Document Type

Dissertation

Date of Degree

Fall 2013

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmacy

First Advisor

Dale Eric Wurster

Abstract

Transarterial chemoembolization (TACE) has been practiced in patients for over 30 years and describes the infusion of chemotherapeutic agents followed by embolic particles. This infusion is normally performed by selecting tumor feeding arteries with a catheter under image guidance. The overall goal of TACE is to deliver a high dose of drug directly to a tumor, prevent drug clearance, and induce ischemic necrosis of the tumor. The limitations for current beads system including non-biodegradable and biodegradable beads used for TACE are low drug loading and only water soluble drug can be loaded in beads. The drug loading methods used in current beads system were ion-exchange method and expanding-loading-shrinking method, but these methods didn't allow loading high drug content (up to 10% drug loading) and water insoluble drug. The other limitation for current biodegradable beads used for TACE only had narrow size range beads. In those instances where treatment is not complete or the tumor recurs, physicians would like to be able to access a tumor on multiple occasions in order to administer additional TACE treatments as needed. It may not be possible to re-enter the feeding artery once this artery had been occluded by non-biodegradable beads. For overcoming above limitations, the goal in this study is developing a new biodegradable bead which should have wide size range, achieve high drug loading and high drug loading efficiency, and load water soluble and water insoluble drug.

Extrusion/spheronization technology was chosen for drug loading method. It must be noted that not every polymer can be successfully extruded and spheronized. Oxidized cellulose (OC) was chosen in this study, which is biodegradable polymer. OC was evaluated as new excipient for extrusion/spheronization in this study. Differential scanning calorimetry (DSC) and dynamic vapor sorption analysis were used to compare the interaction and distribution of water within MCC and OC. The amounts of nonfreezing and freezing water in hydrated samples were determined from melting endotherms obtained by DSC. The moisture sorption profiles were analyzed according to the GAB equations. The adsorbed monolayer was not statistically different for MCC and OC after accounting for the amorphous content of the polymers. These results suggest that OC can act as a “molecular sponge,'' and thus aid in the production of beads by extrusion and spheronization. A composite central design was used to evaluate the influence of spheronizer speed, spheronizer time and water level (granulation liquid,) on pellet yield and sphericity. All factors as well as the interactions between water level and spheronizer speed were significant (P<0.05) for sphericity. And water level was significant (P<0.05) for pellet yield.

The water insoluble drug, methotrexate (MTX), was used in this study. The drug content of OC and OC/carbopol beads was up to 40% and drug loading efficiency was 100%. The swelling ratio of the MTX loaded OC/carbopol beads were up to 200%, and the swelling ratio was decreased when drug content was increased. Comparing to commercial embolization produce Contour SE, OC and OC/carbopol beads were significantly more compressible. Recoverability of OC/carbopol beads is close to Contour SE. The beads stability increased with an increase in the MTX content. 100-900 μm beads could be delivered through from 18G to 23G needles. The release method involved the use of a T-Apparatus where the drug experiences an element of diffusion through a static environment. This method was developed to resemble the in -vivo situation in embolization procedures more closely. Release results showed from 57% to 78% MTX was released from OC/carbopol beads in 6 days depending on the drug content.

OC as new pelletization aid can be used to produce beads by using extrusion/spheronization. The new biodegradable OC base beads have wide size range, achieve high drug loading (up to 40%) and high drug loading efficiency, and are able to load water soluble and water insoluble drug. Physical and mechanical properties of MTX loaded OC base beads match the requirement for catheter deliverability. The result of release study showed slow release. The biodegradable OC base beads are suitable for TACE.

Pages

xii, 193 pages

Bibliography

Includes bibliographical references (pages 180-193).

Copyright

Copyright 2013 Jinzhou Zhang

Share

COinS