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Controlled release of alendronate from polymeric films Long, Karen


Bisphosphonate drugs are used for bone disorders such as osteoporosis, hypercalcaemia of malignancy and Paget's disease. Bisphosphonates have been shown to reduce bone resorption and increase bone mass, but have low oral bioavailability. Localized delivery of bisphosphonates has the potential to improve efficacy and decrease side effects common to oral bisphosphonate therapy. A sensitive high performance liquid chromatography method for the determination of the bisphosphonate, alendronate, was developed and validated. Novel alendronateloaded biodegradable polymeric films were prepared, which could be used as a targeted drug delivery device in areas where predictable bone ingrowth was desired. The drug release profiles of various formulations of alendronate in films composed of poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol or poly(DL-lactic acid)- block-methoxy poly(ethylene glycol) (termed "diblock") were determined. Increasing the proportion of diblock copolymer in the formulation decreased the glass transition temperature of PLGA, as measured by differential scanning calorimetry, and a miscible blend was formed. Controlled release over a 3 week period was observed for films composed of 10% diblock in PLGA. Scanning electron microscopy and X-ray powder diffraction showed that grinding the alendronate prior to film preparation did not adversely affect the crystal structure. In addition, evidence from thermogravimetric analysis and powder diffraction patterns showed that preparation of the films in dichloromethane did not result in the formation of solvates. Alendronate-loaded films were sterilized by glow discharge in preparation for in vitro studies with osteoblast cells. The drug release profiles of films that had and had not been glow discharged were the same and no difference in the mean molecular weight of the diblock was observed by gel permeation chromatography after 7 days at 37°C in phosphate buffered saline. The effect of various concentrations (10⁻⁴ to 10⁻⁸ M) of alendronate on the proliferation of osteoblast cells in vitro was determined. Drug-loaded polymeric films containing 0.25% alendronate increased osteoblast proliferation after 4 days compared to polymer alone. However, films containing 0.5% alendronate appeared to inhibit proliferation. When these experiments were repeated using the MTS assay rather than manual counting, the results showed no significant effect of alendronate on osteoblast proliferation.

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