Research paperPreparation and in vitro characterization of amifostine biodegradable microcapsules
Introduction
Amifostine, also known in the literature as ethiofos, ethyol (MedImmune, Gaithersburg, MD, USA), or WR-2721, is an organic thiophosphate, which has been extensively studied as a cytoprotective agent [1], [2], [3]. It has been studied as a protector of normal tissue against the damaging effects of ionizing radiation and/or chemotherapy and was approved by the United States Food and Drug Administration in 1997. Amifostine's current indicated use in clinical practice is limited to that of reduction in the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian or non small cell lung cancer [4], [5]. Amifostine, however, continues to be evaluated as a cytoprotector in a variety of other clinical settings involving radiotherapy and/or chemotherapy [6], [7]. Even if amifostine were shown to be successful in these trials, its clinical use is likely to remain severely limited due to the following facts: (1) amifostine in its presently available formulation must be administered intravenously in order to be effective [8]; (2) serious adverse effects of amifostine such as hypotension, nausea, and vomiting are significantly augmented upon intravenous route of administration [9], [10]; (3) amifostine does not cross the blood–brain-barrier even when administered systemically; and (4) amifostine in its present formulation is not effective when administered orally [11], [12]. Most, if not all, of the above-mentioned barriers to amifostine use can, however, be overcome by utilizing alternative formulation strategies, which are based upon modern techniques in drug delivery including microencapsulation using biodegradable polymers [12]. The most widely investigated biodegradable polymers are aliphatic polyesters based on lactic acid and glycolic acid. The copolymers of these two acids have attracted much attention because the biodegradation rate of the copolymer is easily controlled by altering their ratios [13], [14], [15]. These polymers have been used with numerous drugs and have been shown to be biocompatible [16].
The long-term objective of this project is to develop orally active amifostine microcapsules. In our previous report [17], we demonstrated that amifostine microcapsules prepared by the solvent evaporation technique using high molecular weight PLGA (RG506) released the drug in 3 days. However, these microcapsules had very low efficiency of encapsulation. Now we report on increasing the efficiency of encapsulation of amifostine by modifying the method of preparation.
Section snippets
Materials
The copolymer poly(dl-lactic/glycolic acid), PLGA 50:50 (RG 502; inherent viscosity 0.2 dl/g) was obtained from Boehringer Ingelheim (Germany). The surfactant l-α phosphatidylcholine was obtained from Avanti Polar-lipids Inc. (Birmingham, AL, USA). Amifostine, polyvinyl alcohol (PVA), gelatin (Type A), chloroform, and dichloromethane were obtained from Sigma Chemical Co. (St. Louis, MO, USA).
Experimental design
Three samples were prepared where the PLGA amount was fixed at 500 mg while the amount of amifostine
Results and discussion
Six different formulations (A–F) were prepared, following a partial factorial design, to study the combined effects of the amount of PLGA and amifostine on the microcapsules characteristics. In an effort to improve the efficiency of encapsulation of amifostine, three additional formulations (G–I) were also prepared by incorporating 2, 7, or 14 mg gelatin within the amifostine aqueous phase. All microcapsules were evaluated for total drug content, i.e. efficiency of encapsulation, particle size
Acknowledgements
The authors wish to thank Dr. Nikhil Sarkar and Ms. Raisa Moiseyev from the LSU School of Dentistry for the SEM analysis. This work was funded in part by the NIH/NIGMS grants #GM08008 and GM08008-32S1.
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