Investigation of a time-controlled release drug delivery system: Particulate-filled polymer effect on drug release

One of the goals of chronotherapeutically delivering the decongestant drug, pseudoephedrine sulfate (PE), is to precisely time the maximum effect during the early morning hours when congestion symptoms are at a peak. Several mutiparticulate technologies were evaluated for their ability to deliver the drug in this fashion. The technology exhibiting the most desirable release characteristics was a multilaminated PE loaded sugar sphere. The layers consisted of low substituted hydroxypropyl cellulose (L-HPC) and talc-filled ethylcellulose external barrier. The system is called Time-Controlled Explosion System and is designed to rupture over time.; In order to gain a better understanding of the rupture mechanism and to select fillers that could optimize the PE release, the failure properties of particulate-filled ethylcellulose cast films were evaluated using a tensile test. The solids studied were titanium dioxide (TiO{dollar}sb2{dollar}), talc, magnesium stearate, milled candelilla wax and FD&C yellow no. 6. The break strength, break strain and energy-to-break showed that all of the filled ethylcellulose films were weaker and more brittle than the unfilled ethylcellulose and therefore more fracturable. The higher fracturability was attributed to the aggregation of the filler particles in the cast films. The tensile test parameters also showed that TiO{dollar}sb2{dollar} and talc filled films were the most and least easily fractured filled films, respectively.; A Box-Behnken designed experiment coupled with response surface analysis was performed to: determine the correlatability of the tensile test data for talc and TiO{dollar}sb2{dollar}-filled films with PE dissolution profile, determine the main and interaction effect of L-HPC, filler and coat thickness on the release parameters (lag time, release rate and extent PE dissolved). The response surface analysis was facilitated by fitting the sigmoidal release profile to a log normal cumulative distribution function. A simultaneous optimization technique was used to determine how reducing the L-HPC level would affect the PE release parameters. It was concluded that the L-HPC must be at a critical level in order for rupture to occur in the external barrier. The critical level depends on the filler, filler level and coat level. There is significant interaction effect between L-HPC and filler, filler level and coat level on the dissolution parameters. The lag time and release rate of the PE dissolution curve can increase or decrease depending on the combination of the interacting factors. A inverse relationship exists between the cast ethylcellulose unfilled and filled film break stress and break strain obtained from the tensile test and the drug release rate in the TES.