Title

Development of in vitro release testing methods for modified release parenterals and correlation with in vivo performance

Date of Completion

January 2009

Keywords

Health Sciences, Pharmacy

Degree

Ph.D.

Abstract

The foreign body response compromises the sensitivity, functionality and lifetime of implantable biosensors. To control the foreign body response, poly(vinyl alcohol) hydrogel composites containing dexamethasone microspheres were investigated. In addition, the feasibility of liposomes for sustained delivery of dexamethasone was investigated. ^ The temporal aspects of dexamethasone delivery to control the foreign body response were investigated using sequential pharmacodynamic studies. Fast releasing (5 kDa microspheres) composites controlled the acute inflammatory phase for one week, however, a delayed foreign body response developed after dexamethasone was exhausted. Similarly, medium releasing composites (25 kDa microspheres) protected against the foreign body response for one month. Again the foreign body response developed after dexamethasone exhaustion. This indicated that controlling the foreign body response for short-term was inadequate and sustained delivery of dexamethasone was required for the implant lifetime. A combination of 25 kDa and 75 kDa microspheres in the same composite controlled the foreign body response for a three month period. Therefore, this strategy of combining different microspheres in the same composite can be used to provide sustained delivery for a desired time period. ^ Sonication and extrusion processing of non-extruded DMPC, DPPC and DSPC liposomes significantly decreased particle size and drug encapsulation as well as changed the phase transition behavior. Dexamethasone release from the extruded liposomes was complete within 48 h. Non-extruded liposomes showed a slower release which was dependent upon the lipid transition temperature. Due to the structural similarity between cholesterol and dexamethasone, the incorporation of cholesterol decreased dexamethasone encapsulation and increased the release rates from the liposomes. ^ To address the lack of a standard in vitro release testing method for dispersed system dosage forms, a novel dialysis adapter was developed for the USP apparatus 4. The USP4 method could discriminate among solution, suspension and liposome formulations of dexamethasone. Comparison with currently used dialysis and reverse dialysis sac methods showed that only the USP4 method could discriminate among liposomes formulation variants. This novel USP4 based method might be suitable to be developed as a compendial method for dispersed system dosage forms. ^