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GHWHUPLQHG ZKHUH4LVWKHWRWDODPRXQWSHUPHDWHGDWWLPH XVLQJ D PLFURPHWHU 5HSRUWHG YDOXHV DUH DQ W Δ4ΔW LV WKH VWHDG\VWDWH VORSH RI WKH OLQHDU DYHUDJHRIPHDVXUHPHQWVIRUHDFKILOP SRUWLRQRIWKHSORW IRUWKHDPRXQWRIWKHGUXJ 5KHRPHWULF PHDVXUHPHQWV $ +DDNH LQWKHUHFHLYLQJFKDPEHU4YHUVXVWLPHW$ 5KHRVWUHVV UKHRPHWHU 7KHUPR +DDNH LV WKH H[SRVHG FRUQHDO VXUIDFH FP DQG *HUPDQ\ ZLWK GDWD DFTXLVLWLRQ VRIWZDUH &RLVWKHLQLWLDOFRQFHQWUDWLRQRIWKHGUXJLQWKH 5KHR:LQ DQG D FLUFXODWRU IRU VDPSOH GRQRUFHOO WHPSHUDWXUH FRQWURO ZDV XVHG 6DPSOHV ZHUH Results and discussion DOORZHG WR UHVW IRU DW OHDVW V SULRU WR Homogeneous, flexible and transparent DQDO\VLV,QDOOFDVHVWKHH[SRVHGHGJHVRIWKH films were obtained from the prepared VDPSOH ZHUH FRYHUHG ZLWK VLOLFRQH RLO solutions. All films were easily removed 'LPHWKLFRQH 5)( 3K (XU WR SUHYHQW from the cast plate and no pores or cracks HYDSRUDWLRQRIZDWHUGXULQJPHDVXUHPHQWV$OO were detected. Thickness of films varied PHDVXUHPHQWVZHUHPDGHLQWULSOLFDWHDW& 7KH IRUPXODWLRQV ZHUH VXEMHFWHG WR YLVFRVLW\ from 92.7 ± 8.9 (Film I) to 95.3 ± 9.1 (Film PHDVXUHPHQWV DIWHU PL[LQJ ZLWK ODFKU\PDO II) to 99.5 ± 10.2 μm (Film III). IOXLGWRDVVHVVWKHGLOXWLRQDFWLRQRIWKHWHDUVLQ YLYR7KHIORZFXUYHVZHUHFDUULHGRXWXVLQJD ,;&RQJUHVRGHOD6(),* 7HFQRORJtD)DUPDFpXWLFD Errors bars represent standard deviations based on four experiments. 10 Viscosity (Pas) Fim I Film II Film III Conclusions HA/HPMC films showed the capability to control diclofenac transcorneal permeation rate in vitro. Moreover, the drug permeation rate was affected by the HA concentration in the film: the higher the concentration the slower the permeation. Therefore, these preliminary results indicate that HA/HPMC in appropriate ratio can be used as drug controlled delivery systems for topical ocular administration. 1 0.1 0.01 1 10 100 1000 Shear rate (s-1) Fig. 1. Effect of shear rate on shear viscosity of HA/HPMC films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qQFLD 9DOHQFLDQ *HQHUDOLWDW IRUWKHILQDQFLDOVXSSRUW*9 The flow curves, which show viscosity as a function of the shear rate, are reported in Fig.1 for the three studied formulations. The viscosity decreased by increasing the shear rate, that is, these systems showed a shear thinning or a pseudoplastic behaviour. The Films I presents ηo values (0.165±0.001) lower than the Film II (0.556±0.003) and Film III (0.981±0.006). Therefore, the viscosity increased as a function of the HA amount. The transcorneal permeation profiles of diclofenac are shown in Fig. 2. Results indicate that the Film I presented the highest drug penetration rate across the cornea and that the incorporation of growing quantities of HA into the film systems reduced the drug permeation capacity. Permeation coefficient values calculated for each formulation confirmed these results: Film I (0.271±0.014), Film II (0.119±0.003) and Film III (0.033±0.003). These results could be explained as the consequence of the increased film viscosity as HA concentration increased. Film I Film II Film III -2 -1 Cumulative amount (mg.cm .h ) 3.0 2.5 2.0 1.5 1.0 0.5 0.0 0 2 4 6 0,&52(1&$368/$7,212)385,),('+80$1%,2$&7,9(5(&20%,1$17*'1) ($QVRUHQD(*DUED\R-//DQFLHJR06$\PHULFK0-%ODQFR3UtHWR 'HSDUWPHQWRI3KDUPDF\DQG3KDUPDFHXWLFDO7HFKQRORJ\8QLYHUVLW\RI1DYDUUD3DPSORQD 1DYDUUD 1HXURPRUSKRORJ\7UDFLQJ/DE&,0$8QLYHUVLW\RI1DYDUUD3DPSORQD1DYDUUD. HDQVRUHQD#XQDYHV 8 Time (h) Fig. 2. Permeation of diclofenac through excised cornea from the bovine eye. 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