Text

theses

Pain is a physiological protective system that helps prevent damage from a harmful stimulus or detect the presence of a disease or injury. When a patient cannot tolerate the pain experienced, analgesic drugs are used to achieve pain relief. These drugs are needed for long-term, however, their analgesic effects typically have short duration and serious side effects. To address these issues, polymers that contain analgesic drugs chemically incorporated within the polymer backbone or as pendant groups were designed, synthesized, characterized, and formulated. Non-steroidal anti-inflammatory drugs (NSAIDs) [i.e., salicylic acid (SA), ibuprofen, and naproxen] and opioids (i.e., morphine and nalbuphine) were polymerized to develop drug delivery systems with potential to extend analgesic effect, reduce side effects, and prevent accidental drug withdrawal or overdose. Extended (i.e., weeks and months) NSAID release could be beneficial for treatment of chronic inflammatory diseases that cause pain and controlled release of opioids could improve chronic pain treatment. Salicylate-based poly(anhydride-ester) (PAE) microspheres were designed as injectable delivery systems for long-term SA release. Three polymers with chemical compositions comprised of either linear or branched aliphatic linkers were used. In addition, the formulation was optimized to improve the overall microsphere morphology. The presence of a lag time characterizes the slow-degrading salicylate-based PAEs and is unfavorable for constant long-term drug release applications. The use of copolymers and polymer blends was explored to modify the physicochemical properties and drug release profiles and thus achieve long-term SA release. The salicylate-based PAEs have great potential in various biomedical applications. However, the polymer should meet the pharmacopeial and commercial requirement of sterility. Therefore, the effect of electron beam and gamma radiation on the physicochemical properties of the salicylate-based PAEs was studied. Morphine was chemically incorporated into a PAE backbone. The polymer termed “PolyMorphine” was designed, synthesized, and fully characterized. The hydrolytic degradation pathway of the polymer was determined by in vitro studies. In vitro studies demonstrated that PolyMorphine is non-cytotoxic towards fibroblasts. In vivo studies using mice showed that PolyMorphine provides analgesia for 3 days, 20 times the analgesic window of free morphine. Novel biodegradable polyester comprised of all biocompatible elements: tartaric acid, 1,8-octanediol, and ibuprofen or naproxen as pendant groups, were synthesized and characterized. The polymers release the free drug (ibuprofen or naproxen) in vitro in a controlled manner without burst release. These new biomaterials are not cytotoxic towards mouse fibroblasts and human blood-derived macrophages, and the drugs retain their bioactivity after being released from the polymer.

ETD_4396

Ph.D.

Includes bibliographical references

Includes vita

by Roselin Rosario-Meléndez

http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000067825

doi:10.7282/T30Z7207

ETD doctoral

The author owns the copyright to this work.