Poly(ethylene-co-vinyl acetate) copolymer matrix for delivery of chlorhexidine and acyclovir drugs for use in the oral environment: effect of drug combination, copolymer composition and coating on the drug release rate.

Objectives: This study utilizes a bio-compatible ethylene vinyl acetate (EVA) copolymer to deliver drugs at therapeutic levels over extended periods of time. The release rate of an anti-fungal and an anti-microbial drug namely acyclovir (ACY) and chlorhexidine diacetate (CDA) from EVA was investigated individually and as a mixture. The effect of drug combination, the composition of the copolymer and the coating of the matrix with a different polymer on the rate of drug release are presented.

Method: Polymer casting solutions were prepared by homogeneously dissolving EVA copolymer and the drugs in the ratio (40:1) in dichloromethane. The drugs ACY and CDA were used individually as well as in three different weight ratios maintaining the total drug concentration in the polymer at 2.5%. Different concentrations of vinyl acetate (VA) 28, 32 and 40% in the EVA matrix were used to study the release of either ACY or CDA alone while 40% VA was used for the release study of the individual drug as well as their mixtures. Thin square films of 3cmx3cm with a thickness of 0.7mm were cut from the dry sheet obtained by solvent evaporation. Coated films were prepared by dipping ACY and CDA drug-loaded EVA films (VA 40%) into EVA copolymer of VA 32% and then dried. All of the drug-loaded samples were extracted at 37 degrees C in 10ml distilled water that was replaced daily. The rate of individual drug release was measured by UV-spectrophotometer while the mixtures of drugs were measured by high performance liquid chromatography (HPLC).

Results: The release rate of ACY is higher than that of CDA both individually and in the ACY/CDA 50/50 mixture. In the other mixtures, the release of the drug is proportional to its concentration in the mixture. Total release of ACY is higher than CDA in most compositions. The effect of increasing the vinyl acetate content of the EVA matrix increased the drug release rate (p=0.02) while coating of films resulted in a decrease of the release rate of the drugs.

Significance: Measurements of the in vitro rate of drug release showed that there was a sustained release of drug at an almost constant concentration over extended period of time, thus providing a basis for oral treatment modality. We show that it is possible to alter the rate of drug release in the EVA matrix to a desired value by: (1) changing the composition of the EVA copolymer, (2) altering the mixtures of drugs and (3) coating the matrix with additional polymer. The use of mixtures of drugs that can enhance or decrease the rate of drug release may prove more effective in treating persistent oral infections in immunocompromised patients.