Pharmaceutical Technology: Controlled Drug Release, Volume 2

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CH. 16] TOBRAMYCIN SULPHATE FROM POLYMETHYLMETHACRYLATE IMPLANTS 173 METHODS Materials Tobramycin sulphate (Nebcin ® , lot number 1CE30C) was donated by Eli Lilly Co., Indianapolis, IN. Palacos ® cement (lot number 608/7796) was donated by Richards Medical, Memphis, TN. Simplex ® cement (lot number HR203–4) and Zimmer Low Viscosity ® cement (lot number 51738000) were donated by Howmedica, New York, NY, and Zimmer, Warsaw, IN, respectively. Disodium phosphate (lot number 0201ML) and polyethylene glycols PEG 3400 (lot number 01224MP) and PEG 400 (lot number 97901DM) were purchased from Aldrich Chemical Co. Inc., Milwaukee, WS. Potassium dihydrogen phosphate (lot number 7100KBS) and methylene chloride (lot number 4881KBCL) were obtained from Mallinckrodt Inc., St. Louis, MO. o- Phthaldialdehyde reagent solution (lot number 58F-5985) and isopropanol (lot number 78F-6185) were purchased from Sigma Chemical Co., St. Louis, MO. Lactose was obtained from Amend Drugs and Chemical Co., Irvington, CO. Preparation of implants Spherical PMMA implants containing tobramycin sulphate were prepared using a Teflon-coated stainless steel mould. All chemicals and equipment were cooled at 4°C before use to retard polymerizatioti rate and to facilitate easier preparation of the implants. Known quantities of tobramycin sulphate were mixed with solid PMMA using geometric dilution, and then the liquid monomer was added to initiate polymerization. Where applicable, solid additives (lactose and PEG 3400) were added to the solid PMMA before the addition of monomer while the liquid additive PEG 400 was added after the addition of monomer. Immediately after mixing thoroughly, the liquid dispersion was injected into the lubricated mould. After solidifying, the implants were removed, allowed to dry at room temperature for 24 h, and then stored for at least four days before testing to ensure loss of residual monomer and completion of polymerization. Initial studies indicated that polymerized methylmethacrylate bone cement attained constant weight after about 24 h. Weight variation and diameter variation The mean weight and standard deviation of ten samples from each batch were determined for weight variation. Variation in diameter of beads was determined using a micrometer. The mean diameter (n=6) and the standard deviation were calculated for each batch. Assay of drug content Three implants from each batch were assayed separately for tobramycin sulphate content by dissolving the PMMA in 45 ml of dichloromethane and extracting the tobramycin sulphate five
174 IMPLANTS [CH. 16 times with 5 ml of deionized distilled water. The aqueous extracts were bulked and the volumes adjusted to 50 ml. Analysis of tobramycin sulphate Tobramycin sulphate was determined spectrophotometrically using a derivatization procedure [6]. A 0.5–1 ml aliquot of the extracted solution was mixed with 1 ml of o-phthaldialdehyde reagent solution followed by addition of 1.5 ml of isopropanol to prevent precipitation. The volume was adjusted to 5 ml with distilled water and the absorbance was determined after 45 min on a Beckman DU-7 spectrophotometer at the maxima of 333 nm. The concentrations were obtained from a calibration curve of o-phthaldialdehyde-derivatized tobramycin. The assay had a coefficient of variation of less than 3% and a detection limit of 0.5 µg/ml. In vitro dissolution Dissolution kinetics was studied under sink conditions by placing one implant in varying volumes (usually 100 ml) of phosphate buffer pH 7.4, while agitating in a horizontally shaking water bath (50±1 rev/min) at 37±1°C. Samples were withdrawn at varying time intervals for a duration of 21 days (an estimate of the expected duration of clinical use) and the amount of tobramycin sulphate released was determined spectrophotometrically. Equal volumes of fresh medium were added to replace aliquots removed for assay and the amount of drug release was corrected for dilution. Triplicate measurements were performed for each batch of implants prepared. Formulation factors The influence of the following formulation factors on the release of tobramycin sulphate from PMMA carrier was studied: (1) Drug loading: the drug-to-carrier ratio (tobramycin sulphate: PMMA). Drug:-carrier ratios (dry weight) of 1:33 (clinically used), 1:20, 1:10, and 1:5 were used. (2) Influence of water-soluble formulation additives: PEG 400, PEG 3400 and lactose. (3) Type of commercial PMMA bone cement: the cements studied were Simplex, Zimmer and Palacos. (4) Effect of dissolution volume: 100 ml, 10 ml, 5 ml, and 2 ml. (5) Effect of size: implants in two sizes of 2.9 mm and 6.2 mm diameter were studied. Palacos bone cement was used for studies in (1), (2), (4) and (5) above. A drug-to-carrier ratio of 1:10 was used for studies in (2)–(5). Implants of diameter 6.2 mm were used in studies (l)–(4).
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PHARMACEUTICAL TECHNOLOGY Controlle
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First published in 1991 by ELLIS HO
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CH. 1] INFLUENCE OF DRUG SOLUBILITY
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Pharmaceutical Technology: Controlled Drug Release, Volume 2

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