Pharmaceutical Technology: Controlled Drug Release, Volume 2

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OPHTHALMIC FORMULATION [CH. 15 165 inspection of the data shows that, within each couple, a 100% increased concentration resulted in very little or no increase of the activity parameters. Even if in some cases slightly increased Imax (vehicle 6 vs. 5, or vehicle 8 vs. 7) or duration (vehicle 2 vs. 1, or vehicle 8 vs. 7) values were apparent, in no case were the AUC values of each couple of preparations statistically different. Effect of complexation of DAP-B by PGA This effect is evidenced by a comparison of the activity data within each one of two vehicle couples, 1-3 and 2-4. In each couple the vehicles contained an equivalent amount of drug (0.5% or 1.0%), but in a different form (HCl or PGA complex). Within each couple, the presence of the PGA complex resulted in a significant (c. 3 times) increase in bioavailability, associated with an increase in duration and intensity of activity. Complexation of DAP-B by PGA had little effect on the apparent (Newtonian) viscosities of the vehicles (which were 1.4 and 1.7 mPa s for vehicles 3 and 4, vs. c. mPa 1.0 s for vehicles 1 and 2, at 30°C) so that a possible influence of viscosity effects on the ocular retention, and hence on the activity of the PGA complex, should be ruled out. The apparent elimination kinetics of vehicles 1-4 (reflected by the K′ values in Table 2), which were in the same range as those of vehicles 1 and 2, suggests a relatively short pre-ocular retention. This is in contrast with the high AUC values of the vehicles. Effect of gelling by HPC This effect can best be appraised by comparing the activity parameters within each of two groups of vehicles 1-3-5-7 (0.5% DAP) or 2-4-6-8 (1.0% DAP). The reported data show that, within the first group, the presence of HPC (and the associated great increase of vehicle viscosity) had a positive effect on bioavailability (2.5×) when the drug was present as the hydrochloride (vehicle 7 vs. 1). A similar AUC increase was not apparent when the drug was present in the gels as the PGA complex (vehicle 5 vs. 3). In other words, addition of the gel-forming cellulose derivative was apparently unable to increase the AUC values displayed by the liquid vehicles containing the PGA salt. Similar considerations apply to the other group of vehicles (1.0% DAP). The gel vehicles, however, appeared to exert some control on DAP release and absorption, as indicated by an increased duration of activity (cf. for example vehicles 7 and 8 vs. 1 and 2 respectively) and by consistently lower K′ values, corresponding to a prolongation of the apparent absorption and elimination phases of the drug in the eye. In vivo reversion of mydriasis Administration of 0.1 mg tropicamide to both eyes of the rabbits produced an intense mydriatic effect, which began slowly to decline after 90 min, but was still very evident (c. 70% of the peak intensity) after 7 h. The results of tests in which the dapiprazole vehicles 1 (reference), 5 and 6 were applied to one of the dilated eyes are illustrated in Fig. 1, where the area corresponding to the reversion effect vs. time of each vehicle are outlined. In Fig. 1, the data are expressed as differences in pupillary diameter, ∆, between the DAP-treated and the dilated, contralateral eye,
166 CH. 15] A SUSTAINED RELEASE OPHTHALMIC VEHICLE FOR DAPIPRAZOLE Fig. 1—Effect of DAP vehicles 1 (▲), 5 (●) and 6 (■) on reversal of tropicamide-induced mydriasis. vs. time. As shown, vehicle 1 produced a reversion of short duration, while the effect of an equivalent dose of DAP (as PGA complex) administered in the gel vehicle 5 was significantly greater, for both intensity and duration, and was still evident after 7 h. Contrary to the miosis experiments, in these tests a 2-fold increase of the administered drug dose (vehicle 6 vs. 5) produced a significantly increased biological response. The relative AUC values for vehicles 1,5 and 6 (calculated at 2 h, corresponding to the end of the effect of vehicle 1) were 1, 1.94 and 3.2. The corresponding relative AUC values at the end of the experiment (7 h) were 1.0, 4.5 and 8.5, respectively. DISCUSSION The approaches to enhance and/or prolong the ocular activity of DAP evaluated in the present study, although not unprecedented, differ in some respects from previous literature examples. Salification of pilocarpine with alginic acid [8], with poly(acrylic acid-lauryl methacrylate) [9], with poly(acrylic acid) [10,11], etc. has been reported to prolong the activity of the drug when the salts were administered in a solid dosage from (insert) [8,10] or when the complex itself was insoluble in water [9]. The ‘hydrogel’ approach, on the other hand, has been applied to various ophthalmic drugs, and 3–5-fold increases in penetration and activity have been reported. The combined effect of the two techniques has apparently never been investigated, with the possible exception of an example mentioned in the patent literature, (a poly(acrylic acid) hydrogel partially neutralized by pilocarpine base [11]). The PGA salt of D AP has shown pharmacological results (peak timer shifted to a later time, increased Imax) corresponding to an increased contact time [12]. PGA consists of linear chains of D-galacturonic acid units (pyranose form), joined in α(1– 4)-glycosidic linkages, with a molecular weight ranging from 25×10 3 to100 ×10 3 . It formed a soluble salt or polyanionic complex with the
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PHARMACEUTICAL TECHNOLOGY Controlle
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3 TABLET MACHINE INSTRUMENTATION IN
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First published in 1991 by ELLIS HO
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1 Influence of drug solubility in t
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CH. 1] INFLUENCE OF DRUG SOLUBILITY
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6 Controlled release matrix tablets
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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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