J. Pharm. Sci., 57, 274 (1968). 7 [] A.Wellstein, D.Palm, G.Wiemer, M.Schäfer-Korting and E.Mutschler, Simple and reliable radioreceptor assay for beta-adrenoceptor antagonists and active metabolites in native human plasma, Eur. J. Clin. Pharmacol., 27, 545 (1984).
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PHARMACEUTICAL TECHNOLOGY Controlle
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First published in 1991 by ELLIS HO
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CH. 1] INFLUENCE OF DRUG SOLUBILITY
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CH. 6] CONTROLLED RELEASE MATRIX TA
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CH. 7] A NEW IBUPROFEN PULSED RELEA
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Pharmaceutical Technology: Controlled Drug Release, Volume 2

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