Pharmaceutical Technology: Controlled Drug Release, Volume 2

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CH. 16] TOBRAMYCIN SULPHATE FROM POLYMETHYLMETHACRYLATE IMPLANTS 175 In vivo release The rabbit osteomyelitic model described by Norden [7] was used to assess in vivo release of tobramycin sulphate from PMMA implants. The implants contained a mean tobramycin sulphate content of 6.1 mg per implant (which corresponds to almost double the drug loading used clinically). Osteomyelitis was induced in the tibia of nine New Zealand rabbits using Pseudomonas aeruginosa. One implant was surgically placed immediately adjacent to the tibia infection site in each rabbit 23 days post-infection. Implants were then surgically removed from each of three rabbits 1, 3 and 7 days after implantation and the amount of drug remaining unreleased determined spectrophotometrically after extraction as described above. Scanning electron microscopy A Philips model 515 scanning electron microscope was used to study the changes in surface topography of implants both before and after in vitro dissolution and after implementation in the rabbit. Data analysis Non-linear regression analysis of the in vitro release data was performed using the JANA multiexponential curve stripping computer program. The mono-, bi- and triexponential fits were generated. Statistical analysis of computer generated parameters was performed using ANOVA and Student’s t test. Fisher’s LSD was used for the multiple comparison of statistically significant groups. RESULTS AND DISCUSSION The mean diameters of the large and small beads were 6.2 mm and 2.9 mm respectively with the coefficients of variation less than 2% within a batch. Mean masses of the batches of the larger beads ranged from 151.8 to 162.5 mg and the smaller beads had a mean mass of 19.9 mg. In no instance was the coefficient of variation for within batch variation greater than 3%. The correlation coefficients generated for mono-, bi- and triexponential fits obtained by nonlinear regression analyses are summarized in Table 1. Wilson et al. [8] reported that the rate of tobramycin release from Simplex PMMA beads could be fitted to monoexponential and power functions; however, they obtained r 2 values0.9. Since the biexponential relationship in equation (2) is proposed to fit our physical model, this approach was adopted in analysis of computer fits to release data. The rate constants, a and β, represent an initial, rapid surface release and a prolonged matrix diffusion-controlled release respectively. Several investigators have reported that palacos PMMA cement releases antibiotics at higher concentrations over more prolonged periods than other commercially available cements [9–11]; others have suggested that there are no significant differences [12]. Von Frauhofer et al. [13]
176 IMPLANTS [CH. 16 noted that the rates of leaching of tobramycin from three commercial brands of cement were similar, but the initial amount of drug released differed. Our studies indicated that statistical comparison of the rate constants obtained using Palacos, Simplex and Zimmer cements (at similar levels of drug loading) revealed no significant differences (p>0.1). Also all three cements showed similar extents of release for the duration of study. Palacos bone cement was used for all subsequent studies. Table 2 summarizes the effect of various formulation factors on the f fast and slow phase rate constants influence of various formulation factors. For all subsequent discussion, the criterion for statistical significance was p
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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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24 MATRIX FORMULATIONS [CH. 2 MATER
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26 MATRIX FORMULATIONS [CH. 2 Fig.
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28 MATRIX FORMULATIONS [CH. 2 Table
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30 MATRIX FORMULATIONS [CH. 2 The e
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34 CH. 3] THE FORMULATION OF SUSTAI
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4 Statistical optimization of a con
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MATRIX FORMULATIONS [CH. 4 45 (4) G
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MATRIX FORMULATIONS [CH. 4 47 Fig.
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Columns 1-4 lead to the matrix of e
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MATRIX FORMULATIONS [CH. 4 51 Table
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MATRIX FORMULATIONS [CH. 4 53 Fig.
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Fig. 5—Linearization of the relea
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58 MATRIX FORMULATIONS [CH. 5 Pevik
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60 MATRIX FORMULATIONS [CH. 5 The d
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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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104 MULTIPARTICULATES [CH. 9 parace
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108 MULTIPARTICULATES [CH. 9 Fig. 2
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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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