Evaluation of ion exchange processes in drug-eluting embolization beads by use of an improved flow-through elution method.

n improved method for evaluating drug release behaviour of drug-eluting embolization beads (DEBs) was developed utilizing an open-loop flow-through system, in which the beads were packed into an occlusive mass within the system and extracted with a flowing elution medium over time. Glass beads were introduced into the beads mass in order to ensure laminar flow, reduce dead volume and improve reproducibility by compensating for swelling phenomena. The effects of glass bead ratio, elution medium flow rate and ion concentration, DEB size and drug concentration and drug type (doxorubicin and irinotecan) were evaluated using DEB composed of a sulfonate-modified polyvinyl alcohol hydrogel (DC Bead™) as the test article. The rate and amount of drug elution from the packed beads was affected by flow rate, the bead size and initial loading dose. The raw data from the concentration profile analysis provided valuable information to reveal the drug elution behaviour akin to the pharmacokinetic data observed for embolized beads (yielding in vitro Cmax and tmax data) which was complementary to the normal cumulative data obtained. A good correlation with historical reported in vivo data validated the usefulness of the method for predicting in vivo drug elution behaviour

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

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.

Controlled release of dexamethasone from PLGA microspheres embedded within polyacid-containing PVA hydrogels

The development of zero-order release systems capable of delivering drug(s) over extended periods of time is deemed necessary for a variety of biomedical applications. We hereby describe a simple, yet versatile, delivery platform based on physically cross-linked poly(vinyl alcohol) (PVA) microgels (cross-linked via repetitive freeze/thaw cycling) containing entrapped dexamethasone-loaded poly(lacticco-glycolic acid) (PLGA) microspheres for controlled delivery over a 1-month period. The incorporation of polyacids, such as humic acids, Nafion, and poly(acrylic acid), was found to be crucial for attaining approximately zero-order release kinetics, releasing 60% to 75% of dexamethasone within 1 month. Microspheres alone entrapped in the PVA hydrogel resulted in negligible drug release during the 1-month period of investigation. On the basis of a comprehensive evaluation of the structure-property relationships of these hydrogel/microsphere composites, in conjunction with their in vitro release performance, it was concluded that these polyacids segregate on the PLGA microsphere surfaces and thereby result in localized acidity. These surface-associated polyacids appear to cause acid-assisted hydrolysis to occur from the surface inwards. Such systems show potential for a variety of localized controlled drug delivery applications such as coatings for implantable devices