Michael Philbrook

Drug Delivery and Medical Applications of Chemically Modified Hyaluronan

Publisher Summary Hyaluronan (HA) is a linear naturally occurring polyanionic polysaccharide that is ubiquitous in nature and is produced virtually by every tissue in higher organisms and some bacteria. HA has excellent biocompatibility and is readily catabolized and cleared in vivo. For these reasons, there has been a significant commercial focus on the development of products either from HA or from chemically modified derivatives of HA. HA and HA plus chemically cross-linked HA preparations are the principal components in several viscosupplements for patients with early-stage osteoarthritis of the knee. Conjugation of drugs to HA holds great promise for the generation of a new class of polymer-based therapeutics. These polymer-based systems can serve not only a biomaterials-based function, such as the separation or bulking of tissue, but also as concomitant drug delivery systems for the local delivery of therapeutics. Drugs conjugated to HA could also serve to target the drug to cells or tissues in the body that are rich in HA-binding receptors, such as CD44, RHAMM, TLR2, and TLR4. One of the most promising uses of chemically modified HA is in the area of tissue engineering. HA is found in the extracellular matrix of virtually all tissues so its use as a cell delivery vehicle is obvious. The combination of cell delivery and drug attachment to HA offers a very versatile material for the development of sophisticated products to address complex and unmet medical needs.

Hyaluronan-Tethered Opioid Depots: Synthetic Strategies and Release Kinetics In Vitro and In Vivo

We proposed the use of opioid drug bound covalently to hyaluronan (HA) via ester linkages as a method to prolong drug delivery and to possibly increase the quality of perioperative pain management. The in vitro release profile of morphine conjugated to HA (1.3 million MW) was studied. The influence of parameters such as conjugation site and steric protection of the labile ester bonds was investigated in phosphate buffered saline (PBS) medium. HA--codeine and HA--naloxone conjugates were used as structural controls. Codeine and morphine conjugated via the allylic hydroxyl group had a release half-life of 14.0 days in PBS. Naloxone conjugated via the phenolic hydroxyl group showed a half-life of 0.3 days, and all drugs admixed in HA showed half-lives of 0.1 days. Methyl, ethyl, or n-propyl introduced in vicinal position to the ester bond prolonged release of naloxone with half-lives of 0.5, 4.0, and 4.0 days in PBS, respectively. Incorporation of a methyl group prolonged codeine release with a half-life of 55.0 days in PBS. Drugs were released chemically unaltered from the conjugates as confirmed by LC-MS/MS. Further, morphine was conjugated to divinylsulfone cross-linked HA (Hylan B) particles and the release profiles in rat plasma were studied in vitro and in vivo. Release in rat plasma was faster than in PBS with a half-life of 2.5 days, but the release was similar (ca. 12 days) when a cocktail of protease inhibitors was added to the plasma. Sustained release of morphine was observed in a rat surgical model over 30 h. Morphine was released chemically unaltered from the conjugate and morphine intermediates were not detected in significant amounts as confirmed by LC-MS/MS. These results suggest that the morphine release profile from the HA conjugates depends on the alkyl groups vicinal to the ester and the nature of the leaving group. In rat plasma, hydrolysis seems to be controlled by esterase activity.