Stability and release of antiviral drugs from ethylene vinyl acetate (EVA) copolymer.
The use of polymer based drug delivery systems in dentistry is a relatively new area of research with the exception of the inhibition of secondary caries by the release of fluoride ions from polyalkenoate cements and their predecessors silicate cements. The present study was to test on orally biocompatible material, ethylene vinyl acetate copolymer (EVA), for release of antiviral drugs at oral therapeutic levels over extended periods of time. We also determined their stability during film casting and release. Materials studied include gancyclovir (GCY), acyclovir (ACY), dichloromethane (DCM), and ethylene vinyl acetate (EVA). The square films (3 x 3 x 0.1 cm) were prepared from the dry sheet obtained by solvent evaporation of polymer casting solutions. These solutions were made of EVA and the drug (40:1) in 70 ml of dichloromethane at 38 degrees C. Then drug release characteristics from the drug loaded films were examined at 37 degrees C for a minimum of 14 days in 10 ml medium (ddwater) replaced daily. Kinetics of drug release were followed by spectral measurements using previously determined lambda(max) values (GCY = 250 nm; ACY = 253 nm). A minimum of three samples was tested and reproducible results were obtained. Drug stability (ACY) during film casting and its release was determined using 1H NMR spectrometer (Bruker DRX-500 and 400). Rate of drug release was determined from the part of the curve (rate vs. time) after the onset of the "burst." Although GCY has a larger molecular weight (255) than ACY (225), GCY exhibited about three times higher rate of release than ACY. This difference in rate values may be explained due to its relatively greater solubility in EVA, facilitating faster diffusion of the molecules through the channels present in EVA. This is consistent with the observation that the rate at which drug molecules diffuse through the channels of the polymer, can be increased by decreasing the molecular weight. In the case of ACY, the molecules may be undergoing molecular associations, perhaps dimerization or trimerization in addition to its lower solubility in EVA. The diffusion of ACY tends to be slower under these circumstances compared to GCY resulting in lower rate value than in the case of GCY. Biological studies revealed that ACY exhibited a remarkable decrease in a number of viral organisms present in virus infected cell culture system using real-time polymerase chain reaction (RT-PCR). NMR analysis indicates that the chemical structure of the drug remains stable during film casting process and release.
Kalachandra
S
S
Dental Research Center, University of North Carolina, Chapel Hill, NC 27599-7450, USA. sid_kalachandra@dentistry.unc.edu
Takamata
T
T
Lin
D M
DM
Snyder
E A
EA
Webster-Cyriaque
J
J
D000212:Acyclovir / Q000493:pharmacokinetics*; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001672:Biocompatible Materials / Q000493:pharmacokinetics; D002461:Cell Line, Transformed; D016503:Drug Delivery Systems; D004355:Drug Stability; D006801:Humans; D008752:Methylene Chloride / Q000493:pharmacokinetics; D019906:Nuclear Magnetic Resonance, Biomolecular; D020959:Polyethylene / Q000493:pharmacokinetics*; D011145:Polyvinyls / Q000493:pharmacokinetics*; D014753:Vinyl Compounds / Q000493:pharmacokinetics*
D000998:Antiviral Agents; D001672:Biocompatible Materials; D011145:Polyvinyls; D014753:Vinyl Compounds; C016438:ethylenevinylacetate copolymer; D008752:Methylene Chloride; D020959:Polyethylene; C011566:vinyl acetate; D000212:Acyclovir