Pharmaceutical Technology: Controlled Drug Release, Volume 2

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CH. 16] TOBRAMYCIN SULPHATE FROM POLYMETHYLMETHACRYLATE IMPLANTS 179 drug release due to increases in drug loading and incorporation of additives can be attributed to modifications in the porosity of the implants with changes in formulation. Fig. 3—The effect of increasing levels of PEG 400 on tobramycin sulphate release profiles. The solid lines represent the lines of best fit. The symbols represent the observed values. Studies using smaller implants of 2.9 mm diameter indicated statistically significant differences in the two rate constants (Table 2) and extent of drug released from the implant in comparison with implants of mean diameter 6.2 mm. This could be attributed to an increase in surface area per unit volume of the smaller implant. The effect of varying dissolution volumes on the release rates from beads prepared using a 1:10 ratio of drug: carrier indicated that no statistically significant differences were observed either in the rates or in the extent of drug release, when release studies were performed using different dissolution volumes. This is to be expected since the ability of tobramycin was not a limiting factor in controlling release rate. This fact is of clinical significance since implants placed in the diseased tissue may be exposed to varying amounts of fluids. The amount of tobramycin sulphate remaining unreleased from the PMMA implant after 1, 3 and 7 days in vivo is summarized in Table 3. The very low percentage of tobramycin sulphate released in vivo (10.57%) after 7 days supports the in vitro findings (18–20% released). Scanning electron microscopic examination before and after dissolution and in vivo implantation show no significant changes in surface topography for the implants prepared as they are clinically used, that is, without additives. However, distinct changes in surface characteristics and the appearance of pores are evident with the inclusion of water-soluble additives such as polyethylene glycol 400.
180 IMPLANTS [CH. 16 Table 3—Tobramycin sulphate released in vivo using the osteomyelitic tibia rabbit model CONCLUSIONS (1) The release of tobramycin sulphate from non-biodegradable, spherical PMMA implants is biphasic and can be described by biexponential linear regression analysis. (2) Both in vitro and in vivo results indicate that drug release is incomplete and poorly controlled from implants prepared at the drug:carrier ratio used clinically. (3) Although the release of tobramycin sulphate can be significantly improved with the addition of water-soluble additives such as polyethylene glycol 400, our current investigations are directed toward the design and development of biodegradable implants. ACKNOWLEDGEMENTS We gratefully acknowledge the assistance from Eli Lilly Co., for the donation of tobramycin, and Richards Medical, Howmedica and Zimmer for the donation of the bone cements used in this study. We also would like to thank Dr D.Scott for supplying the moulds. REFERENCES 1 [] C.Torholm, L.Lidgren, L.Lindberg and G.Kahlmeter, Clin. Orthop., 181,99 (1983). 2 [] D.J.Schurman, C.Trinidade, H.P.Hirshman, K.Moser, G.Kajiyama and P. Stevens, J. Bone Joint Surg. A, 60, 978 (1978). 3 [] R.Soto-Hall, L.Saenz, R.Tavernetti, H.E.Cabaud and T.P.Cochran, Clin. Orthop., 175, 60 (1983). 4 [] H.Wahlig, E.Dingeldein, R.Bergman and K.Reuss, J. Bone Joint Surg. B, 60, 270 (1978). 5 [] R.H.Guy, J.Hadgraft, I.W.Kellaway and M.S.Taylor, Int. J. Pharm., 11, 199 (1982). 6 [] S.Sampath and D.H.Robinson, unpublished results. 7 [] C.W.Norden, J. Infect. Dis., 122, 5410 (1970). 8 [] K.J.Wilson, G.Cierny, K.R.Adams and J.T.Mader., J. Orthop. Res., 6, 279 (1988). 9 [] S.W.Hoff, R.H.Fitzgerald and P.J.Kelly, J. Bone Joint Surg. A, 63, 798 (1981). 10 [] R.A.Elson, A.E.Jephcott, D.B.Gechie and D.Verettas, J. Bone Joint Surg. B, 59, 200 (1977). 11 [] K.E.Marks, C.L.Nelson and E.P.Lautenschlager, J. Bone Joint Surg. A, 58, 358 (1976). 12 [] B.Picknell, L.Mizen and R.Sutherland, J. Bone Joint Surg. B, 59, 302 (1977).
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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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24 MATRIX FORMULATIONS [CH. 2 MATER
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MATRIX FORMULATIONS [CH. 4 45 (4) G
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Fig. 5—Linearization of the relea
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6 Controlled release matrix tablets
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CH. 6] CONTROLLED RELEASE MATRIX TA
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7 A new ibuprofen pulsed release or
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CH. 7] A NEW IBUPROFEN PULSED RELEA
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90 CH. 8] TOPICAL RELEASE AND PERME
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118 CH. 10] CONTROLLED DELIVERY OF
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126 CH. 11] THE EFFECT OF FOOD ON G
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Pharmaceutical Technology: Controlled Drug Release, Volume 2

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