Pharmaceutical Technology: Controlled Drug Release, Volume 2

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16 <strong>Release</strong> kinetics of tobramycin sulphate from polymethylmethacrylate implants D.H.Robinson and S.Sampath Department of <strong>Pharmaceutical</strong> Sciences, University of Nebraska Medical Center, Omaha, NE 68105 USA SUMMARY The effects of various formulation factors on the in vitro release characteristics of spherical polymethylmethacrylate implants were studied. Physical and mathematical models were proposed to describe the in vitro release profiles. The in vitro release data could be described by a biexponential equation of the following type: fraction of tobramycin remaining in the implant at time t=Ae −αt +Be −βt , where a, and β represent the rate constants for the initial rapid and subsequent slow phases of release. The influence of drug loading, volume of dissolution medium, implant size and type of cement and the incorporation of water-soluble additives on the release profiles and α and β rate constants is described. INTRODUCTION Antibiotic-impregnated polymethylmethacrylate (PMMA) bone cement has been used for localized drug delivery in osteomyelitis since 1970 [1–3]. More recently, antibiotic-bone cement composites have been fabricated as spherical, non-biode-gradable implants [4]. The primary advantage of localized drug delivery with implants is that relatively high local tissue antibiotic concentrations are obtained without corresponding high serum levels and associated toxicity. Implants containing various antibiotics have been extemporaneously prepared for clinical use. However, many aspects regarding the preparation and release characteristics of these implants have not been clearly defined.
172 IMPLANTS [CH. 16 The purpose of this study was to adopt a systematic approach to optimize formulation and to characterize the properties of tobramycin-PMMA implants. Tobramycin was selected as it is active against both Gram-positive and Gram-negative bacteria, including gentamicin-resistant Pseudomonas. The specific aims of the study were (1) to study the in vitro and in vivo release characteristics of tobramycin sulphate from the PMMA implant delivery system, and (2) to develop physical and mathematical models which describe the drug release profiles in vitro and account for the observed changes in rate and extent of release between formulations. THEORETICAL Mathematical model Guy et al. [5] derived an equation for the diffusion-controlled release of a drug from a sphere, radius r, by applying the three-dimensional form of Fick’s second law of diffusion after transformation to spherical coordinates. This equation can be rearranged as: The term 1−M t /M ∞ represents the fraction of drug remaining unreleased while τ is a function of the diffusion constant, D, as defined by the equation τ=Dt/r 2 . Therefore, the decline in the fraction of drug remaining (fraction released) can be described by a multiexponential equation of the type: (2) Since r is constant for a non-biodegradable carrier such as PMMA, the slopes a, β, etc., should reflect changes in the diffusion coefficient D, and therefore differences in porosity, between formulations. The first-order drug release rate constants can be calculated from the slopes of the α and β phases of the release profile. (1) Physical model Since PMMA is non-biodegradable and resistant to erosion, the dimensions of the spherical implant will not change for the duration of the release process. It was proposed that a biphasic release profile would be observed. An initial, relatively rapid release phase would be observed as a result of the diffusion and dissolution of drug on, or near, the surface of the implant. A second, more prolonged release phase would then follow because of the slow diffusion of the drug from within the PMMA implant matrix. Further, the rate and extent of drug release from the implant during the second prolonged phase could be significantly altered using formulation additives which modify the porosity of the PMMA implant matrix.
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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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7 10 Controlled delivery of theophy
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Slow and steady wins the race Poems
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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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Fig. 5—Linearization of the relea
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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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118 CH. 10] CONTROLLED DELIVERY OF
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Pharmaceutical Technology: Controlled Drug Release, Volume 2

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