Date of Award
Doctor of Philosophy (PhD)
James R. Johnson, Ph.D.
James Dalton, Ph.D. Vivian S. Loveless, Ph.D. Bernd Meibohm, Ph.D. George C. Wood, Ph.D.
Poly lactide‑co‑glycolide (PLGA) polymer has been the polymer of choice for many parenteral controlled drug release applications. This is mainly due to the inherent advantages of this polymer i.e. biodegradability, biocompatibility and non-toxic nature. The polymer, however, has a characteristic degradation pattern whereby the final erosion phase does not begin until the polymer reaches a certain molecular weight (MW) limit. After this, the accumulated acidic degradation byproducts initiate a bulk erosion phenomenon that leads to a disruption of the polymer matrix and release of the remaining drug in a short period of time. Furthermore, most of the delivery systems or devices made from PLGA polymer i.e. microspheres or polymeric solutions forming in situ implants are associated with another limitation of an initial drug burst. A major percentage of the drug is released during first few hours thereby leaving a relatively smaller portion of the total drug load to be released slowly over the remaining duration. By and large it results in a characteristic "tri-phasic release pattern" from the PLGA matrices consisting of a first burst release phase, a second plateau phase and a final burst release phase.
Plasticizer molecules are well known for their ability to create a flexible polymer matrix thereby allowing a continuous drug release. Polymer solutions made with certain highly hydrophilic plasticizers however, are not completely devoid of the initial burst release of drug due to a lag time between injection of the polymer solution and complete precipitation of the polymer. Other most common drawbacks of the PLGA polymeric solution based delivery systems is their high viscosity and therefore painful injections and poor injectability, and a variable surface area of implant resulting in a highly variable drug release.
The objective of present work was therefore to make an in situ polymer gelling system formulated as polymer micro particle suspension for low viscosity and better injectability. The system comprised of a hydrophobic polymer plasticizer(s) that resulted in a more diffusion controlled drug release. Necessary physical stability of the suspension based formulation was derived from a glycerol lipid (polymer immiscible component) and polycaprolactone (PCL) crystallites/spherulites. The system was structurally characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and polarized microscopy studies. Drug release mechanism was studied by conducting plasticizer release studies and mathematical modeling.
Results indicated transformation of drug release from an erosion based process to a complete diffusion controlled phenomenon by the use of a hydrophobic polymer plasticizer(s). Glycero‑lipid provided extra physical stability to the PLGA micro particle suspension. The PCL crystallites not only provided the essential stability characteristics to the delivery system i.e. structural stability of the micro particle suspension and a thixotropic and shear thinning behavior for the ease of injectability but further controlled the initial drug release. Biocompatibility studies indicated that the in situ PLGA micro particulate implant formulation containing PCL crystallites is safe and biocompatible with only a normal tissue response.
Bedi, Sonia , "A Novel Shear Thinning and Thixotropic Plga Micro Particulate Suspension System for Controlled Drug Delivery" (2011). Theses and Dissertations (ETD). Paper 23. http://dx.doi.org/10.21007/etd.cghs.2011.0024.